Xyrem – not addictive

1: J Toxicol Clin Toxicol. 2003;41(2):131-5.

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Comment in:

·         J Toxicol Clin Toxicol. 2004;42(1):121-3; author reply 125-7.

The abrupt cessation of therapeutically administered sodium oxybate (GHB) does not cause withdrawal symptoms.

Sodium oxybate (gamma-hydroxybutyrate; GHB) has demonstrated efficacy for the treatment of narcolepsy. However, there are reports of withdrawal following chronic abuse of illicit GHB which involve escalating both doses and dosing frequency. The present trial afforded an opportunity to test the hypothesis that chronic daily therapeutic dosing of sodium oxybate in narcoleptics does not cause withdrawal following abrupt cessation. Fifty-five narcoleptic patients, taking sodium oxybate (dose range 3-9 gm/night) for 7-44 months (mean 21 months), were randomized into a 2-week double-blind period: 29 patients received placebo and 26 continued to receive sodium oxybate. During this 2-week trial period, the following symptoms were reported in patients receiving placebo (N): anxiety (2), dizziness (1), insomnia (1) and somnolence (1). While these symptoms may represent possible symptoms of mild GHB withdrawal, they are also highly consistent with the returning symptoms of narcolepsy. We conclude there is minimal evidence of withdrawal symptoms following abrupt cessation of chronic sodium oxybate dosing in the therapeutic range.


 

2: Sleep Med. 2004 Mar;5(2):119-23.

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Sodium oxybate demonstrates long-term efficacy for the treatment of cataplexy in patients with narcolepsy.

U.S. Xyrem Multicenter Study Group.

BACKGROUND AND PURPOSE: This study was conducted to demonstrate the long-term efficacy of sodium oxybate for the long-term treatment of cataplexy in patients with narcolepsy. PATIENTS AND METHODS: Fifty-five (55) narcoleptic patients with cataplexy who had received continuous treatment with sodium oxybate for 7-44 months (mean 21 months) were enrolled in a double-blind treatment withdrawal paradigm. A 2-week single-blind sodium oxybate treatment phase established a baseline for the weekly occurrence of cataplexy. This was followed by a 2-week double-blind phase in which patients were randomized to receive unchanged drug therapy or placebo. Patients recorded the incidence of cataplexy attacks and adverse events in daily diaries. RESULTS: During the 2-week double-blind phase, the abrupt cessation of sodium oxybate therapy in the placebo patients resulted in a significant increase in the number of cataplexy attacks (median=21; P<0.001 ) compared to patients who remained on sodium oxybate (median=0). Cataplexy attacks returned gradually with placebo patients reporting a median of 4.2 and 11.7 cataplexy attacks during the first and second weeks, respectively. There were no symptoms of frank withdrawal. CONCLUSIONS: This controlled trial provides evidence supporting the long-term efficacy of sodium oxybate for the treatment of cataplexy. In contrast with antidepressant drug therapy, there is no evidence of rebound cataplexy upon abrupt discontinuation of treatment.

 


 


 

3: Alcohol Alcohol. 2002 Jan-Feb;37(1):67-73.

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Double-blind controlled trial of gamma-hydroxybutyrate and clomethiazole in the treatment of alcohol withdrawal.

Nimmerrichter AA, Walter H, Gutierrez-Lobos KE, Lesch OM.

Anton-Proksch-Institute Vienna, Dominikanerbastei 21/49, A-1010 Vienna, Austria.

The aim of this double-blind, comparative study was to assess the efficacy and safety of gamma-hydroxybutyrate (GHB) in ameliorating the symptoms of alcohol withdrawal. Newly admitted alcohol-dependent patients (n = 98) were randomized to receive either clomethiazole 1000 mg daily (CLO group) (n = 33), or 50 mg GHB/kg body wt (n = 33) or 100 mg GHB/kg body wt (n = 32). This dose was administered for 5 days, halved on day 6, and on days 7 and 8 only placebo was given. As CLO is available as capsules and GHB as syrup, a double-dummy method was used to try to ensure blindness. The groups were matched in terms of baseline demographic and alcohol-related variables. There was no difference between the three treatments in ratings of alcohol withdrawal symptoms nor requests for additional medication. After tapering off the active medication, there was no increase in withdrawal symptoms, indicating that physical tolerance did not develop to either GHB or CLO within the 5-day treatment period. The most frequently reported side-effect of GHB was transient vertigo, particularly after the evening double dose.

 


 



 

 

8: Lancet. 1989 Sep 30;2(8666):787-9.

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Gamma-hydroxybutyric acid for treatment of alcohol withdrawal syndrome.

Gallimberti L, Canton G, Gentile N, Ferri M, Cibin M, Ferrara SD, Fadda F, Gessa GL.

Centro di Alcologia e Farmacodipendenza, General Hospital of Dolo, Venice, Italy.

The effect of gamma-hydroxybutyric acid (GHB) on ethanol withdrawal syndrome in alcoholics was investigated in a randomised double-blind study. Patients with withdrawal symptoms were treated either with GHB (orally in a syrup preparation) (11 patients) or with the syrup alone (12). GHB treatment (50 mg/kg) led to a prompt reduction in withdrawal symptoms, such as tremors, sweating, nausea, depression, anxiety, and restlessness. The only side-effect was dizziness. GHB may be useful in the management of alcohol withdrawal syndrome in man.

Publication Types:

·         Clinical Trial

·         Randomized Controlled Trial

PMID: 2571021 [PubMed – indexed for MEDLINE]


 

9: Neuropsychopharmacology. 1993 Aug;9(1):77-81.

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Gamma-hydroxybutyric acid for treatment of opiate withdrawal syndrome.

Gallimberti L, Cibin M, Pagnin P, Sabbion R, Pani PP, Pirastu R, Ferrara SD, Gessa GL.

Addiction Treatment Service, Padova, Italy.

In a double-blind placebo-controlled trial, gamma-hydroxybutyric acid (GHB) (25 mg/kg orally) suppressed most of the withdrawal symptomatology in 14 heroin addicts and 13 methadone-maintained subjects. The GHB effect was prompt (within 15 minutes) and persisted for between 2 and 3 hours. Subsequently, the same patients received GHB in an open study every 2 to 4 hours for the first 2 days and 4 to 6 hours for the following 6 days: most abstinence signs and symptoms remained suppressed and patients reported felling well. Urine analysis failed to detect any presence of opiate metabolites. No withdrawal symptomatology recurred after 8 days of treatment when GHB was suspended, and patients were challenged with an intravenous injection of 0.4 mg naloxone. The results indicate that GHB may be useful in the management of opiate withdrawal.

Publication Types:

·         Clinical Trial

·         Randomized Controlled Trial

PMID: 8397726 [PubMed – indexed for MEDLINE]


 


 

11: Drug Saf. 2004;27(5):293-306.

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The Xyrem risk management program.

Fuller DE, Hornfeldt CS, Kelloway JS, Stahl PJ, Anderson TF.

Orphan Medical Inc., Minnetonka, Minnesota 55305, USA.

Sodium oxybate, also known as gamma-hydroxybutyric acid (GHB), was discovered in 1960 and has been described both as a therapeutic agent with high medical value and, more recently, a substance of abuse. The naturally occurring form of this drug is found in various body tissues but has been studied most extensively in the CNS where its possible function as a neurotransmitter continues to be studied. Sodium oxybate has been approved in different countries for such varied uses as general anaesthesia, the treatment of alcohol withdrawal and addiction, and, most recently, cataplexy associated with narcolepsy. During the 1980s, easy access to GHB-containing products led to various unapproved uses, including weight loss, bodybuilding and the treatment of sleeplessness, sometimes with serious long-term effects. The availability of these unapproved and unregulated forms of the drug led to GHB and its analogues being popularised as substances of abuse and subsequent notoriety as agents used in drug-facilitated sexual assault, or ‘date rape’, eventually leading to the prohibition of GHB sales in the US. Legal efforts to control the sale and distribution of GHB and its analogues nearly prevented the clinical development of sodium oxybate for narcolepsy in the US. However, following extensive discussions with a variety of interested parties, a satisfactory solution was devised, including legislative action and the development of the Xyrem Risk Management Program. Amendments to the US Controlled Substances Act made GHB a schedule I drug, but also contained provisions that allow US FDA-approved products to be placed under schedule III. This unique, bifurcated schedule for sodium oxybate/GHB allowed the clinical development of sodium oxybate to proceed and, in July 2002, it was approved by the FDA as an orphan drug for the treatment of cataplexy in patients with narcolepsy as Xyrem(sodium oxybate) oral solution. To promote the safe use of sodium oxybate, as well as alleviate concerns over possible diversion and abuse following product approval, a proprietary restricted drug distribution system was created, called the Xyrem Success Program. Components of the programme include a centralised distribution and dispensing system, a physician and patient registry, compulsory educational materials for patients and physicians, a specially trained pharmacy staff, a method for tracking prescription shipments, and an initial post-marketing surveillance programme. The system has created a unique opportunity to provide both physician and patient education and ongoing patient counselling, promoting greater drug safety and enhanced patient compliance.

 


 

12: Ann Emerg Med. 2001 Feb;37(2):147-53.

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Comment in:

·         Ann Emerg Med. 2001 Nov;38(5):605-7.

·         Ann Emerg Med. 2001 Sep;38(3):345-6.

Click here to read
Gamma-hydroxybutyrate withdrawal syndrome.

Dyer JE, Roth B, Hyma BA.

California Poison Control System, San Francisco Division, San Francisco General Hospital, CA 94110, USA. jodyer@itsa.ucsf.edu

STUDY OBJECTIVE: Gamma-hydroxybutyrate (GHB) withdrawal syndrome is increasingly encountered in emergency departments among patients presenting for health care after discontinuing frequent GHB use. This report describes the characteristics, course, and symptoms of this syndrome. METHODS: A retrospective review of poison center records identified 7 consecutive cases in which patients reporting excessive GHB use were admitted for symptoms consistent with a sedative withdrawal syndrome. One additional case identified by a medical examiner was brought to our attention. These medical records were reviewed extracting demographic information, reason for presentation and use, concurrent drug use, toxicology screenings, and the onset and duration of clinical signs and symptoms. RESULTS: Eight patients had a prolonged withdrawal course after discontinuing chronic use of GHB. All patients in this series were psychotic and severely agitated, requiring physical restraint and sedation. Cardiovascular effects included mild tachycardia and hypertension. Neurologic effects of prolonged delirium with auditory and visual hallucinations became episodic as the syndrome waned. Diaphoresis, nausea, and vomiting occurred less frequently. The onset of withdrawal symptoms in these patients was rapid (1 to 6 hours after the last dose) and symptoms were prolonged (5 to 15 days). One death occurred on hospital day 13 as withdrawal symptoms were resolving. CONCLUSION: In our patients, severe GHB dependence followed frequent ingestion every 1 to 3 hours around-the-clock. The withdrawal syndrome was accompanied initially by symptoms of anxiety, insomnia, and tremor that developed soon after GHB discontinuation. These initial symptoms may progress to severe delirium with autonomic instability.

 


 

13: Sleep. 1998 Aug 1;21(5):507-14.

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Pharmacokinetics of gammahydroxybutyrate (GHB) in narcoleptic patients.

Scharf MB, Lai AA, Branigan B, Stover R, Berkowitz DB.

Center For Research In Sleep Disorders, Cincinnati, Ohio, USA.

Sodium gammahydroxybutyrate (GHB) is an endogenous compound that has been under investigation in the management of narcolepsy for about two decades. The data confirm that GHB treatment decreases daytime sleepiness and episodes of cataplexy, sleep paralysis, and hypnagogic hallucinations. The current study evaluated the pharmacokinetics of GHB, given twice in one night to six narcoleptic patients who had been chronically taking GHB nightly on a similar basis. Results confirmed earlier reports and showed nonlinear pharmacokinetics. Maximum concentrations were reached in 40 +/- 6.2 and 35.7 +/- 7 minutes after the first and second dose respectively. Mean AUCinf was 17731.6 +/- 4867 mg/mL/m. Mean GHB T1/2 was 53 +/- 19 minutes. GHB elimination appears to be capacity-limited in some patients when administered at a fixed dose of 3 g twice nightly at a 4-hour interval.
 


 

14: Anaesthesist. 1999 Feb;48(2):89-96.

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[Gamma-hydroxybutyrate for treatment of alcohol withdrawal syndrome in intensive care patients. A comparison between with two symptom-oriented therapeutic concepts]

[Article in German]

Lenzenhuber E, Muller C, Rommelspacher H, Spies C.

Klinik fur Anaesthesiologie und operative Intensivmedizin, Universitatsklinikum Benjamin Franklin, Freie Universitat Berlin.

Seeing as gamma-hydroxybutyrate (GHB) and benzodiazepines interact with the GABA-transmitter system, we investigated whether GHB can replace the conventional therapy, which uses benzodiazepines in the treatment of alcohol withdrawal syndrome in ICU settings. METHODS: 42 chronic alcoholics were included in this prospective and randomized study. Following the development of alcohol withdrawal syndrome, the patients were randomly allocated to the GHB or to the flunitrazepam group. In addition to this, clonidine was administered in order to treat autonomic signs of withdrawal. In cases were hallucinations occurred, haloperidol was administered. RESULTS: There was no significant difference in the efficacy of treatment used in the duration of mechanical ventilation and intensive care unit stay between groups. The patients in the GHB-group required significantly higher dosages of haloperidol and significantly lower dosages of clonidine. 14 out of 21 patients from the GHB-group developed hypernatriaemia and 15 out of 21 developed a metabolic alkalosis. CONCLUSIONS: Symptoms of the autonomic nervous system were more effectively prevented by GHB as evident in the lower dosage requirement of clonidine. However, GHB may not sufficiently block the hyperactivity of the dopaminergic system or may have an hallucinogenic effect itself. This may be evident from the higher dosages of haloperidol which were necessary. Due to the latter fact, the administration of GHB cannot be recommended in all patients suffering from AWS in ICU settings.

 


 

16: Am J Addict. 2001 Summer;10(3):232-41.

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Gamma-hydroxybutyric acid: patterns of use, effects and withdrawal.

Miotto K, Darakjian J, Basch J, Murray S, Zogg J, Rawson R.

UCLA Dept. of Psychiatry and Biobehavioral Sciences, 760 Westwood Plaza, Los Angeles, CA 90024, USA. kmiotto@mednet.ucla.edu

Gamma-hydroxybutyric acid (GHB) is gaining popularity as a drug of abuse. Reports of toxicity and lethality associated with GHB use have increased. This survey study was designed to identify patterns of GHB use, its effects, and withdrawal syndrome. A survey inquiring about the effects of GHB was administered to 42 users. The results showed that GHB was used to increased feelings of euphoria, relaxation, and sexuality. Adverse effects occurred more frequently in daily users and polydrug users than in occasional GHB users. Loss of consciousness was reported by 66%, overdose by 28%, and amnesia by 13% of participants during GHB use and by 45% after GHB use. Three daily users developed a withdrawal syndrome that presented with anxiety, agitation, tremor, and delirium. Participants described GHB intoxication as having similarities to sedative-hypnotic or alcohol intoxication. Regular use has been shown to produce tolerance and dependence. Participants dependent on GHB reported using multiple daily doses around the clock. High frequency users appeared at the greatest risk for developing withdrawal delirium and psychosis after abrupt discontinuation of GHB use.

 


 

17: Eur Arch Psychiatry Clin Neurosci. 1994;244(3):113-4.

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Clinical efficacy of gamma-hydroxybutyric acid in treatment of opiate withdrawal.

Gallimberti L, Schifano F, Forza G, Miconi L, Ferrara SD.

Addiction Treatment Unit, Padua, Italy.

This paper describes the role of gamma-hydroxybutyric acid (GHB) in the treatment of opiate withdrawal syndrome. In the two patients described, after having abruptly withdrawn from long-term methadone treatment, GHB was orally administered (each dose given every 4-6 h) for 8-9 days. The GHB showed both a high efficacy (some mild and transient symptoms attributable to opiate withdrawal were observed, but only in the first days of therapy) and a good tolerability (no clinical phenomena interpreted as GHB side effects were found). These results could be of interest in improving the pharmacological treatment of drug addiction.


 

19: Pharmacotherapy. 2003 Sep;23(9):1205-9.

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From club drug to orphan drug: sodium oxybate (Xyrem) for the treatment of cataplexy.

Fuller DE, Hornfeldt CS.

Orphan Medical, Inc., Minnetonka, Minnesota 55305, USA.

Narcolepsy, a rare disease with a prevalence of 0.05% in the general population, affects an estimated 140,000 patients in the United States. Patients have been able to lead fuller personal and professional lives since the Food and Drug Administration approved sodium oxybate (Xyrem) in 2002 for treatment of cataplexy in patients with narcolepsy. Previously, gamma-hydroxybutyrate (GHB), the active ingredient of sodium oxybate, had been a substance of abuse, most notoriously as a date-rape drug. Public Law 106-172, the date-rape prohibition act enacted in 2000, was modified to allow the drug to be legally administered for medical purposes. Because of the apprehension regarding the risk of possible drug diversion after the approval of sodium oxybate and concerns about safety, the Xyrem Risk Management Program was created. This program has been successful in satisfying the needs of patients and physicians while ensuring responsible distribution of the drug.
 


 


 

22: Tidsskr Nor Laegeforen. 1998 Nov 20;118(28):4390-3.

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[Gamma-hydroxybutyrate–an endogenous substance and an intoxicant]

[Article in Norwegian]

Hovda KE, Liberg JP, Nordby G, Jacobsen D.

Klinikk for akuttmedisin, Ulleval sykehus, Oslo.

Gamma-hydroxybutyrate (GHB), a compound found in the mammalian brain, meets many criteria of a neurotransmitter. Experimentally, GHB has been used as a model for petit mal epilepsy; clinically it has been used as a general anaesthetic, to treat certain sleep disorders and alcoholism. Lately GHB has been abused for its euphoric, sedative and anabolic effects. Coma and seizures following abuse of GHB have been reported, but dependency has received little attention. Adverse effects of GHB include seizure activity and a withdrawal syndrome characterised by insomnia, anxiety and tremor. The present paper reviews the neuropharmacology, potential therapeutic uses and acute adverse effects of GHB, together with a presentation of three cases.
 


 

24: Psychiatry Res. 1983 May;9(1):1-8.

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Gamma-hydroxybutyrate in the treatment of schizophrenia.

Levy MI, Davis BM, Mohs RC, Trigos GC, Mathe AA, Davis KL.

Gamma-Hydroxybutyrate (GHB) inhibits firing of dopaminergic neurons and is thus potentially useful in the treatment of schizophrenia. GHB was administered to 10 schizophrenics concurrently with low-dose fluphenazine in a 6-week double-blind crossover study. No antipsychotic efficacy of GHB was noted. GHB had little if any effect on plasma prolactin levels after a single administration and caused few side effects. Trials with higher doses of GHB may be warranted.

 


 

25: Alcohol Alcohol. 1996 Jul;31(4):341-5.

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An open multicentric study evaluating 4-hydroxybutyric acid sodium salt in the medium-term treatment of 179 alcohol dependent subjects. GHB Study Group.

Addolorato G, Castelli E, Stefanini GF, Casella G, Caputo F, Marsigli L, Bernardi M, Gasbarrini G.

Internal Medicine II Chair, Catholic University Sacro Cuore, Rome, Italy.

We report the results of an “open’ multicentre study evaluating the use, tolerability and therapeutic efficacy of the sodium salt of 4-hydroxybutyric acid (GHB) for the medium-term treatment of withdrawal symptoms in 179 patients with alcohol dependence followed up as outpatients. The follow-up of patients was 6 and 12 months after drug discontinuation. Following a daily oral administration of 50 mg/kg for approximately 6 months, no serious systemic or single-organ consequences leading to drug discontinuation were reported, and tolerability was fair in all patients. Eleven subjects (10.1%) showed craving for the drug and voluntarily increased their doses (6-7 times the recommended levels). GHB led to complete abstinence during drug administration in 78.0% of the patients. A significant reduction of compulsive desire (“craving’) was observed in parallel, as deduced from evaluation of a specific questionnaire, the Alcohol Craving Scale. At follow-up examination, 43 of the treated subjects remained abstinent at 6 months, and 30 subjects were abstinent for 1 year after drug discontinuation.

 


 

27: South Med J. 2002 Aug;95(8):926-8.

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Self-medication with gamma-hydroxybutyrate to reduce alcohol intake.

Glisson JK, Norton J.

Department of Neurology and Psychiatry, University of Mississippi Medical Center, Jackson, USA.

We describe a 52-year-old man who self-medicated with gamma-hydroxybutyrate (GHB), a widely available illicit substance, to obtain a decrease in ethanol consumption. He successfully reduced his ethanol intake over a 3-month period, but he was unable to sustain abstinence. Although case reports on the use of GHB to induce euphoria have been published, this is the first report of GHB self-medication to facilitate ethanol abstinence. This report highlights the importance of considering GHB self-medication not only for euphoric and mood altering effects, but also as a potential treatment for ethanol intake reduction.

=


 

28: Clin Neuropharmacol. 1989 Feb;12(1):29-36.

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Nocturnal gamma-hydroxybutyrate. Effect on periodic leg movements and sleep organization of narcoleptic patients.

Bedard MA, Montplaisir J, Godbout R, Lapierre O.

Centre d’etude du sommeil, Hopital du Sacre-Coeur, Montreal, Quebec, Canada.

Periodic leg movements during sleep (PMS) is a disorder frequently encountered in narcolepsy. In the present study, 12 narcoleptic patients (six with PMS and six without) were recorded in a sleep laboratory for 2 consecutive nights before and after treatment with gamma-hydroxybutyrate (GHB) taken at bedtime for 1 month. Treatment resulted in decreased rapid eye movement (REM) sleep latency and increased REM efficiency without change in the total duration of REM sleep. GHB was associated with the appearance of pathological levels of PMS in patients who were unaffected before treatment. These results are discussed in relation to the role of dopamine in the physiopathology of narcolepsy and PMS.

 


 

29: J Rheumatol. 2003 May;30(5):1070-4.

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The effects of sodium oxybate on clinical symptoms and sleep patterns in patients with fibromyalgia.

Scharf MB, Baumann M, Berkowitz DV.

Tri-State Sleep Disorders Center, Cincinnati, Ohio 45246, USA.

OBJECTIVE: Fibromyalgia (FM) is associated with the sleep phenomenon of alpha intrusion, and with low growth hormone secretion. Sodium oxybate has been shown to increase both slow-wave sleep and growth hormone levels. This double blind, randomized, placebo controlled crossover trial was conducted to evaluate the effects of sodium oxybate on the subjective symptoms of pain, fatigue, and sleep quality and the objective polysomnographic (PSG) sleep variables of alpha intrusion, slow-wave (stage 3/4) sleep, and sleep efficiency in patients with FM. METHODS: Patients received either 6.0 g/day sodium oxybate or placebo for 1 month, with an intervening 2 week washout period. Efficacy measures included PSG evaluations, tender point index (TPI), and subjective measurements from daily diary entries. Safety measures included clinical laboratory values, vital signs, and adverse events. RESULTS: Twenty-four female patients were included in the study; 18 completed the trial. TPI was decreased from baseline by 8.5, compared with an increase of 0.4 for placebo (p = 0.0079). Six of the 7 pain/fatigue scores (overall pain, pain at rest, pain during movement, end of day fatigue, overall fatigue, and morning fatigue) were relieved by 29% to 33% with sodium oxybate, compared with 6% to 10% relief with placebo (p < 0.005). Alpha intrusion, sleep latency, and rapid-eye-movement sleep were significantly decreased, while slow-wave (stage 3/4) sleep was significantly increased, compared with placebo (p < 0.005). Two of the 5 subjective sleep related variables were significantly different from placebo: morning alertness (improved by 18% with sodium oxybate, compared with 2% for placebo; p = 0.0033) and quality of sleep (improved by 33% and 10%, respectively; p = 0.0003). CONCLUSION: Sodium oxybate effectively reduced the symptoms of pain and fatigue in patients with FM, and dramatically reduced the sleep abnormalities (alpha intrusion and decreased slow-wave sleep) associated with the nonrestorative sleep characteristic of this disorder.

 

 


 

32: Sleep. 2004 Nov 1;27(7):1327-34.

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A pilot study on the effects of sodium oxybate on sleep architecture and daytime alertness in narcolepsy.

Mamelak M, Black J, Montplaisir J, Ristanovic R.

Department of Psychiatry, University of Toronto, Toronto, Canada. m.mamelak@utoronto.ca

STUDY OBJECTIVES: To measure the effect of nocturnal sodium oxybate administration on sleep architecture in patients with narcolepsy. DESIGN: Open-label study. SETTING: Four accredited sleep clinics. PARTICIPANTS: 25 adult patients with narcolepsy-cataplexy. INTERVENTIONS: Patients were weaned from previously used anticataplectic medications and administered increasing nightly doses of sodium oxybate over a 10-week period: 4.5 g for 4 weeks, 6 g for 2 weeks, 7.5 g for 2 weeks, and 9 g for 2 weeks. The effect of sodium oxybate was measured using nocturnal polysomnograms, the Epworth Sleepiness Scale, the Maintenance of Wakefulness Test, and a narcolepsy symptoms questionnaire. RESULTS: The nightly administration of sodium oxybate produced dose-related increases in slow-wave sleep and delta power, rapid eye movement sleep increased initially and then decreased in a dose-related manner, nocturnal awakenings decreased, and daytime sleep latency increased. Significant improvements in daytime symptoms were measured by the Maintenance of Wakefulness Test, the Epworth Sleepiness Scale, and the narcolepsy symptom questionnaire. CONCLUSIONS: Nocturnal administration of sodium oxybate in patients with narcolepsy produces significant improvements in sleep architecture, which coincide with significant improvements in daytime functioning.

PMID: 15586785 [PubMed – in process]


 

33: Alcohol Alcohol. 1989;24(5):447-51.

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Suppression by gamma-hydroxybutyric acid of ethanol withdrawal syndrome in rats.

Fadda F, Colombo G, Mosca E, Gessa GL.

Institute of Physiology, University of Cagliari, Italy.

The ability of gamma-hydroxybutyric acid to suppress ethanol withdrawal syndrome was tested in male rats rendered physically dependent on ethanol by several intragastric administrations of ethanol (9-15 g/kg daily for 7 days). Gamma-hydroxybutyrate (0.25, 0.50 and 1.00 g/kg i.p.), administered 8 hr after the last ethanol dose, produced a dose-dependent inhibition of withdrawal signs such as tremors and audiogenically-induced seizures; the highest dose tested suppressed all ethanol withdrawal symptoms.

PMID: 2818752 [PubMed – indexed for MEDLINE]


 

34: Curr Opin Investig Drugs. 2002 Feb;3(2):278-83.

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Gamma-Hydroxybutyrate (orphan medical).

Tunnicliff G, Raess BU.

Indiana University School of Medicine, Evansville 47712, USA. gtunnic@iupui.edu

Orphan Medical is developing gamma-hydroxybutyrate (Xyrem) for the potential treatment of narcolepsy [183352]. In October 2000, an NDA was filed with the FDA [384422], [405504] and Xyrem received an FDA approvable letter in July 2001. Orphan Medical stated that it believed it could meet the requirements in the letter, including a trial in respiratory-compromised patients, by the end of 2001 [414461]. The FDA also requested follow-up safety data from patients in previous Xyrem trials. At that time, the drug was not expected to be launched until mid-2002 [415301], [416305]. In October 1999, the US House of Representatives passed the HR 2130 bill, allowing the medical use of gamma-hydroxybutyrate, which is classified as a Schedule I controlled substance in the US [343562]; the Senate approved this legislation in November 1999 [348206]. In February 2000, a congressional bill supporting the continued development of medically formulated gamma-hydroxybutyrate was passed, making medically formulated gamma-hydroxybutyrate products Schedule III substances [354108], [356597]. GHB occurs naturally in many human tissues. It has previously been used in the treatment of narcolepsy and is not patentable for that indication.

Publication Types:

·         Review

·         Review, Tutorial

PMID: 12020060 [PubMed – indexed for MEDLINE]


 

35: Br J Psychiatry. 2001 Feb;178:183.

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Comment on:

·         Br J Psychiatry. 2000 Aug;177:181.

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Diazepam in the treatment of GHB dependence.

Addolorato G, Caputo F, Capristo E, Gasbarrini G.

Publication Types:

·         Comment

·         Letter

PMID: 11157447 [PubMed – indexed for MEDLINE]


 

36: Arch Gen Psychiatry. 1980 Jan;37(1):101-5.

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Withdrawal reaction from long-term, low-dosage administration of diazepam. A double-blind, placebo-controlled case study.

Winokur A, Rickels K, Greenblatt DJ, Snyder PJ, Schatz NJ.

Symptoms of diazepam withdrawal developed in a young man who had been taking diazepam in dosages of 15 to 25 mg/day during a six-year period. This was verified in a study conducted under placebo-controlled, double blind conditions, with plasma levels of diazepam and its major metabolite, desmethyldiazepam, monitored throughout the course of the study. Severe symptoms of physiological withdrawal were observed within two days of replacement of diazepam with placebo capsules. The patient recovered promptly on reinstitution of diazepam administration, and relapsed during a second withdrawal phase. During an additional two week-period of placebo administration, the patient’s condition first worsened, then gradually improved. Examination of plasma levels of diazepam and desmethyldiazepam indicated no obvious pharmacokinetic abnormalities. Thus, with long-term administration of diszepam, even in therapeutically accepted doses, withdrawal reactions can be encountered on abrupt termination.

Publication Types:

·         Clinical Trial

·         Controlled Clinical Trial

PMID: 6986133 [PubMed – indexed for MEDLINE]


 

37: J Emerg Med. 2001 May;20(4):418-20.

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Comment on:

·         J Emerg Med. 2000 Jan;18(1):65-70.

Click here to read
Lack of efficacy of benzodiazepines in treating gamma-hydroxybutyrate withdrawal.

Mullins ME, Fitzmaurice SC.

Publication Types:

·         Case Reports

·         Comment

·         Letter

PMID: 11396429 [PubMed – indexed for MEDLINE]


 

38: Toxicol Rev. 2004;23(1):45-9.

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The gamma-hydroxybutyrate withdrawal syndrome.

Tarabar AF, Nelson LS.

New York City Poison Control Center, New York, New York, USA. asim.tarabar@yale.edu

gamma-Hydroxybutyrate (GHB) is endogenous inhibitory transmitter that, when administered in pharmacological doses, has sedative-hypnotic properties. It is used in anaesthesia for the treatment of narcolepsy/catalepsy and in alcohol/opioid detoxification treatment regimens. Based on its purported anabolic effects, GHB use became established among bodybuilders. As the euphorigenic effects of GHB became publicised, attendees at dance clubs and rave parties began to use it alone or in combination with other psychoactive drugs. Following the ban of GHB in 1990, several precursor products (e.g. gamma-butyrolactone, butanediol) became widely used as replacement drugs until their ultimate proscription from lawful use in 2000. GHB and its precursors, like most sedative-hypnotic agents, can induce tolerance and produce dependence. Although many GHB users will experience a mild withdrawal syndrome upon drug discontinuation, those with chronic heavy GHB use can experience severe withdrawal. This syndrome clinically resembles the withdrawal syndrome noted from alcohol and other sedative-hypnotic drugs (e.g. benzodiazepines). Distinct clinical features of GHB withdrawal are its relatively mild and brief autonomic instability with prolonged psychotic symptoms. Patients with fulminant GHB withdrawal require aggressive treatment with cross-tolerant sedative hypnotics, such as benzodiazepines.

Publication Types:

·         Review

PMID: 15298492 [PubMed – in process]


 

39: J Pharm Pharm Sci. 2001 May-Aug;4(2):167-75.

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GHB: an important pharmacologic and clinical update.

Okun MS, Boothby LA, Bartfield RB, Doering PL.

Emory University, Department of Neurology, Atlanta, Georgia, USA and University of Florida, Department of Neurology, The Brain Institute, Gainesville, Florida, USA. msokun@dnamail.com

Gamma-hydroxybutyrate (GHB) intoxication is a significant cause of morbidity and mortality in patients taking the drug for recreational purposes. Due to the recent increase in emergency room visits, hospital admissions, and deaths, it has become necessary to re-examine the pharmacology, pharmacokinetics, pharmacodynamics, clinical manifestations, and potential adverse effects associated with GHB use. We present an important pharmacologic and clinical update on GHB.

Publication Types:

·         Review

·         Review, Tutorial

PMID: 11466174 [PubMed – indexed for MEDLINE]


 

40: Neurosci Biobehav Rev. 1994 Summer;18(2):291-304.

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Gamma-hydroxybutyrate: an overview of the pros and cons for it being a neurotransmitter and/or a useful therapeutic agent.

Cash CD.

Centre de Neurochimie, Strasbourg, France.

Gamma-hydroxybutyrate (GHB) is a catabolite in brain of gamma-aminobutyrate (GABA) and is also found in nonneuronal tissues. It is present in the brain at about one thousandth of the concentration of its parent compound. High affinity and specific uptake, and energy dependent transport systems for GHB have been described in brain in addition to a class of high affinity binding sites, functional at a rather unphysiologically low pH. Administration of large doses of GHB to animals and man leads to sedation, and at the highest doses, anaesthesia. These effects are prominent when GHB brain levels are over one hundred-fold the endogenous levels. In some animals, GHB administration also induces an electroencephalographic and behavioural changes resembling that of human petit mal epilepsy. GHB has been used in man as an anaesthetic adjuvant. GHB lowers cerebral energy requirements and may play a neuroprotective role. Administered GHB profoundly effects the cerebral dopaminergic system by a mechanism which remains to be unravelled. GHB has been tested with success on alcoholic patients where it attenuates the withdrawal syndrome. It is indicated here that in this situation, it may owe its effect by acting as a pro-drug of the neurotransmitter GABA into which it can be transformed. As administration of GHB, a GABAB receptor agonist and a natural opioid peptide all elicit similar abnormal EEG phenomena, it may be suggested that they are acting via a common pathway. The petit mal epileptic effects of GHB might be ascribed to its direct, or indirect agonist properties after transformation to a pool of GABA at the GABAB receptor or via interactions at its own binding sites linked to a similar series of biochemical events. Some anticonvulsant drugs, the opiate antagonist naloxone and a synthetic structural GHB analogue antagonise certain behavioural effects of GHB administration. It is postulated that GHB exerts some of its effects via transformation to GABA pools, and that substances which inhibit this process antagonise its effects by blocking GABA formation. GHB has been proposed as a neurotransmitter, although straightforward evidence for this role is lacking. Evidence for and against GHB, as a neurotransmitter, is reviewed here together with a discussion of its potential as a therapeutically useful drug.

Publication Types:

·         Review

PMID: 7914688 [PubMed – indexed for MEDLINE]


 

41: FDA Consum. 2002 Sep-Oct;36(5):7.

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Xyrem approved for muscle problems in narcolepsy.

[No authors listed]

Publication Types:

·         News

PMID: 12412541 [PubMed – indexed for MEDLINE]


 

42: Pharmacopsychiatria. 1981 Jul;14(4):129-34.

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Gamma-hydroxybutyrate treatment of schizophrenia: a pilot study.

Schulz SC, van Kammen DP, Buchsbaum MS, Roth RH, Alexander P, Bunney WE Jr.

Gamma-hydroxybutyrate (GHB) was administered to seven chronic schizophrenic patients in the first double-blind, placebo-replacement trial of this compound. No significant drug effect in this group was obtained. Two patients became nonpsychotic during the drug trial, three got worse and two patients did not respond. The two patients who responded with improvement were augmenters, as measured by average evoked potential (EP), had low platelet MAO activity and high cerebrospinal fluid (CSF) homovanillic acid (HVA). A number of patients developed akathisia and dystonia during the trial, especially after receiving probenecid for lumbar puncture. Further study is warranted, possibly in a selected patient group.

PMID: 7280012 [PubMed – indexed for MEDLINE]


 

43: Br J Psychiatry. 2000 Aug;177:181.

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Comment in:

·         Br J Psychiatry. 2001 Feb;178:183.

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In-patient detoxification after GHB dependence.

Price G.

Publication Types:

·         Case Reports

·         Letter

PMID: 11026962 [PubMed – indexed for MEDLINE]


 

44: Sleep. 1981;4(1):105-11.

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Treatment of narcolepsy and sleep apnea with gammahydroxybutyrate: a clinical and polysomnographic case study.

Mamelak M, Webster P.

Gammahydroxybutyrate was administered to a patient who experienced narcolepsy associated with central sleep apnea. The treatment relieved the major symptoms of narcolepsy, and significantly decreased the number of apneic periods. Gammahydroxybutyrate did not cause the prolonged and potentially fatal apneic periods associated with the use of other hypnotic agents.

Publication Types:

·         Case Reports

PMID: 7232968 [PubMed – indexed for MEDLINE]


 

45: Am J Psychiatry. 2000 Oct;157(10):1706.

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gamma-Hydroxybutyrate withdrawal and chloral hydrate.

Hutto B, Fairchild A, Bright R.

Publication Types:

·         Case Reports

·         Letter

PMID: 11007738 [PubMed – indexed for MEDLINE]


 

46: Ann Emerg Med. 2001 Nov;38(5):605-7.

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Comment on:

·         Ann Emerg Med. 2001 Feb;37(2):147-53.

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Management of gamma-hydroxybutyrate withdrawal.

Sharma AN, Lombardi MH, Illuzzi FA, Nelson LS.

Publication Types:

·         Comment

·         Letter

PMID: 11679881 [PubMed – indexed for MEDLINE]

48: J Forensic Sci. 2001 May;46(3):728-30.

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Blood, brain, and hair GHB concentrations following fatal ingestion.

Kalasinsky KS, Dixon MM, Schmunk GA, Kish SJ.

Office of the Armed Forces Medical Examiner, Armed Forces Institute of Pathology, Rockville, MD 20850, USA. kalasink@afip.osd.mil

Despite the increasing incidence of illicit use of gamma-hydroxybutyrate (GHB), little information is available documenting levels of the drug in GHB fatalities. We measured GHB levels in postmortem blood, brain and hair specimens from a suspected overdose case by gas chromatography/mass spectrometry (GC/MS) following solid phase extraction (SPE) and derivatization with bis(trimethyl-silyl) trifluoroacetamide (BSTFA). Examination found 330 microg/mL GHB in femoral blood and 221 ng/mg GHB in frontal cortex brain tissue, values higher than those typically reported in the literature. The hair shaft was negative for GHB whereas the plucked root bulbs with outer root sheath attached (2,221 ng/mg) and root bulbs after washing and removal of the outer root sheath (47 ng/mg) contained the drug. Our results are consistent with an acute single dose of GHB and, as the toxicology screen was negative for other drugs of abuse, emphasize the significant danger of this drug.

Publication Types:

·         Case Reports

PMID: 11373018 [PubMed – indexed for MEDLINE]


 

49: Ann Emerg Med. 2001 May;37(5):551-2.

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A case of severe withdrawal from gamma-hydroxybutyrate.

Chin RL.

Publication Types:

·         Case Reports

·         Letter

PMID: 11326198 [PubMed – indexed for MEDLINE]


 

50: J Anal Toxicol. 2004 Jan-Feb;28(1):20-6.

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Further evidence for the presence of GHB in postmortem biological fluid: implications for the interpretation of findings.

Elliott SP.

Regional Laboratory for Toxicology, City Hospital N.H.S. Trust, Dudley Road, Birmingham B18 7QH, United Kingdom. simontox@yahoo.co.uk

Analysis and interpretation of the findings for the drug of abuse gamma hydroxybutyric acid (GHB) in fatalities has become very problematic. This is primarily because of variable data in postmortem biological fluids resulting from the endogenous nature of the compound, possible postmortem production, and varying methods of detection. Preliminary studies support the use of plasma standards in determining urinary GHB concentrations and indicate measurement of GHB in postmortem biological fluids may be dependent on the method of analysis. In order to assist interpretation of postmortem data based on gas chromatography-mass spectrometry (GC-MS) analysis using GHB-d6 internal standard, the results of GHB concentrations measured routinely in postmortem blood and urine specimens in 40 fatalities received during a three-month period are shown. In all cases, GHB was not implicated in the cause of death; there was no apparent correlation between manner of death and resultant GHB concentrations. Mean concentrations of GHB determined in postmortem blood were found to be 12.3 mg/L (range = 2-29 mg/L, n = 38) and 12.6 mg/L (range = 4-25 mg/L, n = 17) (unpreserved and sodium fluoride-preserved samples, respectively) and 5.5 mg/L in unpreserved urine (range 0-18 mg/L, n = 39) and 4.8 mg/L in sodium fluoride-preserved (range 0-10 mg/L, n = 15) urine samples. Vitreous humor was available in two of the cases analyzed (GHB = 1 and 3 mg/L). The data support the potential use of sodium fluoride-preserved samples for interpretation of GHB concentrations, particularly if there has been an extended postmortem interval. In addition, interpretative cut-offs can be proposed for both postmortem blood and urine, based on the specific GC-MS method used. At blood concentrations less than 30 mg/L and at urine concentrations less than 20 mg/L, it is possible that any GHB detected could represent only endogenous GHB production.

PMID: 14987420 [PubMed – indexed for MEDLINE]


 

51: West J Med. 1992 Apr;156(4):380-4.

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Acute poisoning from gamma-hydroxybutyrate in California.

Chin MY, Kreutzer RA, Dyer JE.

California Department of Health Services, Environmental Epidemiology and Toxicology Branch, Emeryville 94608.

We report a series of 5 representative patients in California who experienced adverse reactions from the illicitly marketed substance gamma-hydroxybutyrate (GHB). The drug is a putative neurotransmitter marketed as a growth hormone releaser for bodybuilders. The most commonly reported symptoms included abrupt drowsiness, dizziness, and a “high”. Other effects were headache, nausea, vomiting, myoclonic jerking, and short-term coma. There have been no reported deaths. If product use is discontinued, full recovery with no long-term side effects is universal. No clear dose-response effect was observed; this may be attributable to differences in susceptibility, wide variations in doses taken by the same person, or the coingestion of other substances. Case interviews confirm that, despite being banned by the US Food and Drug Administration, GHB is still widely available in the underground drug market. Athletes and bodybuilders may take drugs for which there are claims of improved performance or body image. Physicians should be alert for signs of GHB poisoning in emergency department and clinic patients.

Publication Types:

·         Case Reports

PMID: 1574880 [PubMed – indexed for MEDLINE]


 

52: Am J Addict. 2004 Mar-Apr;13(2):120-7.

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Use of GHB compounds by HIV-positive individuals.

Camacho A, Matthews SC, Dimsdale JE.

Department of Psychiatry, School of Medicine, University of California-San Diego, 8677 Villa La Jolla Drive, #1106, La Jolla, CA 92037, USA. acamacho@ucsd.edu

Gamma hydroxybutyrate (GHB) has been used by body-builders to enhance performance and by young adults in rave parties. Warnings have been posted about its addictive potential. The use of these dietary compounds is currently banned by the Food and Drug Administration, but they are widely available through the Internet and in certain communities. The purpose of the study was to examine the use of these compounds by HIV-positive individuals and to investigate their knowledge of the addictive potential of GHB and its related dietary compounds. One hundred HIV-positive individuals from the UCSD outpatient HIV clinic responded to an anonymous survey that inquired about their knowledge, use, and effects produced by GHB containing dietary compounds. The most common reported dietary compound beside GHB was Growth Hormone Release Extract (GHRE). Fifty-two percent of individuals reported using at least one GHB containing dietary compound. Gay subjects reported the highest use of GHB compounds (76.9%; p < or = 0.001). The most common effect reported by users was increased energy (71%). Only 24% of the total responders knew about GHB’s addictive potential. Among reported users of GHB containing compounds, fourteen (27%) knew about its addictive potential and nine (17%) knew that the compound is illegal. This study shows that HIV-positive gay individuals attending our clinic are using GHB compounds. Reported GHB users have limited knowledge about its addictive potential and serious adverse effects. More controlled studies are needed to evaluate long-term effects of dietary compounds containing GHB, especially among HIV-positive individuals who are actively receiving antiretroviral treatment.

PMID: 15204663 [PubMed – indexed for MEDLINE]


 

53: Int J Exp Pathol. 1993 Jun;74(3):275-81.

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Cardioprotective action of sodium gamma-hydroxybutyrate against isoproterenol induced myocardial damage.

Kolin A, Brezina A, Mamelak M, Pandula E.

Department of Pathology, Sunnybrook Health Science Centre, University of Toronto, Canada.

In this study, the effects of graded doses of isoproterenol (IP) on the heart were examined in untreated gerbils and in gerbils anaesthetized with gamma-hydroxybutyrate (GHB), an endogenous metabolite with energy sparing properties. We were interested in the cardioprotective potential of GHB. IP was administered intraperitoneally in doses of 0.1, 0.3. 2.5 and 10.0 mg/kg to different groups of gerbils. Half the gerbils in each treatment group received 500 mg/kg of GHB 30 min before IP, and 250 mg/kg at three subsequent 2-hour intervals. The remaining gerbils in each treatment group received saline at these time points. The animals were sacrificed after 8 hours. The accumulation of neutral fat droplets in the sarcoplasm was the most consistent effect of IP. The highest dose also produced some scattered myofibre death. The accumulation of fat in the cells could be estimated semi-quantitatively using a histochemical reaction for succinic dehydrogenase, and the volume of fat could be measured more accurately by electron microscopic morphometry. These measurements showed that IP produced a three to five-fold increase in sarcoplasmic fat volume. GHB either abolished or significantly reduced the accumulation of fat and it also completely prevented the myofibre death caused by the highest doses of IP. This cardioprotective effect of GHB was independent of its hypothermic action. Based on this experience, ultrastructural morphometry of sarcoplasmic fat appears to be a promising method for evaluating cardioprotective measures.

PMID: 8334077 [PubMed – indexed for MEDLINE]


 

54: Pol J Pharmacol. 2004 Jan-Feb;56(1):43-9.

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Gamma-hydrobutyric acid (GHB) and its chemical modifications: a review of the GHBergic system.

Waszkielewicz A, Bojarski J.

Department of Organic Chemistry, Jagiellonian University Medical College, Medyczna 9, PL 30-688 Krakow, Poland. AM.Waszkielewicz@interia.pl

Gamma-hydroxybutyric acid (GHB) is a naturally occurring substance with function of an inhibitory neurotransmitter in the central nervous system in mammals. GHB can be used as a medicine in narcolepsy (Xyrem) and for general anesthesia (sodium oxybate). It is also a popular drug of abuse, causing coma, addiction and severe withdrawal syndrome, and, therefore, demanding thorough studies on the GHBergic system and expanded research on toxicology of this compound. The aim of this review is to present the proved and some suggested mechanisms of its action from pharmacological point of view, which may help to properly treat intoxication or other pathological states caused by GHB ingestion. Some new GHB derivatives studied for analogous action and their present use are also described.

Publication Types:

·         Review

·         Review, Tutorial

PMID: 15047976 [PubMed – in process]


 

55: Acad Emerg Med. 2003 Jan;10(1):95-6; author reply 96.

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Comment on:

·         Acad Emerg Med. 2002 Jul;9(7):730-9.

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Unsupported “Efficacy” claims of gamma hydroxybutyrate (GHB).

Zvosec DL, Smith SW.

Publication Types:

·         Comment

·         Letter

PMID: 12511324 [PubMed – indexed for MEDLINE]


 

56: Hum Psychopharmacol. 2004 Jan;19(1):57-61.

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Effect of glucose on tobacco withdrawal symptoms in recent quitters using bupropion or nicotine replacement.

McRobbie H, Hajek P.

Tobacco Dependence Research and Treatment Centre, Institute of Community Health Sciences, Barts and The London, Queen Mary’s School of Medicine and Dentistry, University of London, Turner Street, London E1 2AD, UK. h.j.mcrobbie@qmul.ac.uk

RATIONALE AND OBJECTIVES: Glucose has been shown to alleviate the desire to smoke in abstaining heavy smokers and to increase 1-month abstinence rates on its own as well as when combined with nicotine patches. It is not known whether a single dose of glucose can provide additional withdrawal relief in patients who have already abstained for a period of time, and whether it can assist patients using bupropion. METHODS: Seventy-five volunteers from a smoking cessation clinic who maintained 1 week of validated continuous abstinence were randomized to receive four 3 mg dextrose or placebo (sorbitol) tablets. There were 31 bupropion and 44 NRT users. Measures of desire to smoke and of five withdrawal symptoms were taken before taking the tablets, and then at 5 min intervals for 20 min. RESULTS: Despite low baseline ratings of withdrawal discomfort, glucose tablets significantly reduced irritability and hunger in bupropion users. Two other effects including reduction in composite withdrawal score approached but did not reach statistical significance. The effects emerged 10-15 min after taking the tablets. No glucose effect was detected in patients using NRT. CONCLUSIONS: A single dose of glucose taken after a week of sustained abstinence may reduce withdrawal discomfort in patients on bupropion. Further research is warranted in combining glucose and bupropion, and in opportunistic use of glucose tablets in tempting situations during a smoking cessation attempt. Copyright 2004 John Wiley & Sons, Ltd.

Publication Types:

·         Clinical Trial

·         Randomized Controlled Trial

PMID: 14716714 [PubMed – indexed for MEDLINE]


 

57: Ann Emerg Med. 2001 Dec;38(6):660-5.

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Pentobarbital for severe gamma-butyrolactone withdrawal.

Sivilotti ML, Burns MJ, Aaron CK, Greenberg MJ.

Department of Emergency Medicine, University of Massachusetts Medical School, Worcester, MA, USA. sivilotm@meds.queensu.ca

STUDY OBJECTIVE: Gamma-hydroxybutyrate (GHB) and gamma-butyrolactone (GBL) have become popular drugs of abuse. Acute overdose with either agent results in a well-recognized syndrome of central nervous system and respiratory depression. Recently, a withdrawal syndrome has been described for GHB. We report a severe form of GBL withdrawal, characterized by delirium, psychosis, autonomic instability, and resistance to benzodiazepine therapy. METHODS: We performed a chart review of consecutive admissions for GBL withdrawal in a regional toxicology treatment center. RESULTS: During a 6-month period, 5 patients presented with severe withdrawal attributed to abrupt GBL discontinuation. Patients manifested tachycardia, hypertension, paranoid delusions, hallucinations, and rapid fluctuations in sensorium. Test results for ethanol and routine drugs of abuse were negative. Initial treatment with high doses of lorazepam proved ineffective. Pentobarbital was then administered, resulting in excellent control of behavioral, autonomic, and psychiatric symptoms and in rapid reduction or avoidance of benzodiazepines. Median hospital stay was 5 days. No patient had respiratory depression or required mechanical ventilation. Patients were discharged on tapering doses of benzodiazepines or pentobarbital and were free of psychotic symptoms at follow-up. CONCLUSION: GBL discontinuation can result in severe withdrawal, necessitating ICU admission. Pentobarbital may be more effective than benzodiazepines at controlling delirium in patients with abnormal vital signs, paranoid delusions, and hallucinations as a result of GBL withdrawal.

Publication Types:

·         Case Reports

PMID: 11719746 [PubMed – indexed for MEDLINE]


 

58: Anaesth Intensive Care. 1976 Nov;4(4):351-4.

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Reversal of the anaesthetic action of sodium gamma-hydroxybutyrate.

Henderson RS, Holmes CM.

Physostigmine was administered intravenously to 25 patients, anaesthetised with sodium gamma-hydroxybutyrate (GHB), and their emergence from anesthesia was studied. Physostigmine (2 mg) brought about rapid, safe, reliable and sustained awakening after a “latent period” varying from 2-10 minutes (mean 6-2 minutes+/-S.D. 2-2) in 24 patients. In the one patient not awake at 10 minutes, a second dose of physostigmine produced awakening in an additional 8 minutes. No serious side effects were attributable to the physostigmine. This finding may warrant a reconsideration of the place of GHB in anaesthetic practice.

PMID: 984396 [PubMed – indexed for MEDLINE]


 

59: J Pharm Pharmacol. 2003 May;55(5):609-15.

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Tolerance to the hypnotic and electroencephalographic effect of gamma-hydroxybutyrate in the rat: pharmacokinetic and pharmacodynamic aspects.

Van Sassenbroeck DK, De Paepe P, Belpaire FM, Boon PA, Buylaert WA.

Heymans Institute of Pharmacology, Faculty of Medicine and Health Sciences, Ghent University, De Pintelaan 185, B-9000 Ghent, Belgium. diederik.vansassenbroeck@rug.ac.be

Tolerance to gamma-hydroxybutyrate (GHB) has been suggested in illicit users and has been described for the hypnotic effect in the rat. The aim of this study was to investigate whether tolerance is also observed for the EEG effect, and whether the EEG can give insight into the pharmacodynamic aspects of GHB tolerance. In three series of experiments, rats were pre-treated with either the GHB precursor gamma-butyrolactone (GBL) or saline intraperitoneally twice daily. In the first series, a reduction in sleeping time was observed in the GBL pre-treated rats compared with controls. In the second series, a fast infusion of GHB (300 mg kg(-1) over 5 min) was given after 10 days pre-treatment. The GHB plasma concentration-time curves showed a slightly faster decrease in GHB concentration in the GBL pre-treated rats, suggesting a small induction of the GHB metabolism (V(max) = 2882 +/- 457 microg min(-1) kg(-1) vs 2205 +/- 315 microg min(-1) kg(-1), P < 0.01). In contrast to controls, GBL pre-treated rats did not lose righting reflex. In the third series, a slow infusion of 480 mg kg(-1) h(-1) was given after 7 days pre-treatment, which allowed fitting a sigmoid E(max) model to the EEG amplitude versus GHB plasma concentration curve. This showed reduced end-organ sensitivity to GHB in the GBL pre-treated rats (EC50 (concentration required to obtain 50% depression of the baseline effect) = 653+/- 183 microg mL(-1) vs 323 +/- 68 microg mL(-1), P < 0.001). In conclusion, chronic pre-treatment with gamma-butyrolactone in the rat results in a reduced sleeping time and this tolerance is reflected by the EEG. This can mainly be explained by reduced end-organ sensitivity.

PMID: 12831503 [PubMed – indexed for MEDLINE]


 

60: Ann Neurol. 1981 Feb;9(2):198.

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gamma-Hydroxybutyrate in narcolepsy.

Price PA, Schachter M, Smith SJ, Baxter RC, Parkes JD.

Publication Types:

·         Letter

PMID: 7235637 [PubMed – indexed for MEDLINE]


 

61: Neurol Res. 2003 Oct;25(7):759-63.

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Different actions of gamma-hydroxybutyrate: a critical outlook.

Greiner C, Rohl JE, Ali-Gorji, Wassmann H, Speckmann EJ.

Klinik und Poliklinik fur Neurochirurgie, Universitatsklinikum Munster, Albert-Schweitzer-Str. 33, 48149 Munster, Germany. greiner@uni-muenster.de

Gamma-hydroxybutyrate acid (GHB) is a naturally occurring analog of GABA in the mammalian brain and can be therapeutically used for basic sedation in intensive care units. Although its application is discussed controversially, GHB is suspected to protect neuronal tissue against ischemic damage. GHB was tested for an acute effect on electrophysiologic parameters of guinea pig hippocampal tissues exposed to ischemic conditions. With application of 0.5 mM GHB, an acute protective effect was observed. The aim of the present paper is to discuss our experimental results as well as pathophysiological mechanisms of GHB and its clinical applicability.

Publication Types:

·         Review

·         Review, Tutorial

PMID: 14579796 [PubMed – indexed for MEDLINE]


 

62: Am J Drug Alcohol Abuse. 1997 Nov;23(4):637-42.

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GHB: a home brew.

Sanguineti VR, Angelo A, Frank MR.

Department of Psychiatry and Human Behavior, Thomas Jefferson Medical College, Philadelphia, Pennsylvania, USA.

Gamma-hydroxybutyric acid is an allegedly benign illicit substance that is gaining increasing recognition and attention among substance abusers and athletes. Alongside foreign-made brands, the compound is also easily available, at low cost because of the facility with which it can be produced in one’s kitchen. Named by some “Nature’s Quaalude” or sold as a health product, it is often used with a false sense of security as it may cause serious and disabling complications, as illustrated by this clinical vignette.

Publication Types:

·         Case Reports

PMID: 9366979 [PubMed – indexed for MEDLINE]


 

63: Int J Neurol. 1991-1992;25-26:29-40.

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The neurobiology of narcolepsy-cataplexy syndrome.

Aldrich MS.

Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA.

The pathophysiology of narcolepsy is closely related to the abnormalities of REM sleep that are the electrophysiologic signature of the syndrome. Evidence from studies of canine narcolepsy and postmortem human narcoleptic brain tissue provide strong evidence that cholinergic and monoaminergic systems involved in REM sleep regulation are abnormal in narcolepsy but the primary neurochemical abnormality has not yet been determined. There is now conclusive evidence that a genetic basis is required for all or almost all cases of narcolepsy. In the vast majority of narcoleptics, a gene closely linked to the HLA-DR/DQ region appears to confer narcoleptic susceptibility, but the penetrance of the gene is low and additional environmental and perhaps genetic factors are required to express the disease. In a minority of narcoleptics, there may be a second autosomal dominant gene not linked to HLA-DR2 that facilitates the occurrence of narcolepsy. This gene may be related to the mu-immunoglobulin heavy-chain switch-like segment that has been implicated in canine narcolepsy. There appear to be at least two narcoleptic phenotypes associated with the narcoleptic susceptibility gene or genes: narcolepsy-cataplexy syndrome and monosymptomatic narcolepsy, or narcolepsy with REM sleep abnormalities but without cataplexy. Idiopathic hypersomnia without cataplexy or REM sleep abnormalities may represent a third phenotype, although most cases of idiopathic hypersomnia are probably unrelated to the HLA-D linked gene. The link between the genetic basis of narcolepsy and its neurochemical abnormalities is still entirely unknown. Although the hypothesis that a transient immune-mediated reaction leads to a permanent alteration of monoaminergic function is appealling, there is no direct evidence to support this hypothesis. Several important questions concerning the neurobiology of narcolepsy remain to be answered. What is the specific gene in the HLA-D region that is linked to human narcolepsy and what are the products or functions of the gene that predispose to narcolepsy? Does the human mu-switch region contain genetic material homologous to the 85-kb band linked to canarc-1 that predisposes to narcolepsy? What are the environmental factors required for expression of the disease in susceptible individuals and do they incite immunologic processes? Which of the neurochemical abnormalities are primary, which are secondary or compensatory, and how do they relate to the predisposing genetic and environmental elements? Additional familial, genetic, and neurochemical studies over the next decade should lead to more complete understanding of the neurobiology of narcolepsy and ultimately to better treatments for this chronic disabling disease.

Publication Types:

·         Review

·         Review, Tutorial

PMID: 11980061 [PubMed – indexed for MEDLINE]


 

64: J Emerg Med. 2001 Jul;21(1):31-3.

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A case of withdrawal from the GHB precursors gamma-butyrolactone and 1,4-butanediol.

Schneir AB, Ly BT, Clark RF.

Division of Medical Toxicology, Department of Emergency Medicine, UCSD Medical Center, California Poison Control System-San Diego Division, 200 West Arbor Drive, San Diego, CA 92103-8925, USA.

We describe a case of withdrawal from the gamma hydroxybutyric acid (GHB) precursors gamma butyrolactone and 1,4-butanediol. Symptoms included visual hallucinations, tachycardia, tremor, nystagmus, and diaphoresis. Administration of benzodiazepines and phenobarbital successfully treated the withdrawal symptoms. As predicted from the metabolism of gamma butyrolactone and 1,4-butanediol to GHB, the symptoms were nearly identical to those reported from GHB withdrawal. Because GHB is now illegal in the United States, individuals have begun abusing the legal and easier to acquire GHB precursors. More frequent cases of both abuse and withdrawal from these GHB precursors can be expected.

Publication Types:

·         Case Reports

PMID: 11399385 [PubMed – indexed for MEDLINE]


 

65: CNS Drugs. 2004;18(6):379-96.

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Mitoxantrone: a review of its use in multiple sclerosis.

Scott LJ, Figgitt DP.

Adis International Limited, Auckland, New Zealand. demail@adis.co.nz

Mitoxantrone (Novantrone), a synthetic anthracenedione derivative, is an antineoplastic, immunomodulatory agent. Its presumed mechanism of action in patients with multiple sclerosis (MS) is via immunomodulatory mechanisms, although these remain to be fully elucidated. Intravenous mitoxantrone treatment improved neurological disability and delayed progression of MS in patients with worsening relapsing-remitting (RR) [also termed progressive-relapsing (PR) MS] or secondary-progressive (SP) disease. In a pivotal randomised, double-blind, multicentre trial, mitoxantrone 12 mg/m(2) administered once every 3 months for 2 years provided significant improvements in neurological disability ratings, including Kurtzke Expanded Disability Status Scale (EDSS), Ambulatory Index (AI) and Standardised Neurological Status (SNS) scores, compared with placebo. The drug also significantly reduced the mean number of corticosteroid-treated relapses and prolonged the time to the first treated relapse, with the beneficial effects on disease progression supported by magnetic resonance imaging. Post hoc analyses suggest that the benefits associated with mitoxantrone treatment may be sustained for at least 12 months after cessation of treatment, mean changes from baseline at 36 months in EDSS, AI and SNS scores of 0.10, 0.61 and 0.19, respectively, in the mitoxantrone group versus 0.46, 1.13 and 3.38 with placebo.Concomitant intravenous mitoxantrone 20mg plus intravenous methylprednisolone 1g once every month for 6 months was more effective than intravenous methylprednisolone monotherapy in preventing the development of new gadolinium-enhanced lesions in patients with very active RRMS or SPMS.The drug was generally well tolerated in patients with MS. Adverse events were generally mild to moderate in severity and usually resolved upon discontinuation of treatment or with appropriate pharmacotherapy. At the recommended dosage, mitoxantrone appears to have a low potential to cause cardiotoxicity.In conclusion, intravenous mitoxantrone reduces the relapse rate and slows progression of the disease in patients with worsening RRMS, PRMS or SPMS; thus providing a new option for the management of these patients. The drug was generally well tolerated at the recommended dosage, although potential cardiotoxicity limits the total cumulative dose to 140 mg/m(2). Further studies are warranted to determine which patients with worsening RRMS, PRMS or SPMS are most likely to benefit from mitoxantrone treatment and to more fully define the long-term safety and tolerability of mitoxantrone, including the use of concomitant cardioprotectants to extend the therapeutic lifespan of the drug.Pharmacodynamic Profile. Mitoxantrone, a synthetic anthracenedione derivative, is an established cytotoxic, antineoplastic agent. Its presumed mechanism of action in multiple sclerosis (MS) is immunosuppression. In antineoplastic studies, the drug showed several immunomodulatory effects, inducing macrophage-mediated suppression of B-cell, T-helper and T-cytotoxic lymphocyte function. Currently, the pharmacodynamic properties of mitoxantrone have not been investigated to any extent in patients with MS. In one study, 6 months’ treatment with intravenous mitoxantrone generally had no effect on the distribution of cytokine-positive peripheral blood monocyte cells in patients with MS. In an animal model of the disease, mitoxantrone suppressed the development and progression of both actively and passively induced acute experimental allergic encephalomyelitis (EAE). It appeared to be 10-20 times more effective than cyclophosphamide in the suppression of EAE. Moreover, mitoxantrone approximately doubled the mean time to onset of EAE versus control animals (279 vs 148 days after immunisation; p < 0.00005). In vitro, mitoxantrone 10 and 100 micro g/L inhibited myelin degradation by leucocytes and peritoneal macrophages derived from mice with acute EAE by approximately 60% and 100%.Pharmacokinetic Profile. Currently, there are no published pharmacokinetic data for intravenous mitoxantrone in pitoxantrone in patients with MS, paediatric patients or in those with renal impairment. All studies, to date, have been in patients with cancer receiving a single, approximately 30-minute intravenous infusion of mitoxantrone 5-14 mg/m(2). The drug exhibits triexponential pharmacokinetics, with a rapid initial distribution (alpha) phase, an intermediate distribution (beta) phase and a much slower elimination (gamma) phase. The mean half-life of the alpha phase appears to be 6-12 minutes and that of the beta phase 1.1-3.1 hours. Mitoxantrone has a high affinity for tissue, with a volume of distribution of up to 2248 L/m(2). Mitoxantrone persists for prolonged periods in tissues and was detectable in autopsy tissue from patients who last received the drug up to 272 days before death. At concentrations of 10-10000 ng/mL, the drug was 70-80 % bound to plasma proteins in dogs.Elimination of mitoxantrone occurs predominantly through biliary excretion and may be impaired in patients with hepatic dysfunction or third space abnormalities (e.g. ascites). The mean terminal elimination half-life of mitoxantrone ranged from 23 hours to 215 hours. Renal clearance accounts for 10 % of the total clearance of the drug. Total clearance of mitoxantrone ranged from 13 to 34.2 L/h/m(2) and renal clearance from 0.9 to 2.7 L/h/m(2). The drug appears to have a low potential for interaction with other concomitantly administered agents.Therapeutic Efficacy. Intravenous mitoxantrone (infusion of > or = 5 minutes), either as monotherapy or in combination with intravenous methylprednisolone, delayed the progression of the disease in patients with secondary-progressive (SP) or worsening relapsing-remitting (RR) MS (the latter is also termed progressive-relapsing MS) in comparative, randomised, multicentre trials.In a double-blind, monotherapy trial (Mitoxantrone In Multiple Sclerosis [MIMS] trial), mitoxantrone 12 mg/m(2) (n = 60) once every 3 months for 2 years significantly improved neurological disability relative to placebo (n = 64), as assessed by changes in mean Kurtzke Expanded Disability Status Scale (EDSS) score, mean Ambulatory Index (AI) score and mean Standardised Neurological Status (SNS) score. The drug also significantly reduced the mean number of corticosteroid-treated relapses per patient and prolonged the time to the first treated relapse. A Wei-Lachin multivariate analysis of these five efficacy variables indicated that the global difference between the two treatment groups was 0.30 (p < 0.0001). Mitroxantrone was also more effective than placebo according to secondary endpoints in this study, with fewer mitoxantrone recipients experiencing a relapse, a deterioration of > or =1 EDSS point or a confirmed deterioration in EDSS score over a 3-month period. Mitoxantrone recipients also showed less deterioration in quality-of-life ratings and had fewer hospital admissions, whereas more placebo recipients had new gadolinium-enhanced lesions at study end (the latter parameter was assessed using magnetic resonance imaging [MRI] in a subgroup of 110 patients, including 40 patients who received an exploratory 5 mg/m(2) dose). Furthermore, post hoc analyses indicated that the beneficial effects of mitoxantrone treatment on EDSS, SNS and AI scores were sustained for at least 12 months after cessation of treatment, with mean changes from baseline at 36 months in EDSS, AI and SNS scores of 0.10, 0.61 and 0.19, respectively, in the mitoxantrone group versus 0.46, 1.13 and 3.38 with placebo.Preliminary data from a cost-minimisation analysis based on results from the MIMS trial indicated that approximately half of the cost of mitoxantrone was offset by cost savings in other areas associated with the treatment of MS (direct and indirect major costs), with a total annual incremental cost for mitoxantrone of dollar 1661 per patient.Combination therapy once-monthly with intravenous mitoxantrone 20mg plus intravenous methylprednisolone 1g was more effective than intravenous methylprednisolone 1g once every month in preventing the development of gadolinium-enhanced lesions in patients with very active RRMS or SPMS (double-blind assessment using MRI scans). After 6 months, significantly more combination therapy recipients had no new gadolinium-enhanced lesions (90.5% vs 31.3% with monotherapy; p < 0.001) [primary endpoint]. There were also significant reductions in both the mean number of new enhancing lesions and the total number of gadolinium-enhanced lesions in patients receiving combination therapy versus methylprednisolone monotherapy.Tolerability. Mitoxantrone was generally well tolerated in patients with MS. Treatment-emergent adverse events occurring significantly more frequently with mitoxantrone (12 mg/m(2) once every 3 months for 2 years) than placebo were nausea, alopecia, menstrual disorders, urinary tract infection, amenorrhoea, leucopenia and elevated gamma-glutamyltranspeptidase levels. Adverse events were usually mild to moderate in severity and generally resolved with discontinuation of treatment or when treated with appropriate pharmacotherapy. Eight percent of patients discontinued treatment in the mitoxantrone 12 mg/m(2) group due to an adverse event versus 3% of placebo recipients. The incidence of drug-related acute myelogenous leukaemia was very low (0.12%) in a cohort of 802 patients with MS receiving mitoxantrone.Evidence suggests that the risk of cardiotoxicity is low in patients with MS. After 1 year of monotherapy, 3.4% of mitoxantrone recipients had a reduction in left ventricular ejection fraction (LVEF) to < or =50% compared with 0% of placebo recipients; at the end of the second year, respective incidences were 1.9% and 2.9% (total cumulative dose of mitoxantrone per patient was 96 mg/m(2) after 2 years’ treatment). (ABSTRACT TRUNCATED)

Publication Types:

·         Review

·         Review, Tutorial

PMID: 15089110 [PubMed – indexed for MEDLINE]


 

66: J Psychoactive Drugs. 2001 Apr-Jun;33(2):135-42.

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Long-term therapy using GHB (sodium gamma hydroxybutyrate) for treatment-resistant chronic alcoholics.

Maremmani I, Lamanna F, Tagliamonte A.

Department of Psychiatry, Neurobiology, Pharmacology and Biotechnology, University of Pisa, Italy.

Thirty-five alcohol-dependent patients according to DSM-IV criteria who also met criteria for treatment resistance were treated with doses of gamma hydroxybutyrate (GHB) ranging between 25 and 100 mg/kg/die in an open one-year study. The results show that no patients discontinued the program during the first month of treatment. Sixty percent of these patients successfully completed the protocol; 11.4% showed complete abstinence (full responder patients); 14.3% strongly reduced their alcohol intake (partial responder patients) and 34.3% of the patients were still under treatment after one year. Forty percent of the patients were nonresponders. The retention rate under treatment of the studied sample was statistically higher than that found during the last treatment of the same subjects. No significant differences were found between full responder and partial responder patients regarding changes in clinical features, alcohol intake or social adjustment. Patients still in treatment after one year significantly differed from nonresponder patients on all the variables investigated. A six-times/daily fractionated administration of the GHB dose was the only significant predictor of the retention rate.

PMID: 11476260 [PubMed – indexed for MEDLINE]


 

67: Eur J Pharmacol. 2004 Jan 12;483(2-3):289-93.

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Neuroleptic-like effects of gamma-hydroxybutyrate: interactions with haloperidol and dizocilpine.

Sevak RJ, France CP, Koek W.

Department of Pharmacology, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900, USA.

gamma-Hydroxybutyrate (GHB) is a drug of abuse with multiple mechanisms of action. Consistent with its ability to modulate dopaminergic systems, GHB reportedly shares behavioral effects with neuroleptics and interacts with them in a synergistic manner. Here, we examined the ability of GHB and haloperidol to induce catalepsy and to affect operant responding. When given alone, both compounds induced catalepsy and decreased response rate. When given together, however, they produced these effects in an additive manner. This is further evidence that GHB has neuroleptic-like effects, but suggests that GHB interacts additively, not synergistically, with neuroleptics. The mechanisms involved in GHB- and haloperidol-induced catalepsy are different because the N-methyl-D-aspartate (NMDA) receptor antagonist, dizocilpine (MK-801), attenuated the cataleptic effects of haloperidol, but enhanced those of GHB. The latter finding suggests that other NMDA receptor antagonists (e.g., the drugs of abuse–phencyclidine and ketamine) may also interact synergistically with GHB.

PMID: 14729119 [PubMed – indexed for MEDLINE]


 

68: Clin Neuropharmacol. 1992;15 Suppl 1 Pt A:303A-304A.

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Gamma-hydroxybutyric acid in the treatment of alcohol dependence.

Gessa GL, Gallimberti L.

Bernard B. Brodie Department of Neuroscience, University of Cagliari, Italy.

Publication Types:

·         Clinical Trial

·         Randomized Controlled Trial

PMID: 1498849 [PubMed – indexed for MEDLINE]


 

69: Mo Med. 1995 Jul;92(7):354-7.

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Acute poisoning from gamma hydroxybutyrate (GHB).

Steele MT, Watson WA.

Department of Emergency Medicine, Truman Medical Center, University of Missouri-Kansas City School of Medicine, USA.

Gamma hydroxybutyrate (GHB) is an illicitly marketed substance promoted by body builders as a growth hormone releaser. Poisoning can produce seizures and coma. Acute poisonings from GHB have primarily been reported on the West coast and the Southeast. We report two cases from Kansas City where the patients presented in, or developed profound coma. Physicians should suspect GHB poisoning in patients who present with unexplained seizures and/or coma, particularly if they are body builders, health food fanatics or dieters.

Publication Types:

·         Case Reports

PMID: 7651315 [PubMed – indexed for MEDLINE]


 

70: Lakartidningen. 2001 Sep 19;98(38):4026-31, 4033-5.

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Comment in:

·         Lakartidningen. 2001 Oct 3;98(40):4381.

[GHB–dangerous, addictive and uncontrollable “party drug”]

[Article in Swedish]

Persson SA, Eriksson A, Hallgren N, Eklund A, Berkowicz A, Druid H.

Totalforsvarets forskningsinstituts avdelning for skydd mot nukleara, biologiska och kemiska vapen, FOI NBC-skydd, Umea. sven-ake.persson@foi.se

This report reviews the pharmacology, toxicity and abuse pattern of gamma-hydroxybutyrate (GHB). The legislative changes pertaining to this substance are also addressed. Examples of abuse, driving under the influence and fatal intoxication are given. It is concluded that GHB is widely abused, particularly among the younger generation, and that further cases of severe intoxication are likely to occur as long as the substance is easily available from countless sources, including via the Internet. Despite the classification of GHB as a narcotic in Sweden and several other countries, continued problems are expected since the precursors gamma-butyrolactone (GBL) and 1,4-butanediol (BD) are widely–and legally–available.

Publication Types:

·         Case Reports

·         Review

·         Review of Reported Cases

·         Review, Tutorial

PMID: 11602959 [PubMed – indexed for MEDLINE]


 

71: Brain Res Mol Brain Res. 2004 Jan 5;120(2):130-7.

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Ethanol withdrawal-induced up-regulation of the alpha2 subunit of the GABAA receptor and its prevention by diazepam or gamma-hydroxybutyric acid.

Follesa P, Biggio F, Mancuso L, Cabras S, Caria S, Gorini G, Manca A, Orru A, Biggio G.

Section of Neuroscience, Department of Experimental Biology, University of Cagliari, Cagliari 09123, Italy. follesa@unica.it

The gamma-aminobutyric acid type A (GABA(A)) receptor is an important pharmacological target of ethanol. The effect of ethanol withdrawal on the expression of the alpha(2) subunit of this receptor was examined with rat cerebellar granule cells in primary culture. Long-term exposure of these cells to ethanol (100 mM, 5 days) did not affect the abundance of the mRNA for the alpha(2) subunit, as revealed by an RNase protection assay. In contrast, subsequent ethanol withdrawal for 3 h induced a marked increase in the amount of this mRNA (2.6-fold) as well as in that of the encoded polypeptide (2.2-fold), the latter revealed by immunoblot analysis. Exposure of the cells to gamma-hydroxybutyric acid (100 mM) during ethanol withdrawal prevented the increase in the amounts of both the alpha(2) mRNA and polypeptide, whereas similar treatment with diazepam (10 microM) blocked the increase in the abundance of the alpha(2) polypeptide but not that in the amount of the alpha(2) mRNA. The effect of gamma-hydroxybutyric acid was not blocked by the competitive GABA(B) receptor antagonist SCH 50911(10 microM). Given that the alpha(2) subunit of the GABA(A) receptor mediates the anxiolytic action of benzodiazepines, its up-regulation during discontinuation of long-term ethanol exposure might be relevant to the therapeutic efficacy of these drugs in the treatment of anxiety associated with ethanol withdrawal.

PMID: 14741402 [PubMed – indexed for MEDLINE]


 

72: J Am Pharm Assoc (Wash). 1999 Jul-Aug;39(4):519-25; quiz 581-3.

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Comment in:

·         J Am Pharm Assoc (Wash). 1999 Jul-Aug;39(4):442-3.

Drugs used in acquaintance rape.

Smith KM.

University of Kentucky Medical Center, Lexington, USA. ksmit1@pop.uky.edu

OBJECTIVE: To describe gamma-hydroxybutyrate (GHB), flunitrazepam, and ketamine and their purported uses to facilitate acquaintance rape. Patient presentation characteristics, treatment regimens, processes to detect the presence of the medications by toxicology screening, and methods to avoid exposure are discussed. DATA SOURCES: MEDLINE search from 1985 to 1998; additional references found within the articles; information obtained from the Internet. STUDY SELECTION: Clinical trials, reviews, and press releases concerning the use of GHB, flunitrazepam, and ketamine to facilitate acquaintance rape. Trials and reviews describing clinical effects, adverse effects, pharmacokinetics/pharmacodynamics, and usage trends were evaluated. Literature judged to be pertinent by the author was included in the discussion. DATA EXTRACTION/DATA SYNTHESIS: Reports of the use of GHB, flunitrazepam, and ketamine in acquaintance rape appear in the medical literature and lay press. Many health care professionals may not be familiar with these medications, and information about caring for patients under their influence is limited. Victims lose their ability to ward off attackers, develop amnesia, and are unreliable witnesses. Because symptoms caused by these agents mimic those of alcohol, not all victims are screened for their presence. Legislative efforts to further limit the use of or access to GHB, flunitrazepam, and ketamine have been initiated at the state and federal levels. Pharmacists should know the symptoms of exposure to the three agents; they should understand treatment regimens, methods to detect the presence of these and other drugs that may have been used in a sexual assault, and techniques individuals can use to avoid becoming victims of drug-assisted acquaintance rape. CONCLUSION: Because of their extensive drug knowledge and frequent access to patients, pharmacists are uniquely positioned to educate patients and other health care professionals about the dangers of acquaintance rape drugs and methods to reduce their risk of becoming victims.

PMID: 10467817 [PubMed – indexed for MEDLINE]


 

73: Pediatrics. 2004 Mar;113(3 Pt 1):e206-16.

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Comment in:

·         Pediatrics. 2004 Oct;114(4):1132; author reply 1132-3.

Click here to read
A comparison of once-daily extended-release methylphenidate formulations in children with attention-deficit/hyperactivity disorder in the laboratory school (the Comacs Study).

Swanson JM, Wigal SB, Wigal T, Sonuga-Barke E, Greenhill LL, Biederman J, Kollins S, Nguyen AS, DeCory HH, Hirshe Dirksen SJ, Hatch SJ; COMACS Study Group.

University of California at Irvine Child Development Center, Irvine, California 92612, USA. jmswanso@uci.edu

OBJECTIVE: The objective of this study was to evaluate differences in the pharmacodynamic (PD) profile of 2 second-generation extended-release (ER) formulations of methylphenidate (MPH): Metadate CD (MCD; methylphenidate HCl, US Pharmacopeia) extended-release capsules, CII, and Concerta (CON; methylphenidate HCl) extended-release tablets, CII. Little empirical information exists to help the clinician compare the PD effects of the available ER formulations on attention and behavior. Previous studies have shown that the near-equal doses of MCD and CON provide equivalent, total exposure to MPH as measured by area under the plasma concentration time curve, yet their pharmacokinetic (PK) plasma concentration versus time profiles are different. We previously offered a theoretical PK/PD account of the similarities and differences among available ER formulations based on the hypothesis that all formulations produce effects related to MPH delivered by 2 processes: 1) an initial bolus dose of immediate-release (IR) MPH that is expected to achieve peak plasma concentration in the early morning and have rapid onset of efficacy within 2 hours of dosing, which for the MCD capsule is delivered by 30% of the total daily dose as uncoated beads and for the CON tablet is delivered by an overcoat of 22% of the total daily dose; and 2) an extended, controlled delivery of ER MPH that is expected to achieve peak plasma concentrations in the afternoon to maintain efficacy for a programmed period of time after the peak of the initial bolus, which for the MCD capsule is delivered by polymer-coated beads and for the CON tablet by an osmotic-release oral system. According to this PK/PD model, clinical superiority is expected at any point in time for the formulation with the highest MPH plasma concentration. METHODS: This was a multisite, double-blind, double-dummy, 3-way crossover study of 2 active treatments (MCD and CON) and placebo (PLA). Children with confirmed diagnoses of attention-deficit/hyperactivity disorder were stratified to receive bioequivalent doses of MCD and CON that were considered to be low (20 mg of MCD and 18 mg of CON), medium (40 mg of MCD and 36 mg of CON), or high (60 mg of MCD and 54 mg of CON), and in a randomized order each of the study treatments was administered once daily in the morning for 1 week. On the seventh day of each treatment week, children attended a laboratory school, where surrogate measures of response were obtained by using teacher ratings of attention and deportment and a record of permanent product of performance on a 10-minute math test at each of the 7 classroom sessions spread across the day at 1.5-hour intervals. Safety was assessed by patient reports of adverse events, parent ratings on a stimulant side-effects scale, and measurement of vital signs. RESULTS: The analyses of variance revealed large, statistically significant main effects for the within-subject factor of treatment for all 3 outcome measures (deportment, attention, and permanent product). The interactions of treatment x session were also highly significant for all 3 outcome measures. Inspection of the PD profiles for the treatment x session interactions suggested 4 patterns of efficacy across the day: 1) PLA > MCD approximately CON (PLA superiority) immediately after dosing; 2) MCD > CON > PLA during the morning (MCD superiority); 3) MCD approximately CON > PLA during the afternoon (PD equivalence of MCD and CON); and 4) CON > MCD approximately PLA in the early evening (CON superiority). The effect of site was significant, because some study centers had low and some high scores for behavior in the lab classroom, but both the low- and high-scoring sites showed similar PD patterns across the day. The interaction of dose x treatment was not significant, indicating that the pattern of treatment effects was consistent across each dose level. There were no statistically significant overall differences among the 3 treatments for the frequency of treatment-emergent adverse events, ratings of side effects, or vital signs. Two additional PK/PD questions were addressed: 1. The a priori hypothesis called for a comparison of the average of sessions (removing session as a factor) during a time period that corresponds to the length of a typical school day (from 1.5 through 7.5 hours after dosing). For the planned contrast of the 2 treatment conditions (MCD versus CON), the difference was significant, confirming the a priori hypothesis of superiority of near-equal daily doses of MCD over CON for this predefined postdosing period. 2. In the design of the study, the dose factor represented the total daily dose, consisting of 2 components: the initial bolus doses of IR MPH, which differ for the near-equal total daily doses of MCD and CON, and the reservoir doses of ER MPH, which were the same for the 2 formulations. To evaluate the moderating effects of the bolus component of dose on outcome, average effect size (ES) was calculated for the efficacy outcomes at the time of expected peak PK concentration times of the initial bolus component for each formulation at the 3 dose levels. The correlation (r) of ES with IR MPH bolus dose was significant for each of the 3 outcome measures (r approximately .9), indicating that the magnitude of effects in the early morning may be attributed to the dose administered by the IR MPH bolus of each formulation. For the 2 dose conditions with equal 12-mg IR MPH boluses (MCD 40 and CON 54), the ESs were large and indistinguishable (eg, deportment ES approximately 0.75 for both). CONCLUSIONS: Once-daily doses of MCD and CON produced statistically significantly different PD effects on surrogate measures of behavior and performance among children with attention-deficit/hyperactivity disorder in the laboratory school setting. As predicted by the PK/PD model, superiority at any point in time was achieved by the formulation with the highest expected plasma MPH concentration.

Publication Types:

·         Clinical Trial

·         Multicenter Study

·         Randomized Controlled Trial

PMID: 14993578 [PubMed – indexed for MEDLINE]


 

74: Ugeskr Laeger. 1999 Dec 13;161(50):6903-7.

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[Gamma-hydroxybutyrate–an endogenous substance and a new central nervous system stimulant. Clinical aspects of acute poisoning]

[Article in Danish]

Engelsen J, Christensen HR.

H:S Bispebjerg Hospital, klinisk biokemisk afdeling.

During the last six months, the Poison Control Centre at Bispebjerg Hospital, Copenhagen, Denmark, has observed an increasing number of patients intoxicated with GHB, a drug of abuse. The patients are often admitted to the emergency ward shortly after having taken the drug, unconscious or comatose. If younger patients present with these symptoms, intoxication with GHB should be seriously considered. The effects are seen within 15 to 30 minutes after oral ingestion of the drug. Spontaneous recovery usually occurs within three to five hours. The most common effects are mild euphoria, sedation, vomiting, somnolence, bradycardia, aggressive behaviour, apnoea, respiratory depression, and coma. Normally the patient breathes adequately, but insufficient respiration may occur and deaths have been described. The drug is often consumed together with alcohol and other drugs of abuse, which strengthens the effect of GHB. Treatment is symptomatic. A review of the literature with special emphasis on clinical effects included toxicology and treatment is given.

Publication Types:

·         Review

PMID: 10643375 [PubMed – indexed for MEDLINE]


 

75: Sleep. 2004 Aug 1;27(5):899-904.

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Effects of gamma-hydroxybutyrate (GHB) on vigilance states and EEG in mice.

Meerlo P, Westerveld P, Turek FW, Koehl M.

Center for Sleep and Circadian Biology, Department of Neurobiology & Physiology, Northwestern University, Evanston, IL, USA. p.meerlo@biol.rug.nl

STUDY OBJECTIVES: Gamma-hydroxybutyrate (GHB) is an endogenous neuromodulator that appears to have wide-ranging effects on vigilance and behavior. In the present study, we examined the effects of GHB on sleep-wake behavior and EEG in mice. In addition, we measured effects of GHB on body temperature and arousal or stress hormones. DESIGN: Adult male BALB/c mice were implanted with electroencephalographic and electromyographic electrodes to record vigilance states and an intraperitoneal transmitter to record body temperature. After recovery from surgery and habituation to the recording procedure, the mice were intraperitoneally injected with saline or GHB (50, 150 or 250 mg/kg) half an hour after light onset. Blood samples to measure effects of GHB on corticosterone and prolactin levels were collected in a separate group of mice. SETTING: N/A PATIENTS: N/A INTERVENTIONS: N/A RESULTS: At the lowest dose, GHB had no conspicuous effects on behavioral vigilance and electroencephalogram, nor on body temperature and endocrine measures. At the 2 higher doses, GHB induced a short period of electroencephalographic hypersynchrony in parallel to complete behavioral inactivity, an unnatural flat body posture, and nonresponsiveness to stimulation. After the highest dose of GHB, this state of reduced vigilance was associated with a decrease in body temperature, while prolactin and corticosterone levels were strongly increased. CONCLUSIONS: The results do not indicate a clear sleep-promoting effect of GHB in mice, but, at higher doses, it caused electroencephalographic hypersynchronization together with a coma-like state.

Publication Types:

·         Evaluation Studies

PMID: 15453548 [PubMed – indexed for MEDLINE]


 

76: Obes Res. 2003 Jun;11(6):722-33.

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A 6-month randomized, placebo-controlled, dose-ranging trial of topiramate for weight loss in obesity.

Bray GA, Hollander P, Klein S, Kushner R, Levy B, Fitchet M, Perry BH.

Pennington Biomedical Research Center, Baton Rouge, Louisiana. Baylor Hospital, Dallas, Texas, USA. brayga@pbrc.edu

OBJECTIVE: To evaluate the efficacy and safety of topiramate (TPM) for weight loss in healthy obese subjects. RESEARCH METHODS AND PROCEDURES: A randomized, double-blind, placebo-controlled, dose-ranging trial was conducted. Three hundred eighty-five subjects, 18 and 75 years of age, were randomized to receive either placebo or TPM at 64, 96, 192, or 384 mg daily. Dosing began at 16 mg once daily. In week 2, the dose was increased to 16 mg twice daily. Thereafter, the dose was raised every week by 32 mg/d (16 mg twice daily) until subjects reached their target dose. Twenty-four weeks after beginning treatment, all subjects were tapered off treatment by a dose reduction of 50% per week. All participants received the same lifestyle program. RESULTS: Mean percent weight loss from baseline to week 24 was -2.6% in placebo-treated patients vs. -5.0%, -4.8%, -6.3%, and -6.3% in the 64, 96, 192, and 384 mg/d TPM groups, respectively. Greater percentages of TPM-treated patients lost at least 5% or 10% of body weight compared with placebo. The most frequent adverse events were related to the central or peripheral nervous system, including paresthesia, somnolence, and difficulty with memory, concentration, and attention. Most events were dose-related, occurred early in treatment, and usually resolved spontaneously; only 21% receiving TPM withdrew due to adverse events compared with 11% on placebo. DISCUSSION: TPM produced significantly greater weight loss than placebo at all doses.

Publication Types:

·         Clinical Trial

·         Randomized Controlled Trial

PMID: 12805393 [PubMed – indexed for MEDLINE]


 

77: Emerg Med Clin North Am. 2000 May;18(2):273-88.

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Withdrawal syndromes.

Olmedo R, Hoffman RS.

New York City Poison Control Center, New York, USA.

The pathophysiology of substance withdrawal is elucidated by a review of classic and cutting-edge research. The manifestation and evaluation of the associated withdrawal syndromes from ethanol, sedative-hypnotics, opioids, and baclofen, are compared. The general management of and pharmacotherapy for these patients are discussed.

Publication Types:

·         Review

·         Review, Tutorial

PMID: 10767884 [PubMed – indexed for MEDLINE]


 

78: Am J Emerg Med. 1991 Jul;9(4):321-4.

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gamma-Hydroxybutyrate: a health-food product producing coma and seizurelike activity.

Dyer JE.

San Francisco Bay Area Regional Poison Control Center, San Francisco General Hospital Medical Center, CA 94110.

Sixteen cases of adverse effects due to a new health-food product, gamma-hydroxybutyrate (GHB), were reported to the San Francisco Bay Area Regional Poison Control Center in the 5-month period from June to October 1990. Cases have also been reported in eight other states. Adverse effects included coma (four patients) and tonic-clonic seizurelike activity (two patients). Doses ranged from 1/4 teaspoon to 4 tablespoons. Acute symptoms resolved within 7 hours. GHB was investigated as an anesthetic agent during the 1960s until seizures and lack of analgesia precluded its use. It was recently introduced in the health-food market as a food supplement for body builders with claims of anabolic effects by stimulating growth hormone release. GHB remains under investigational new drug status with the Food and Drug Administration and is illegal for over the counter sale. The Food and Drug Branch of the California Department of Health Services has prohibited further sale of this product in California as have health departments in Florida and South Carolina; however, new cases continue to be reported. Health professionals should be aware of the potential health hazards of GHB.

Publication Types:

·         Case Reports

PMID: 2054002 [PubMed – indexed for MEDLINE]


 

79: Pharmacotherapy. 2003 Jul;23(7):823-34.

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Efficacy and safety of 4-aminopyridine in patients with long-term spinal cord injury: a randomized, double-blind, placebo-controlled trial.

Grijalva I, Guizar-Sahagun G, Castaneda-Hernandez G, Mino D, Maldonado-Julian H, Vidal-Cantu G, Ibarra A, Serra O, Salgado-Ceballos H, Arenas-Hernandez R.

Research Medical Unit for Neurological Diseases, Specialties Hospital, Centro Medico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Mexico City, Mexico. igrijalvao@yahoo.com

OBJECTIVES: To study the efficacy and safety of 4-aminopyridine (4-AP), and to document sensorimotor changes after discontinuation of the drug in patients with long-term spinal cord injury. DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING: Clinical research unit. PATIENTS: Twenty-seven patients with long-term spinal cord injury. INTERVENTION: Patients were randomized to receive either oral 4-AP 5 mg/day, which was increased by 5 mg/week to a maximum dosage of 30 mg/day, or placebo for 12 weeks. They switched to the opposite treatment for the next 12 weeks. MEASUREMENTS AND MAIN RESULTS: Twenty-five patients finished the study. The results from the first 12 weeks were used to test efficacy. Positive gains in motor function, sensation, and independence occurred more frequently in patients receiving 4-AP (69%) than those receiving placebo (46%). Significant functional improvement was also noted in those treated with 4-AP (chi2, p=0.042). When each evaluation scale was considered separately, significant improvement was seen only in motor function (4-AP 92% vs placebo 46%, Fisher exact test, p=0.03). Persistent effects of the drug were assessed at week 24 in the group that initially received 4-AP. A persistent, significant 4-AP effect was observed in evaluations of sensation and independence (67% and 83% of patients, respectively; Wilcoxon signed rank test, p=0.032 and 0.042, respectively). Fourteen (56%) patients had 26 adverse reactions. One moderate adverse reaction–posterior tibial artery vasospasm–and 25 mild adverse reactions, such as dry mouth, dizziness, nausea, gastritis, oral and peripheral paresthesia, resolved adequately. Six (24%) patients experienced transitory alterations of enzyme levels (alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and creatine kinase) and thrombocytopenia. CONCLUSION: Patients who received 4-AP showed significant improvement in motor function, and a persistent effect on sensation and independent function occurred. The drug is safe; however, after starting 4-AP therapy, patients must be carefully monitored for the possible occurrence of peripheral vasospasm.

Publication Types:

·         Clinical Trial

·         Randomized Controlled Trial

PMID: 12885095 [PubMed – indexed for MEDLINE]


 

80: Lancet. 1994 Jan 1;343(8888):57.

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Physical dependence on sodium oxybate.

Galloway GP, Frederick SL, Staggers F Jr.

Publication Types:

·         Case Reports

·         Letter

PMID: 7905069 [PubMed – indexed for MEDLINE]


 

81: J Psychiatr Res. 2004 May-Jun;38(3):327-34.

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Chronic benzodiazepine usage and withdrawal in insomnia patients.

Poyares D, Guilleminault C, Ohayon MM, Tufik S.

Disciplina de Medicina e Biologia do Sono, Departamento de Psicobiologia da Universidade Federal de Sao Paulo, Brazil. poyares@psicobio.epm.br

We studied the sleep of patients with insomnia during continuous and very long-term use of benzodiazepines (BZDs), and after withdrawal. A group of 25 patients (mean age 44.3+/-11.8 years) with persistent insomnia, who had been taking BZDs nightly for 6.8+/-5.4 years was selected. The control group was comprised of 18 age-matched healthy individuals. Sleep stage parameters were analyzed during Night 1 (while taking BZDs), Night 2 (first night after completing BZD withdrawal), and Night 3 (15 days after gradual BZD withdrawal). Sleep data for control subjects was monitored in parallel. Sleep EEGs of the patients were analyzed using Period Amplitude Analysis (PAA), during Nights 1 and 3 only. During BZD use, a significant reduction of Total Sleep Time (TST) and increased sleep latency were found in the insomniac group when compared to controls. We found an increase in stage 2 non-REM (NREM) sleep, and a reduction in Slow Wave Sleep (SWS) when comparing to night 3 (after withdrawal). Sleep EEGs analysis showed an increase in sigma band and decrease in delta count in stages 2, 3, 4 NREM and REM sleep in the BZD group when comparing to night 3 (after withdrawal). During the BZD withdrawal period, six out of nine subjects taking lorazepam failed withdrawal. In the remaining 19 subjects, gradual withdrawal of BZDs was associated with immediate worsening of nocturnal sleep, as indicated by sleep parameters. However, 15 days after withdrawal (Night 3), some of the sleep structure parameters of patients were not significantly different from baseline (while taking BZDs), except for a significant increase in SWS and in delta count throughout most sleep stages, and a decrease in stage 2 NREM sleep. These values were not different from those shown by control subjects. REM sleep parameters showed no significant variation across the experimental conditions. Subjective sleep quality was significantly improved on Night 3 compared with Night 1. Conclusions: Chronic intake of BZDs may be associated with poor sleep in this population. A progressive 15-day withdrawal did not avoid an immediate worsening of sleep parameters. But at the end of the protocol, SWS, delta count, and sleep quality were improved compared to those recorded during the chronic BZD intake, despite the lack of change in sleep efficiency.

Publication Types:

·         Clinical Trial

PMID: 15003439 [PubMed – indexed for MEDLINE]


 

82: Eur J Pharmacol. 2004 Feb 6;485(1-3):183-91.

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Effect of late treatment with gamma-hydroxybutyrate on the histological and behavioral consequences of transient brain ischemia in the rat.

Ottani A, Vergoni AV, Saltini S, Mioni C, Giuliani D, Bartiromo M, Zaffe D, Botticelli AR, Ferrari A, Bertolini A, Genedani S.

Section of Pharmacology, Department of Biomedical Sciences, University of Modena and Reggio Emilia, Via G. Campi 287, Modena 41100, Italy. alessandroottani@yahoo.it

It has been previously described that gamma-hydroxybutyrate (GHB) provides significant protection against transient global cerebral ischemia in the rat (four vessel occlusion model), when given 30 min before or 10 min after artery occlusion. Here, we show that in the same rat model, significant protection can also be obtained when treatment is started 2 h after the ischemic episode. In saline-treated animals, 30 min of global ischemia followed by reperfusion caused a massive loss of neurons in the hippocampal CA1 subfield (examined 63 days after the ischemic episode), and an impairment of sensory-motor performance (tested on the 51st and 63rd days after ischemia) and of spatial learning and memory (evaluated starting 46 days after the ischemic episode). Treatment with GHB–300 mg/kg intraperitoneally (i.p.) 2 h after the ischemia-reperfusion episode, followed by 100 mg/kg i.p. twice daily for the following 10 days–afforded a highly significant protection, against both histological damage and sensory-motor and learning-memory impairments. These data further suggest the possible therapeutic effectiveness of GHB in brain ischemia, and indicate that the underlying mechanism of action involves non-immediate steps of the ischemia-induced cascade of events.

 

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