Capillary gas chromatographic assay of camphor and m-cresol in dermatological creams

Camphor and m-cresol mixtures are used in antiseptic and anti-itching creams. No compendial method exists for these preparations. This paper reports a capillary gas chromatographic method using FID detection with 2,6-di-tert-butyl-4-methylphenol as internal standard on a 30 m×0.32 mm Supelcowax®-10 column (0.25 μm film) with helium as carrier gas. Ramped temperature programming was applied. The method allows simultaneous quantitation of camphor and m-cresol in the presence of o- and p-cresols, calamine and zinc oxide. Overall percent recoveries (±SD, n=9) of camphor, o-, p- and m-cresol from spiked placebo creams, at a labeled amount of 10 (w/w)% were 96.9±0.6, 98.2±0.6, 99.2±0.5 and 101.0±0.9%, respectively, and at a labeled amount of 1% were 96.7±0.6, 97.8±0.9, 97.8±0.6, and 100.3±1.0%, respectively. The recovery studies were carried out at ±30% of the labeled amounts. Linear peak area or height ratios were obtained (r>0.999) for camphor, o-, p- and m-cresol covering a concentration range of 10–200% of the labeled amount. Linearity (r>0.999) was also obtained for m-cresol when the relative concentration of o- and p-cresol was varied from 5 to 100% of the m-cresol concentration. The resolution between the ‘critical pair’ of p- and m-cresol was ≥1.1. The limit of quantitation was 23 pg for m-cresol and 9.3 pg for camphor using an injection split of 1:50. The repeatability (%RSD) for all compounds were <2% for peak area and <1.4% for peak height ratios. System suitability and robustness of the method were established. The method was successively applied to the assay of available commercial products and allows assay of camphor and the three cresol isomers.     

Drug related hospital admissions

Summary As part of a high-intensity monitoring study of drug events as the cause of admission to departments of internal medicine, the effect of an educational intervention programme was studied. Two departments were included, one specialising in geriatrics and one that received patients by non-selected referral. The series consisted of 607 consecutive admissions studied before and 703 after the intervention. The drug events considered were adverse drug reactions and dose-related therapeutic failures, mainly due to non-compliance.A modest, statistically non-significant decrease in drug related hospital admissions (DRH) was seen, from 14% before to 13% after the intervention period. However, DRHs classified as definitely avoidable showed the significant decrease of 83%.There was no apparent relationship between the topics selected for the intervention programme and changes in the pattern of DRHs. No relationship between alterations in sales data and hospital admissions caused by a given drug could be demonstrated. A blinded external evaluation of case abstracts did not disclose any significant shift in the investigators' assessments.The intervention may have had an non-specific effect on avoidable DRHs.     

A new and highly sensitive method for measuring 3-methoxytyramine using HPLC with electrochemical detection. Studies with drugs which alter dopamine metabolism in the brain

3-Methoxytyramine (3-MT) is a minor metabolite of dopamine which is suggested to reflect the turnover and utilization of dopamine. A novel, isocratic HPLC method has been developed which can be used to analyse 3-MT in homogenates of rat brain without the need for additional purification procedures. Furthermore, the coulometric electrochemical detection system is sensitive enough to measure 3 pg of 3-MT (equivalent to 0.6 ng/g tissue wet weight). 3-Methoxytyramine was measured in the striatum and n. accumbens after decapitation and rapid freezing, using 3-methoxy-4-hydroxybenzylamine as the internal standard. The effects of dopaminergic and other drugs on this metabolite were examined using this method. -Methyl-p-tyrosine (200 mg/kg i.v.) produced parallel linear decreases in dopamine and 3-MT in naive rats, but not those pretreated with tranylcypromine (5 mg/kg i.p.). Methamphetamine (0.3–10 mg/kg i.p.) and amphetamine (0.3–10 mg/kg i.p.) both dose-dependently increased 3-MT in naive and tranylcypromine-pretreated rats. In naive animals, 3-MT was not altered by intraperitoneal injection of the dopamine reuptake inhibitors, bupropion (10 mg/kg) and nomifensine (10 mg/kg) or by sibutramine HCl (3 mg/kg), amitriptyline (10 mg/kg), desipramine (10 mg/kg) and zimeldine (10 mg/kg). 3-Methoxy-tyramine was decreased by apomorphine (5 mg/kg i.p.) and also by large doses of the selective D₂ antagonist, BRL 34778 (5 mg/kg i.p.) or -DOPA (50 mg/kg i.p.). The selective D₁ antagonist, SCH 23390 (0.1 or 5 mg/kg i.p.) was without effect. In tranylcypromine-pretreated rats, 3-MT was dose-dependently reduced and increased by apomorphine (0.01–5 mg/kg i.p.) and BRL 34778 (0.1–5 mg/kg i.p.), respectively. The drug SCH 23390 (0.1–5 mg/kg i.p.) produced much smaller increases in 3-MT which were probably mediated through the striatonigral pathway. Overall, the data suggest that measurement of 3-MT, after inhibition of monoamine oxidase, is a useful index of the release and utilization of dopamine. However, after substantial and prolonged depletion of dopamine, levels of 3-MT in naive animals are a better index. Also, the formation of 3-MT in naive rats provides a sensitive method for distinguishing between dopamine releasing agents and reuptake inhibitors.     

THE EFFECT OF HYPERTENSIVE EPISODES AND CARDIAC HYPERTROPHY ON THE CANINE CARDIAC BAROREFLEX

1. Left ventricular (LV) hypertrophy has been implicated in the reduction of baroreflex sensitivity present in hypertension. The aim of the current study was to investigate the mean arterial pressure-heart rate reflex (MAP-HR) in a model which induced left ventricular hypertrophy but no sustained blood pressure elevation. 2. Five mongrel dogs were exposed to transient blood pressure elevation of between 20 and 30 mmHg, through hindlimb compression using a pneumatic pressure suit, for 7 h per day, 6 days per week for 6 weeks. Resting blood pressure was not altered by the 6 week hindlimb compression intervention. 3. Echocardiographically determined LV mass (mean ± s.e.m.) was 116.0 ± 7.4 g prior to hindlimb compression (baseline) and elevated to 125.4 ± 8.1 g (P= 0.003) after 6 weeks of compression. A reduction in the early (E) to late (A) transmitral diastolic flow ratio (E/A) from 1.80 ± 0.06 at baseline to 1.54 ± 0.09 (P = 0.037) after the 6 week intervention suggested that cardiac compliance was reduced. 4. The maximum gain of the MAP-HR reflex, studied using the ‘steady-state’ drug technique, when blood pressure was normal, showed a trend for reduction from 3.85 ± 0.43 beats/min per mmHg at baseline to 3.10 ± 0.45 beats/min per mmHg (P= 0.067) after 6 weeks of compression. This gain reduction became significant after β-adrenoceptor blockade with propranolol (3.13 ± 0.55 vs 2.32 ± 0.25 beats/min per mmHg; P= 0.039). Covariant analysis showed a significant inverse correlation between LV mass and maximum gain (r= 0.96; P<0.001) during the 6 week compression period. 5. The MAP-HR reflex changes in this model mimic those present in hypertension and implicate cardiac hypertrophy as one possible mediator.     

Adverse drug reactions: physicians' opinions versus a causality assessment method

Since spontaneous reporting of adverse drug reactions depends on the physician's opinion of the relationship between the drug and the adverse event, we compared physicians' opinions with the scores obtained by the causality assessment method used in France. During a 2 month period, all physicians who reported adverse drug reactions (ADRs) to our pharmacovigilance centre expressed their opinions on the causal link by means of visual analogue scales. ADR reports were then assessed with the French causality assessment method by a clinical pharmacologist who was blind to physicians' opinions.The assessment by both physicians and the standardized method was performed for 75 ADR cases involving 120 drugs. Physicians used a wide range of assessments, with a preponderance of extreme scores, resulting in a U-shaped distribution, while the standardized method gave generally low scores. Scores given by physicians were very high (causality considered very likely or likely) in 60% of cases and very low (causality considered unlikely or dubious/possible) in 32% of cases. Scores obtained using the causality assessment method were low (causality dubious/possible) in 89% of cases and causality considered likely in only 11 cases, essentially in cases with positive rechallenge. Complete agreement occurred in only 6% of cases. Adding complete agreement and minor discrepancies raised the percentage to 49%.     

十二烷氮酮氟尿嘧啶凝胶治疗疣及银屑病150例

443例(男225例,女218例;年龄36±14a)皮肤病患者,其中150例(扁平疣52例、寻常疣55例、银屑病43例)外用含1.8％十二烷氮(艹卓)酮的1％氟尿嘧啶(5-FU)凝胶作为治疗组,148例外用1％5-FU凝胶及145例外用2.5％5-FU霜作为2个对照组。经双盲对照临床试验,结果表明含1.8％十二烷氮(艹卓)酮的1％5-FU凝胶的疗效明显优于2个对照组(P<0.01及P<0.005)。证明氮(艹卓)酮对5-FU确有渗透促进作用。     

Dexfenfluramine in the treatment of severe obesity: a placebo-controlled investigation of the effects on weight loss, cardiovascular risk factors, food intake and eating behaviour.

Dexenfluramine, an effective and safe serotoninergic drug with anorectic and possible food-selection-tuning properties, was investigated in a placebo-controlled study of 1 year's duration in severe and refractory obesity. The aim of the study was to assess weight loss, and changes in cardiovascular risk factors, food intake and eating behaviour. Dexfenfluramine- and placebo-treated patients achieved a similar weight loss (greater than 10% of initial weight, by 39.5 and 30.0%, greater than 20% of initial overweight by 42.1% and 32.5% and greater than 10 kg by 41.4 and 33.3%, respectively, of the initial cohorts). Furthermore, the decreases in weight (10.7 vs. 8.0 kg), in body mass index (3.9 vs. 2.9 kg m2) and in waist/hip ratio (0.04 vs. 0.02) were not significantly different. After discontinuation of the drug, the increase in weight (2.8 vs. 1.0 kg) was significantly higher in the dexfenfluramine-treated group. Except for a borderline better effect on glucose of dexfenfluramine, both groups showed similar beneficial changes in food intake and cardiovascular risk factors. Eating behaviour in response to emotional and external stimuli was comparable in the two groups, but placebo-treated patients had to restrain their eating more in order to achieve the same weight loss. Notwithstanding the fact that weight losses and an associated amelioration of health-risk factors were of similar magnitude in dexfenfluramine- and placebo-treated patients, dexfenfluramine might have a useful role in promoting a less stressed adherence to prolonged restriction of energy intake in the severe and refractory obese subject.     

Improvement of Decreased Critical Flicker Frequency (CFF) in Headache Patients With Drug Abuse After Successful Withdrawal

A considerable proportion of headache patients fulfill the criteria of "drug abuse" (definition according to the International Headache Society [IHS] criteria). These patients exhibit markedly reduced vigilance and continuous performance, as shown by the results of critical flicker frequency (CFF) analysis.
The present study deals with the question whether this impairment of vigilance and continuous performance is reversible. Forty-eight headache patients with drug abuse were investigated three times by means of CFF analysis: immediately before (A), immediately after (B), and 3 weeks after having finished (C) inpatient drug withdrawal.
Immediately after withdrawal, a significant decrease of headache intensity was observed. The CFF values, however, remained unchanged at a depressed level, probably due to withdrawal medication and the initial sedative side effects of thymoleptic agents (given as prophylaxis).
Three weeks after withdrawal, however, the CFF values were significantly improved, and were now within a range not far from the normal values known from a healthy general population. Thus, even after many years of drug abuse, headache patients have a good chance to improve their vigilance and continuous performance and to reach normal or close to normal levels.