Edward M. Sellers

A method for estimating the probability of adverse drug reactions

The estimation of the probability that a drug caused an adverse clinical event is usually based on clinical judgment. Lack of a method for establishing causality generates large between‐raters and within‐raters variability in assessment. Using the conventional categories and definitions of definite, probable, possible, and doubtful adverse drug reactions (ADRs), the between‐raters agreement of two physicians and four pharmacists who independently assessed 63 randomly selected alleged ADRs was 38% to 63%, kappa (k, a chance‐corrected index of agreement) varied from 0.21 to 0.40, and the intraclass correlation coefficient of reliability (R[est]) was 0.49. Six (testing) and 22 wk (retesting) later the same observers independently reanalyzed the 63 cases by assigning a weighted score (ADR probability scale) to each of the components that must be considered in establishing causal associations between drug(s) and adverse events (e.g., temporal sequence). The cases were randomized to minimize the influence of learning. The event was assigned a probability category from the total score. The between‐raters reliability (range: percent agreement = 83% to 92%; κ = 0.69 to 0.86; r = 0.91 to 0.95; R(est) = 0.92) and within‐raters reliability (range: percent agreement = 80% to 97%; κ = 0.64 to 0.95; r = 0.91 to 0.98) improved (p < 0.001). The between‐raters reliability was maintained on retesting (range: r = 0.84 to 0.94; R(est) = 0.87). The between‐raters reliability of three attending physicians who independently assessed 28 other prospectively collected cases of alleged ADRs was very high (range: r = 0.76 to 0.87; R(est) = 0.80). It was also shown that the ADR probability scale has consensual, content, and concurrent validity. This systematic method offers a sensitive way to monitor ADRs and may be applicable to postmarketing drug surveillance.

Drug Disposition in Old Age

THE appropriate and rational use of drugs by the elderly is a matter of growing medical and social concern. Life expectancy in the Western world currently stands at 69 years for men and 77 years fo...

Nicotine metabolism defect reduces smoking

Nicotine is the primary compound in tobacco that establishes and maintains tobacco dependence. Most of this nicotine is metabolized to cotinine by the genetically variable enzyme CYP2A6. Here we show that individuals lacking full functional CYP2A6, who therefore have impaired nicotine metabolism, are significantly protected against becoming tobacco-dependent smokers. In addition, smokers whose nicotine metabolism is thus impaired smoke significantly fewer cigarettes than those with normal nicotine metabolism.

Binding of Drugs to Serum Albumin

Most drugs are carried from their sites of absorption to their sites of action and elimination by the circulating blood. Some drugs are simply dissolved in serum water, but many others are partly a...

5-HT and alcohol abuse

Recent experimental data, both in animals and the clinic, suggest that drugs selectively interacting with the 5-HT system may reduce alcohol intake. Although the precise mechanisms underlying these drug effects are unknown, it seems that there are at least two pharmacological strategies available, described in this review by Edward Sellers and colleagues. The first is enhancement of 5-HT neuronal activity using compounds that will release 5-HT, block 5-HT reuptake, or act as selective 5-HT receptor agonists. A second approach involves selective 5-HT3 receptor antagonists. If the initial research findings with these drugs are confirmed and extended, they may present useful therapies for the treatment of alcohol abuse, especially if used in conjunction with psychosocial therapy.

Withdrawal reaction after long-term therapeutic use of benzodiazepines.

We conducted a double-blind, placebo-controlled trail in which 40 patients who had undergone long-term therapy with benzodiazepines were switched to placebo or to diazepam in a dose approximately equivalent to their usual dose of the benzodiazepine; the dose of diazepam was then tapered during an eight-week period. Patients were assessed clinically and psychologically and had weekly sessions of behavioral therapy. The subjects who received placebo had more symptoms, assessed their symptoms as more severe, and stopped taking the study drug at a higher rate than those receiving the tapering doses of diazepam. The subjects in the placebo group also had symptoms shortly after being switched to placebo, whereas those in the diazepam group had symptoms much later. Some withdrawal symptoms were distinct from those of anxiety (e.g., tinnitus, involuntary movement, and perceptual changes). Withdrawal symptoms occurred earlier in patients who had received short-acting benzodiazepines than in those who had received long-acting benzodiazepines. Symptoms gradually disappeared over a four-week period in both the placebo and the diazepam groups. Serial determination of plasma benzodiazepine concentrations was a useful way to assess compliance, treatment outcome, and relapse during withdrawal. We conclude that a clinically important, mild, but distinct withdrawal syndrome occurs after discontinuation of long-term therapeutic use of benzodiazepines.

Ethnic variation in CYP2A6 and association of genetically slow nicotine metabolism and smoking in adult Caucasians.

Genetically variable CYP2A6 is the primary enzyme that inactivates nicotine to cotinine. Our objective was to investigate allele frequencies among five ethnic groups and to investigate the relationship between genetically slow nicotine metabolic inactivation and smoking status, cigarette consumption, age of first smoking and duration of smoking. Chinese, Japanese, Canadian Native Indian, African-North American and Caucasian DNA samples were assessed for CYP2A6 allelic frequencies (CYP2A6*1B-*12,*1x2). Adult Caucasian non-smokers (n = 224) (1-99 cigarettes/lifetime) and smokers (n = 375) (> or = 100 cigarettes/lifetime) were assessed for demographics, tobacco/drug use history and DSM-IV dependence and genotyped for CYP2A6 alleles associated with decreased nicotine metabolism (CYP2A6*2, CYP2A6*4, CYP2A6*9, CYP2A6*12). CYP2A6 allele frequencies varied substantially among the ethnic groups. The proportion of Caucasian slow nicotine inactivators was significantly lower in current, DSM-IV dependent smokers compared to non-smokers [7.0% and 12.5%, respectively, P = 0.03, odds ratio (OR) = 0.52; 95% confidence interval (CI) 0.29-0.95]; non-dependent smokers showed similar results. Daily cigarette consumption (cigarettes/day) was significantly (P = 0.003) lower for slow (21.3; 95% CI 17.4-25.2) compared to normal inactivators (28.2; 95% CI 26.4-29.9); this was observed only in DSM-IV dependent smokers. Slow inactivators had a significantly (P = 0.03) lower age of first smoking compared to normal inactivators (13.0 years of age; 95% CI 12.1-14.0 versus 14.2; 95% CI 13.8-14.6), and a trend towards smoking for a shorter duration. This study demonstrates that slow nicotine inactivators are less likely to be adult smokers (dependent or non-dependent). Slow inactivators also smoked fewer cigarettes per day and had an earlier age of first smoking (only dependent smokers).

Inhibition by fluoxetine of cytochrome P450 2D6 activity

Potent inhibition of cytochrome P450 2D6 (CYP2D6) in human liver microsomes by fluoxetine and its major metabolite norfluoxetine was confirmed (apparent inhibition constant values, 0.2 μmol/L). Several other serotonergic agents were also found to be competitive inhibitors of this genetically polymorphic enzyme. The O‐demethylation ratio of dextromethorphan that expressed CYP2D6 activity in 19 patients receiving fluoxetine fell in the region of the antimode separating the O‐demethylation ratio values observed in 208 extensive metabolizers from 15 poor metabolizers of a control group of healthy subjects. Inhibition of CYP2D6 activity in patients undergoing treatment with fluoxetine or other serotonin uptake inhibitors could contribute to toxicity or attenuated response from concurrent medications that are substrates of this enzyme. Other in vitro studies indicated that CYP2D6 catalyzes the O‐demethylation of oxycodone to form oxymorphone. This reaction was inhibited by fluoxetine and its normetabolite in liver microsomes from both extensive and poor metabolizer individuals, indicating that these compounds are not selective inhibitors of CYP2D6 activity.

Measurement issues in postpartum depression part 1: Anxiety as a feature of postpartum depression

SummaryWe investigated the contribution of anxiety symptoms to scores on the Edinburgh Postnatal Depression Scale (EPDS) between 36 weeks gestation and 16 weeks postpartum in 150 women. The 3-item anxiety subscale of the EPDS accounted for 47% of the total score in late pregnancy, and 38% of the total score in the postpartum period. Two categories of anxiety were common in the perinatal period: subsyndromal, situational anxiety (in particular during the last weeks of pregnancy); and clinically significant comorbid anxiety, which was experienced by nearly 50% of clinically depressed pregnant and postpartum women. The close relationship between anxiety and depression raises questions about whether symptoms of anxiety might be more common in the perinatal period than in other depressions. A strong role for anxiety symptoms in postpartum depression, and implications for its etiology and treatment, are discussed.

The serotonin uptake inhibitor citalopram attenuates ethanol intake

No effective drug for decreasing ethanol intake is available for clinical use. Our previous studies showed that zimeldine decreased ethanol intake in rats and nondepressed alcohol abusers. However, zimeldine was withdrawn from the market because of serious toxicity. We tested citalopram, a selective serotonin uptake inhibitor, in 39 male nondepressed early‐stage problem drinkers (aged 19 to 61 years). Subjects were randomly allocated to receive either citalopram, 20 (n = 20) or 40 (n = 19) mg/day orally, or placebo in a double‐blind, crossover trial. Citalopram administration and ethanol intake were assessed by self‐report and objectively. Citalopram, 20 mg/day, did not show an effect. However, citalopram, 40 mg/day, decreased the number of drinks consumed (F1,17 = 5.27; P < 0.05) and increased the number of abstinent days (F1,17 = 13.18; P < 0.005). The effect is probably through modulation of the neurobiologic mechanisms regulating ethanol intake. Our results suggest a new pharmacologic approach to decrease ethanol intake.