Medical learning curves and the Kantian ideal.

A hitherto unexamined problem for the "Kantian ideal" that one should always treat patients as ends in themselves, and never only as a means to other ends, is explored in this paper. The problem consists of a prima facie conflict between this Kantian ideal and the reality of medical practice. This conflict arises because, at least presently, medical practitioners can only acquire certain skills and abilities by practising on live, human patients, and given the inevitability and ubiquity of learning curves, this learning requires some patients to be treated only as a means to this end. A number of ways of attempting to establish the compatibility of the Kantian Ideal with the reality of medical practice are considered. Each attempt is found to be unsuccessful. Accordingly, until a way is found to reconcile them, we conclude that the Kantian ideal is inconsistent with the reality of medical practice.

Effect of ketoprofen on blood pressure, endocrine and renal responses to chronic dosing with captopril in patients with essential hypertension.

The effects of non-steroidal anti-inflammatory drugs (NSAIDs) on the blood pressure and renal function of essential hypertensive patients depend on the specific type of NSAID and antihypertensive drug administered. Twelve patients with essential hypertension, aged 35 to 59 years, stabilized (blood pressure less than 140/90 mmHg) with captopril, received ketoprofen (100 mg bid for 7 days) or matching placebo in a randomized double-blind cross-over fashion. A 3-week wash-out period was included between treatment periods. Blood pressure on the first and last days of the placebo treatment period (137 +/- 7 (SD)/80 +/- 8 and 139 +/- 11/81 +/- 9 mmHg) was similar to respective values during ketoprofen therapy (136 +/- 10/79 +/- 7 and 143 +/- 10/81 +/- 9 mmHg). The mean differences in systolic and diastolic blood pressures, at the end of the treatment periods, between ketoprofen and placebo were 4 (95% confidence intervals -5, +13) and 0 (-8, +8) mmHg, respectively. Ketoprofen had no effect on 24-h urinary sodium excretion (160 +/- 33 and 147 +/- 39 mmol/24 h for ketoprofen and placebo, respectively). Ketoprofen was without effect on glomerular filtration rate, renal plasma flow and filtration fraction. In conclusion, our data suggest that ketoprofen is a safe choice when short-term treatment with a NSAID is indicated in an essential hypertensive patient treated with a converting enzyme inhibitor such as captopril.

Zopiclone versus flurazepam in insomnia: prolonged administration and withdrawal.

Zopiclone (7.5 mg), a cyclopyrrolone derivative with a 6.5 h half-life, and flurazepam (30 mg) were compared to placebo in a randomized double-blind study involving 36 adult patients suffering from insomnia. All previous psychotropic drugs were discontinued 1 week prior to the study. During 4 weeks, 12 patients received zopiclone, 12 flurazepam and the others placebo. Thereafter, all patients received single-blind placebo for 3 nights. Rapidity of sleep onset, sleep duration, frequency of nocturnal awakenings, psychomotor coordination and side-effects were assessed daily with a questionnaire and a symptom checklist. The results of the study suggest that zopiclone 7.5 mg was at least as potent as flurazepam 30 mg in inducing and maintaining sleep. Both drugs maintained their efficacy during the 4 weeks of treatment. However, the two drugs differed in that flurazepam impaired psychomotor coordination whereas zopiclone did not demonstrate daytime protracted effects on psychomotor performance. Upon discontinuation of drug treatment, score values of the different sleep parameters under study returned to the baseline values. Side-effects were mild and consistent with earlier studies.

Zopiclone and triazolam in insomnia associated with generalized anxiety disorder: a placebo-controlled evaluation of efficacy and daytime anxiety.

In a double-blind placebo-controlled study, following a 1 week washout, 75 outpatients suffering from generalized anxiety disorder with severe insomnia as the target symptom were randomly assigned to 4 weeks of treatment with zopiclone 7.5 mg, triazolam 0.5 mg or placebo at bedtime. Zopiclone was significantly better than placebo on most sleep parameters. Triazolam tended to be superior to placebo, but its superiority was significant only on the sleep induction factor. Triazolam-treated patients presented significantly more day-time-interdose anxiety than zopiclone as assessed by the weekly HARS and Clinical Global Assessment of Anxiety. Although daytime-interdose anxiety was observed with both drugs, this treatment emergent symptom was more frequent and severe with triazolam. Side-effects were of a mild to moderate intensity for both zopiclone and triazolam; however, taste perversion frequently appeared with zopiclone. Although both drugs share similar pharmacological properties and bind to benzodiazepine receptors, they differ significantly with respect to side-effects and daytime anxiety.

A dose-range finding study of zopiclone in insomniac patients.

Sixty insomniac patients participated in a controlled double-blind parallel group study designed to investigate the dose-response relationship of zopiclone. Following 1 day of treatment with placebo, patients were randomly assigned to 1 of 6 groups and received treatment for 7 days with either placebo, or flurazepam 30 mg, or zopiclone, 3.75 mg, 7.5 mg, 11.25 mg or 15 mg. Four patients were dropped from the study; two from the placebo group due to ineffectiveness and one each in zopiclone 11.25 mg and 15 mg groups due to side-effects. Flurazepam 30 mg significantly improved sleep induction and maintenance by comparison to placebo and was indistinguishable from zopiclone 7.5 mg or higher. Results of a self-administered sleep questionnaire found a predominantly linear relationship between the dose of zopiclone administered and the degree of sleep improvement. The greatest increment in improvement was generally obtained with 3.5 mg and 7.5 mg of zopiclone, with some additional benefit occurring with zopiclone 11.25 mg. Clinicians' global impressions showed that the severity of illness clearly decreased in a dose related manner up to zopiclone 11.25 mg. Although zopiclone was well tolerated at 3.75 mg and 7.5 mg, an increase in side-effects occurred at 11.25 mg and 15 mg, which favours the use of 7.5 mg zopiclone as the optimum dose for most patients, although certain patients may benefit from a higher dose of the drug when well tolerated.

Efficacy and safety of zopiclone and triazolam in the treatment of geriatric insomniacs.

Most studies with zopiclone, a cyclopyrrolone derivative with a short elimination half life (5 h) have compared its hypnotic activity with that of long elimination half life molecules. In this double-blind study in geriatric patients, drugs were administered during 3 weeks and the therapeutic effects of zopiclone at optimal dosage (5 or 7.5 mg) were compared to those of triazolam (0.125 or 0.25 mg). After a 3 day single-blind washout period, placebo responders were excluded and 48 patients were thereafter treated with either placebo (Tétreault et al., 1965), zopiclone or triazolam (Pegram et al., 1980). The initial dosage was increased when indicated at the end of the first week and kept constant thereafter. At the end of the third week of double-blind treatment, a 4 day single-blind placebo washout was performed to assess drug withdrawal effects. Results confirmed the safety and efficacy of both drugs over placebo during active administration. Hypnotic activity was maximal at 7.5 mg of zopiclone and 0.25 mg of triazolam. Drug efficacy was found constant over the 3 week administration both for triazolam and zopiclone. During withdrawal, no true rebound effect was demonstrated but the active drugs were significantly worse than placebo during the first day for sleep onset duration, sleep soundness and quality of sleep. With triazolam some effects persisted up to the third day of withdrawal.

Long term efficacy and withdrawal of zopiclone: a sleep laboratory study.

The purpose of this study was to evaluate the short, intermediate, and long-term (8 weeks) effectiveness, as well as the withdrawal effects of zopiclone 7.5 mg. Eleven chronic insomniacs participated in the study where both EEG sleep recordings and a subjective rating scale were used to evaluate drug effects. Zopiclone significantly decreased total wake time and nocturnal awakenings, and increased total sleep time and sleep efficiency. These effects were apparent from first treatment night and tolerance to the hypnotic effect did not develop over the 8 weeks of treatment. The subjective sleep questionnaire data showed significantly decreased sleep latency time but otherwise were consistent with the sleep laboratory findings. Zopiclone decreased the percentage of Stage 1 sleep but did not significantly alter the percentage of Stage 2 sleep, slow wave sleep or REM sleep. The withdrawal of zopiclone was associated with a return of sleep variables towards pre-treatment baseline values. Although 2 patients dropped out, 1 with a marked rebound insomnia and daytime anxiety during the first week of withdrawal, the other because of side-effects and poor hypnotic efficiency, no evidence of rebound insomnia was seen on the sleep EEG or subjective questionnaire data in the study population.

Single and multiple dose pharmacokinetics of enteric coated ketoprofen: effect of cimetidine.

The effect of cimetidine on the single and multiple dose pharmacokinetics of enteric coated ketoprofen was studied in 12 healthy volunteers. Each subject completed two 8-day study treatment periods: either ketoprofen alone (100 mg p.o. twice daily), or co-administered with cimetidine (600 mg twice daily). tlag, Cmax, tmax, t1/2, and k for ketoprofen were not significantly different between single and multiple dose administration. AUC of ketoprofen was slightly but significantly larger following multiple (21.2 micrograms.h.ml-1) as compared to single dose administration (19.0 micrograms.h.ml-1). As a result, plasma clearance of ketoprofen was slightly but significantly reduced following multiple dose administration (80.6 ml/min vs 89.3 ml/min). Cimetidine had no effect on the single or multiple dose pharmacokinetics of enteric coated ketoprofen. Total 12-h urinary recovery of ketoprofen (mostly in the form of ketoprofen glucuronide) was 83.5% of the dose following single dose administration and was significantly greater following multiple dose administration (93.1%). Again cimetidine co-administration had no effect on the single and multiple dose urinary recovery. The results of this study show that cimetidine is not affecting the oral pharmacokinetics of enteric coated ketoprofen.

A comparative double-blind controlled study of trimipramine and amitriptyline in major depression: lack of correlation with 5-hydroxytryptamine reuptake blockade.

Thirty-four hospitalized patients with major depression were enrolled in a 3-week double-blind parallel comparative study of trimipramine and amitriptyline. Following a 1-week washout period, patients randomly received one of the two drugs up to 100 mg twice daily on a fixed increment dosage schedule. Both treatments produced a rapid significant clinical improvement that occurred in a predominantly linear fashion. The pattern of improvement was very similar with both drugs. There was no significant correlation between plasma levels of trimipramine and desmethyl-trimipramine and clinical improvement. A negative correlation between amitriptyline plasma levels and clinical improvement was found, whereas a positive correlation occurred with the nortriptyline levels. Amitriptyline, and to a lesser extent trimipramine, prolonged intracardiac conduction. In the amitriptyline group only, this effect was accompanied by significant increases of heart rate and blood pressure. Platelet serotonin content was decreased by 57% by the amitriptyline treatment but remained unchanged in the trimipramine group. This finding constitutes the first clinical evidence that trimipramine does not exert its antidepressant effect through 5-hydroxytryptamine reuptake blockade. It is proposed that neuronal sensitization to 5-hydroxytryptamine might mediate the therapeutic effect of tricyclic antidepressant drugs.

Double-blind comparison of ketoprofen and mefenamic acid in the treatment of primary dysmenorrhea.

Forty women with moderate to severe primary dysmenorrhea participated in a two-month, double-blind, crossover trial comparing ketoprofen with mefenamic acid. Treatment with ketoprofen provided rapid and marked pain relief similar to that afforded by mefenamic acid. This improvement in symptoms was accompanied by an amelioration of the disability score, which was equivalent for both drugs. There were no differences between the two treatments with respect to duration of menses or amount of menstrual flow. Patients rated both drugs as equally effective and had no preference for one treatment over the other. One patient dropped out because of a mild allergic reaction to ketoprofen. All other side effects were not severe, although slightly more gastrointestinal reactions were observed with ketoprofen. It is concluded that ketoprofen is as safe and effective as mefenamic acid in the treatment of primary dysmenorrhea.

Treatment of status epilepticus with intravenous clonazepam.

1. Intravenous clonazepam was investigated in an open trial conducted in 24 patients suffering from status epilepticus. 2. The administration of 1-2 mg clonazepam resulted in the complete control of 7/7 Petit Mal, 7/14 Grand Mal and 2/3 partial complex cases. 3. The mean time to obtain clinical control of seizures after injection was 1.75 min. In all successfully treated cases normalization or improvement of the post-ictal EEG tracing was observed. 4. Vital signs measured before and immediately after clonazepam injections showed no clinically significant changes in blood pressure, heart rate or respiration. Side effects consisted exclusively of transient mild to moderate drowsiness in 40% of patients. 5. These results indicate that intravenous clonazepam is rapidly effective and safe in the treatment of Petit Mal status and in certain cases of Grand Mal and partial complex status epilepticus. This agent therefore represents a useful alternative to diazepam in the treatment of status epilepticus.

Angiotensinase activity and angiotensin receptor binding in guinea pig aorta.

The angiotensinase (EC 3.4.99.3) activity of the subcellular fractions of guinea pig aorta has been studied in relation to their [14C]angiotensin binding capacity. The enzyme activity occurs in the following decreasing order: supernatant greater than plasma membrane fraction greater than 105 000 X g pellet greater than mitochondrial fraction. The specific binding of [14C]angiotensin to these fractions follows the same pattern. Pretreatment of the subcellular fractions at 47 degrees C for 20 min was performed in an attempt to differentiate binding of angiotensin to the pharmacological receptor from binding to the destroying enzymes. This procedure decreased the angiotensinase activity in the plasma membrane fraction only whereas the specific binding of [14C]angiotensin to this fraction was not significantly decreased, suggesting that the plasma membrane angiotensinase is a thermolabile enzyme.

Characterization of the angiotensin receptor in guinea-pig aorta.

The binding of 14C-angiotensin to the subcellular fractions of guinea-pig aorta was compared to the known physiological data as obtained from the intact preparation. Results show that only the plasma membrane fraction possesses binding characteristics consistent with the physiological data. Equilibrium of specific binding occurs at 10(-7) M 14C-angiotensin which is the physiological maximal dose. This equilibrium is achieved after 3 minutes of incubation, the time required to develop maximal response. 8-Leu-angiotensin, a specific competitive antagonist of angiotensin, blocks the binding of 14C-angiotensin in a manner similar to nonradioactive angiotensin. Neither bradykinin nor angiotensin I has a significant effect on the binding of 14C-angiotensin to plasma membranes. The dissociation constant (Ka) as calculated from the 50% inhibition of the specific binding is 2.2 X 10(-8) M. This value corresponds to the apparent Ka estimated from both the physiological dose-response curve (6.3 X 10(-8) M) and the reversibility of binding curve (4.7 X 10(-8) M). Specific binding of 14C-angiotensin is pH dependent with maximal binding occurring at pH 7.4. The rate of dissociation of 14C-angiotensin bound to plasma membranes is compatible with the recovery of the physiological response. These results indicate that the angiotensin receptor is located in the cell membrane.