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Biomedical subjects

G Somer

Publications and source records attributed to G Somer.

12 recordsLinked to original sources
PubMed2000

Cytochrome P450 2D6 and treatment of codeine dependence.

Oral opioid analgesics such as codeine are used extensively worldwide and are frequently misused. Codeine is a substrate of CYP2D6, a genetically polymorphic P450 enzyme, and is metabolized to the more potent drug morphine. CYP2D6 activity can be inhibited by fluoxetine, and the inhibition of morphine formation may help individuals reduce their use of codeine. Fourteen long-term users of oral opiates (principally codeine) were assessed for an open-label pilot treatment study of fluoxetine 20 mg/day combined with a brief behavioral intervention and structured tapering of the opiate. Eight subjects entered and completed the 8-week treatment. Opiate use decreased by 30% to 100% of baseline use (p < 0.0001) in parallel with a decrease in CYP2D6 activity. Fluoxetine may have a role in the treatment of opiate dependence by decreasing opiate-reinforcing properties.

Adult↗
PubMed2000

Comparative abuse liability of intravenously administered remifentanil and fentanyl.

Remifentanil is a short-acting, esterase-metabolized opioid analgesic. This study compared the abuse liability of remifentanil with that of fentanyl and placebo in a randomized, double-blind, crossover study. Twelve recreational users of opioids received increasing doses of remifentanil (0.6, 1.2, 1.8, 2.4, and 3.0 microg/kg), fentanyl (0.4, 0.8, 1.3, 2.0, 3.0, and 4.5 microg/kg) and placebo via an intravenous infusion pump. Subjective measures (Cole/Addiction Research Center Inventory [ARCI] scales and visual analog scale [VAS] items such as "High" and "Good Effects") and physiologic variables (blood pressure, O2 saturation, pupil diameter) were recorded. For each measure, the differences from baseline were reduced to an area under the response curve (AUC) and a peak, and each subject's response to the maximum tolerable dose for each of the two active drug classes and mean response to several placebo infusions were entered into a 12 x 3 analysis of variance. All differences in drug versus placebo effects were significant. Although a majority of the peak effects that were measurable within 4 minutes after drug infusion reflected greater remifentanil effects, only one, High VAS, was statistically significant. In contrast, observations that could only be made > or = 5 minutes after drug infusion predominantly indicated significantly greater fentanyl peak effects, including High VAS, Liking VAS, Good Effects VAS, and Cole/ARCI Abuse Potential. Fentanyl AUCs were generally significantly larger than the corresponding remifentanil AUCs. A drug abuser seeking longer-lasting drug effects might select fentanyl over remifentanil, but these data do not completely rule out remifentanil abuse by some individuals with access to both the drug and the infusion equipment or by those who prefer briefer, repeated effects.

Adult↗
PubMed1999

Characteristics of dependent and nondependent regular users of codeine.

Although codeine is a widely used medication, the problems of codeine abuse and dependence have not been well-studied. This study characterized regular codeine users (using at least 3 days per week for 6 months, excluding those using codeine for the treatment of cancer pain) through a self-completed questionnaire. Recruitment through newspaper advertisements resulted in a total of 339 eligible questionnaires. Thirty-seven percent of subjects met DSM-IV criteria for codeine dependence. Dependent subjects (mean age, 40 +/- 10 years) were using an average of 179 (+/-171) mg of codeine per day. Codeine was predominantly used in the form of combination products with acetaminophen. Dependent subjects identified specific problems causally related to their codeine use such as depression (23%), anxiety (21%), and gastrointestinal disturbances (13%). The dependent subjects reported problems with other drugs more than did nondependent users (alcohol, 57% vs. 26%; cannabis, 23% vs. 5%; sedative/hypnotics, 33% vs. 12%; and heroin, 11% vs. 2%, respectively). Most were taking codeine primarily for a chronic pain problem (81%), although the dependent subjects currently found codeine less effective for treating pain than did the nondependent subjects and were more likely to use codeine for pleasurable effects, to relax, or to prevent withdrawal symptoms. This study showed that dependence is associated with the regular use of codeine. Pain is a key issue with these users; however, they are probably not receiving optimal treatment. There is a need to identify individuals experiencing problems with their codeine use and to develop optimal prevention and treatment strategies.

Adolescent↗
PubMed1999

Long-term codeine use is associated with depressive symptoms.

A community survey was conducted among long-term (>6 months) users of codeine-containing products to characterize chronic use of these extensively consumed medications. Respondents recruited through newspaper advertisements completed a mailed questionnaire. Three hundred thirty-nine completed questionnaires were obtained, yielding a response rate of 70%. Codeine dependence/abuse as defined by DSM-IV criteria was present in 41% of the respondents. Two thirds of the subjects had sought help for mental health problems, most often depression (70%). Scores on the Symptom Checklist-90 subscales were modestly elevated, particularly on the Depression subscale (1.2 +/- 0.9). Long-term codeine use is strongly associated with dependence. Depression and depressive symptoms are common. These data suggest that dysphoric mood states may be significant in maintaining long-term codeine use.

Adolescent↗
PubMed1998

A controlled trial of ondansetron, a 5-HT3 antagonist, in benzodiazepine discontinuation.

Serotonin is implicated in the etiology of anxiety disorders and in the anxiolytic actions of benzodiazepines. Preclinical studies with 5-HT3 receptor antagonists, including ondansetron, show they have anxiolytic properties and that ondansetron suppresses withdrawal anxiety after abrupt discontinuation of chronic benzodiazepine treatment. We evaluated the efficacy of ondansetron as an adjunctive medication in the discontinuation of benzodiazepines in long-term users. One hundred eight patients who had used alprazolam or lorazepam regularly for > 3 months entered, and 97 completed a randomized double-blind discontinuation treatment program during which they received either ondansetron 2 mg twice daily or placebo and flexibly tapered their benzodiazepine over a 6-week period. There were no significant differences between the patients who had entered and completed treatment. Three weeks postmedication, 63% of the patients discontinued use of benzodiazepine. The percentage of reduction of benzodiazepine daily dosage at all time points in the treatment trial was similar for the ondansetron and placebo groups. Ondansetron had no significant effects on severity of withdrawal symptoms or levels of anxiety. High placebo response may have prevented detection of an ondansetron effect. At 1 year follow-up, 68% of patients reported that they stopped using benzodiazepine. Patient characteristics were more important than ondansetron in tapered benzodiazepine discontinuation.

Alprazolam↗
PubMed1997

Inhibition of cytochrome P450 2D6 metabolism of hydrocodone to hydromorphone does not importantly affect abuse liability.

Enzymatic conversion of hydrocodone to hydromorphone is catalyzed by cytochrome P450 2D6, which is inactive in about 7% of Caucasians [poor metabolizers (PMs)] and can be inhibited by quinidine pretreatment in the remainder [extensive metabolizers (EMs)]. If hydromorphone, having a substantially higher mu-receptor affinity than hydrocodone, contributes importantly to the physiological and subjective effects of oral hydrocodone, then PMs should be less responsive to the same doses, and quinidine pretreatment should cause EMs to temporarily respond as PMs. Seventeen EMs and 8 PMs who previously responded positively to hydromorphone s.c. received placebo and hydrocodone (10 mg, 15 mg and 22.5 mg p.o.) and were retested with their favorite dose after placebo or quinidine (100 mg) pretreatment; physiological and subjective measures were collected at base line and four times after drug administration, and urine was collected for 8 hr. EMs and PMs were equally responsive to oral hydrocodone, and quinidine had no consistent effect on their responses, even though quinidine abolished the pre-existing metabolic differences in hydromorphone production, as measured in urine. These data suggest only a small role of hydromorphone in eliciting abuse-related responses to oral hydrocodone.

Cytochrome P-450 CYP2D6 Inhibitors↗
PubMed1995

Clinical aspects of chronic use of alprazolam and lorazepam.

OBJECTIVE: The authors' goal was to determine the clinical characteristics of persistent users of alprazolam or lorazepam who wished to discontinue their medication. METHOD: Long-term users (daily use for more than 3 months) of alprazolam (N = 34) or lorazepam (N = 97) who entered an outpatient treatment program for discontinuation of benzodiazepines were carefully assessed. Detailed histories of benzodiazepine use were obtained; a structured interview was used to make psychiatric diagnoses based on DSM-III-R criteria. RESULTS: The majority of patients were using low therapeutic doses of medication (lorazepam: mean = 2.7 mg/day; alprazolam: mean = 1.2 mg/day) and had either maintained their initial daily dose over time or decreased it. Individuals tended to shift their use of medication from an as-prescribed to an as-needed pattern. Forty-seven percent of the patients were diagnosed with at least one current anxiety disorder, most commonly generalized anxiety. At least one diagnosable personality disorder was found in 45% of the patients, most commonly obsessive-compulsive personality disorder. Patterns of benzodiazepine use were influenced by age, gender, and past history of alcohol dependence. CONCLUSIONS: Long-term users of alprazolam/lorazepam seeking treatment for discontinuation had clinically important past and current psychiatric histories. They used a constant or decreasing dose of medication and made attempts to stop their use. Persistent use of alprazolam/lorazepam for therapeutic purposes did not represent abuse or addiction as the terms are usually understood. A substantial proportion of these patients may be receiving appropriate maintenance therapy for a chronic psychiatric condition.

Alprazolam↗
PubMed1994

Reconstitution of the water-oxidizing complex in manganese-depleted photosystem II complexes by using synthetic binuclear manganese complexes.

The efficiency of synthetic binuclear manganese complexes in reconstituting PS II electron flow and oxygen-evolution capacity was analyzed in PS II enriched preparations deprived of their manganese and of the extrinsic regulatory subunits. Measurements of the variable fluorescence induced by actinic illumination with continuous light led to the following results: (a) the synthetic binuclear complexes are more efficient than MnCl2 in establishing a PS II electron flow; (b) an almost complete restoration is achieved at concentrations of these complexes that correspond with an overall stoichiometry of two manganese per PS II; and (c) the electron flow restored by the binuclear manganese complexes closely resembles that of normal O2-evolving PS II preparations in its resistance to addition of 50 microM EDTA, while that supported by MnCl2 is practically completely suppressed at the same chelator concentration. The rate of O2 evolution was used as a measure of the capability to function as manganese source in reconstitution of the oxygen evolution capacity. It was found that (i) as in the case of PS II electron transport, the synthetic binuclear manganese complexes are significantly more efficient than MnCl2; (ii) with respect to the manganese concentration, the maximum effect is achieved with a mu-oxo bridged binuclear Mn(III) complex (symbolized by M-3) at concentrations corresponding to four manganese per PS II; and (iii) at all concentrations of binuclear manganese complex M-3 a significantly higher restoration of the O2 evolution rate is achieved if the reconstitution assay contains in addition the extrinsic regulatory 33 kDa protein (PS II-O protein).(ABSTRACT TRUNCATED AT 250 WORDS)

Chlorides↗
PubMed1991

Characterization of DSM-III-R criteria for uncomplicated alcohol withdrawal provides an empirical basis for DSM-IV.

The DSM-III-R criteria for uncomplicated alcohol withdrawal require the presence of coarse tremor of the hands, tongue, or eyelids plus one of a number of other clinical features. We examined the validity and other characteristics of these items in 137 patients in pure alcohol withdrawal using the reliable and valid Clinical Institute Withdrawal Assessment for Alcohol. The DSM-III-R items of hand tremor amplitude, nausea or vomiting, headache, transient hallucinations, autonomic hyperactivity (increased pulse or sweating), and anxiety correlated significantly with total score and significantly indicated clinical severity. Addition of an "agitation" item improved the correlation. The diagnostic accuracy is greater than 95% if any two or more items are present. The number of positive items, of which tremor can be one, to grade clinical severity shows that a score of 2 indicates "very mild"; 3, "mild"; 4, "moderate"; and 5, "severe.". We propose that an Alcohol Withdrawal Diagnostic Inventory and a DSM-III-R-compatible brief Clinical Institute Withdrawal Assessment for Alcohol are useful for clinical research, where graded symptom characterization is needed. Our data may be helpful in the development of criteria for DSM-IV.

Adult↗
PubMed1988

Defining the true therapeutics and clinical pharmacology curriculum in a Canadian medical school: implications for change.

Concern over rational drug therapy has led to the close scrutiny of clinical pharmacology and therapeutics teaching. Course syllabuses and timetables portray the official curriculum but rarely reflect true pharmacology and content. The teaching of clinical pharmacology and therapeutics can be uniquely and comprehensively analyzed with a computer-based curriculum data base that has the capacity to identify overlap, integration, omissions, and correlations. We have developed such a system and applied it to the analysis of one medical school curriculum. Pharmacology and therapeutics teaching represents 22% of the curriculum; however, the majority occurs outside the pharmacology-controlled courses. Overlap is extensive and unplanned. Our data indicate that the true curriculum differs greatly from that in curriculum schedules and probably from that in the minds of most curriculum planners and teachers. Collaboration among pharmacologists and clinical pharmacologists and many other curriculum officers and teachers is essential if education in this area is to be improved.

Canada↗