Plasma serotonin level after 1 day of fluoxetine treatment: a biological predictor for antidepressant response?

Rationale: Antidepressant treatments present a delayed onset of action. Objective: The present study investigated whether plasma or serum serotonin, 5-hydroxytryptamine (5-HT), could predict clinical improvement. Methods: Biological parameters were determined after a 4-week drug-free period (day 0) and 1, 14 and 28 days after the beginning of the treatment with fluoxetine 20 mg daily in depressed patients. Clinical evaluations were assessed on days 0, 14 and 28. Results: One day after a single dose, the mean values of plasma 5-HT (5.4 ± 2.6 nmol/l) and serum 5-HT (484 ± 215 nmol/l) were not statistically different from basal mean values (4.5 ± 2.5 nmol/l and 523 ± 263 nmol/l, respectively). The repeated treatment significantly reduced serum 5-HT to 34% (P = 0.002) and 17% (P = 0.0004) of pretreatment values after 14 and 28 days of treatment, respectively; plasma 5-HT was also reduced significantly to 28% and 15% of pretreatment values (P < 0.05 in both cases). At day 28, four of the eight patients responded by showing a reduction in MADRS score of at least 50% of the baseline score. No correlation was found between pretreatment values of serum or plasma 5-HT and clinical evolution, even if a tendency (P < 0.07) to lower serum 5-HT pretreatment values was observed in responders. Plasma 5-HT after 1 day of treatment was significantly different between responders and non-responders: the plasma 5-HT concentration in responders was 3.4 ± 1.7 nmol/l versus 7.4 ± 1.6 nmol/l in non-responders (P = 0.02). Moreover, plasma 5-HT levels after 1 day of treatment were positively correlated to the final MADRS score (r = +0.89, n = 8, P = 0.003) and inversely correlated to its change from the initial score (r = −0.76, n = 8, P = 0.02). Conclusion: These preliminary data show that fluoxetine and norfluoxetine might influence 5-HT peripheral venous blood parameters and that plasma 5-HT after 1 day of treatment might be a biological predictor for antidepressant response. Received: 10 July 1998/Final version: 12 October 1998     

Induction of the metabolism of etizolam by carbamazepine in humans

Objective To examine the effect of carbamazepine on the single oral dose pharmacokinetics of etizolam.Methods Eleven healthy male volunteers received carbamazepine 200 mg/day or placebo for 6 days in a double-blind, randomized, crossover manner, and on the sixth day they received a single oral 1-mg dose of etizolam. Blood samplings and evaluation of psychomotor function by the Digit Symbol Substitution Test and Stanford Sleepiness Scale were conducted up to 24 h after etizolam dosing. Plasma concentration of etizolam was measured using high-performance liquid chromatography.Results Carbamazepine treatment significantly decreased the peak plasma concentration (17.5±4.1 ng/ml versus 13.9±4.1 ng/ml; P<0.05), total area under the plasma concentration–time curve (194.8±88.9 ng h/ml versus 105.9±33.0 ng h/ml; P<0.001), and elimination half-life (11.1±4.6 h versus 6.8±2.8 h; P<0.01) of etizolam. No significant change was induced by carbamazepine in the two pharmacodynamic parameters.Conclusions The present study suggests that carbamazepine induces the metabolism of etizolam.     

Drug monitoring of imatinib levels in patients undergoing therapy for chronic myeloid leukaemia: comparing plasma levels of responders and non-responders

Purpose  Imatinib mesylate is used as first line therapy in the treatment of chronic myeloid leukaemia. This study was designed to study the correlation of plasma levels of imatinib with response to the therapy. Methods  A total of 40 chronic myeloid leukaemia patients in the chronic phase of the disease were recruited and placed into two groups of 20 patients: imatinib responders and imatinib non-responders, respectively. Each blood sample was taken 24 h after and immediately prior to taking a 400 mg oral dose of imatinib. Drug levels were detected by high-performance liquid chromatography. Results  The mean plasma imatinib levels in the imatinib non-responders were significantly lower than those in the imatinib responders (0.70 vs. 2.34 μM, respectively; p = 0.002). Conclusions  Plasma levels of imatinib were correlated with response to the therapy, so routine monitoring of the therapeutic levels of the drug should be carried out specifically in treatment-resistant cases for determining dose escalation.     

Relationship between plasma concentrations of clozapine and norclozapine and therapeutic response in patients with schizophrenia resistant to conventional neuroleptics

Rationale: Monitoring plasma clozapine concentrations may play a useful role in the management of patients with schizophrenia, but information on the relationship between the plasma levels of the drug and response is still controversial. Objective: The purpose of this study was to assess the relationship between plasma concentrations of clozapine and its weakly active metabolite norclozapine and clinical response in patients with schizophrenia resistant to conventional neuroleptics. Methods: Forty-five patients, 35 males and ten females, aged 19–65 years, were given clozapine at a dosage up to 500 mg/day for 12 weeks. Steady-state plasma concentrations of clozapine and norclozapine were measured at week 12 by a specific HPLC assay. Psychopathological state was assessed at baseline and at week 12 by using the Brief Psychiatric Rating Scale, and patients were considered responders if they showed a greater than 20% reduction in total BPRS score compared with baseline and a final BPRS score of 35 or less. Results: Mean plasma clozapine concentrations were higher in responders (n=18) than in non-responders (n=27) (472±220 versus 328±128 ng/ml, P<0.01), whereas plasma norclozapine levels did not differ between the two groups (201±104 versus 156±64 ng/ml, NS). A significant positive correlation between plasma levels and percent decrease in total BPRS score was found for clozapine (r _s=0.371, P<0.02), but not for norclozapine (r _s=0.162, NS). A cutoff value at a clozapine concentration of about 350 ng/ml differentiated responders from non-responders with a sensitivity of 72% and a specificity of 70%. At a cutoff of 400 ng/ml, sensitivity was 67% and specificity 78%. The incidence of side effects was twice as high at clozapine concentrations above 350 ng/ml compared with lower concentrations (38% versus 17%). Conclusions: These results suggest that plasma clozapine levels are correlated with clinical effects, although there is considerable variability in the response achieved at any given drug concentration. Because many patients respond well at plasma clozapine concentrations in a low range, aiming initially at plasma clozapine concentrations of 350 ng/ml or greater would require in some patients use of unrealistically high dosages and imply an excessive risk of side effects. Increasing dosage to achieve plasma levels above 350–400 ng/ml may be especially indicated in patients without side effects who failed to exhibit amelioration of psychopathology at standard dosages or at lower drug concentrations. Received: 5 May 1999 / Final version: 30 August 1999     

Higher levels of HIV DNA in memory and naive CD4 T cell subsets of viremic compared to non-viremic patients after 18 and 24 months of HAART

The degree of infection of memory and naive CD4⁺ T cells in patients treated with HAART and with durable undetectable or detectable viral load in plasma was evaluated. The following two groups of patients were analyzed cross-sectionally: (i) patients with undetectable HIV RNA plasma levels during follow-up (responders); (ii) patients with no reduction or with rebound in HIV RNA levels during treatment (non-responders). Patients were examined following 6, 12, 18 and 24 months of HAART, respectively, by quantifying: (i) plasma HIV RNA load; (ii) CD4⁺ T cells; (iii) memory and naive CD4⁺ T cells; (iv) HIV DNA levels in memory and naive CD4⁺ T cells. HIV RNA plasma levels were significantly higher in non-responders vs responders at each time point (P<0.02), while CD4⁺ T cell counts as well as memory and naive CD4⁺ T cell levels were comparable in both viremic and non-viremic patients. However, higher HIV DNA values were observed in both memory and naive CD4⁺ T cells of non-responders vs responders after 18 and 24 months of HAART (P<0.02), suggesting an increased amount of HIV-infected naive CD4⁺ T cells and a sustained high degree of infection of memory CD4⁺ T cells. Immunological reconstitution following HAART might potentially be hampered in viremic patients despite the absolute increase in CD4⁺ T cell counts.     

Migraine prophylaxis with botulinum toxin A is associated with perception of headache

The purpose of this study was to test whether the efficacy of prophylactic treatment with botulinum toxin A (BTX-A) on migraine frequency is related to the individual perception of the pain and its directionality, namely, exploding, imploding, or ocular migraine headache. Episodic and chronic migraine patients (n = 82) previously treated with BTX-A were interviewed to characterize their migraine headache and its directionality. The magnitude of their response to treatment was analyzed vis-à-vis their individual type of headache. Patients showing a >67% drop in number of migraine days/month were classified as responders; those showing a drop smaller than 33% were labeled non-responders; patients showing a drop between 34% and 66% were considered questionable responders. After BTX-A treatment, the number of migraine days/month dropped 85.2 ± 1.6% (from 20.1 ± 1.5 to 2.8 ± 0.4; p < 0.0001) in 37 responders, 52.4 ± 2.4% (from 16.3 ± 3.5 to 7.2 ± 1.5; p = 0.003) in 11 questionable responders, and remained unchanged (21.2 ± 1.8 vs. 21.1 ± 1.7; p > 0.78) in 34 non-responders. The frequency of headache types differed significantly (p < 0.0001) across the 3 response sub-groups. Among non-responders, 83% described a buildup of pressure inside their head (exploding headache). Among responders and questionable responders, 84 and 64%, respectively, perceived their head to be crushed, clamped or stubbed by external forces (imploding headache) or an eye-popping pain (ocular headache). The prevalence of exploding, imploding, and ocular headache was similar between episodic and chronic migraine patients. Imploding/ocular migraine headache is more likely than exploding headache to be prevented by prophylactic BTX-A treatment. Further validation of this principle should await large-scale prospective, placebo-controlled studies.     

Subcellular/tissue distribution and responses to oil exposure of the cytochrome P450-dependent monooxygenase system and glutathione S-transferase in freshwater prawns (Macrobrachium malcolmsonii, M. lamarrei lamarrei)

Subcellular fractions (mitochondrial, cytosolic and microsomal) prepared from the tissues (hepatopancreas, muscle and gill) of freshwater prawns Macrobrachium malcolmsonii and Macrobrachium lamarrei lamarrei were scrutinized to investigate the presence of mixed function oxygenase (MFO) and conjugating enzymes (glutathione-S-transferase, GST). Cytochrome P450 (CYP) and other components (cytochrome b₅; NADPH-cytochrome c (CYP) reductase and NADH-cytochrome c-reductase activities) of the MFO system were predominantly present in the hepatic microsomal fraction of M. malcolmsonii and M. lamarrei lamarrei. The results are in agreement with the notion that monooxygenase system is mainly membrane bound in the endoplasmic reticulum, and that the hepatopancreas is the major metabolic tissue for production of biotransformation enzymes in crustaceans. Further, the prawns were exposed to two sublethal (0.9 ppt (parts per thousand) and 2.3 ppt) concentrations of oil effluent. At the end of 30th day, hydrocarbons and detoxifying enzymes were analysed in the hepatopancreas. The accumulations of hydrocarbon in the tissues gradually increased when exposed to sublethal concentrations of oil effluent and were associated with significantly enhanced levels of cytochrome P450 (180.6±6.34 pmol mg⁻¹ protein (P<0.05 versus control, 136.5±7.1 pmol mg⁻¹ protein) for 2.3 ppt and 305.6±8.5 pmol mg⁻¹ protein (P<0.001 versus control, 132.3±6.8 pmol mg⁻¹ protein] for 0.9 ppt of oil exposed M. malcolmsonii; 150±6.5 pmol mg⁻¹ protein (P<0.01 versus control, 84.6±5.2 pmol mg⁻¹ protein) for 2.3 ppt and 175±5.5 pmol mg⁻¹ protein (P<0.01 versus control, 87.6±5.4 pmol mg⁻¹ protein) for 0.9 ppt of oil exposed M. lamarrei lamarrei), NADPH cytochrome c-reductase activity (14.7±0.6 nmol min⁻¹ mg⁻¹ protein (P<0.05 versus control, 6.8±0.55 nmol min⁻¹ mg⁻¹ protein) for 2.3 ppt and 12.1±0.45 nmol min⁻¹ mg⁻¹ protein (P<0.01 versus control, 6.9±0.42 nmol min⁻¹ mg⁻¹ protein) for 0.9 ppt of oil exposed M. malcolmsonii; 12.5±0.31 nmol min⁻¹ mg⁻¹ protein (P<0.001 versus control, 4.6±0.45 nmol min⁻¹ mg⁻¹ protein) for 2.3 ppt and 9.6±0.32 nmol min⁻¹ mg⁻¹ protein (P<0.01 versus control, 4.9±0.41 nmol min⁻¹ mg⁻¹ protein) for 0.9 ppt of oil exposed M. lamarrei lamarrei) and cytochrome b₅ (124.8±3.73 pmol mg⁻¹ protein (P<0.01 versus control, 76.8±4.2 pmol mg⁻¹ protein) for 2.3 ppt and 115.3±3.86 pmol mg⁻¹ protein (P<0.01 versus control, 76.4±4.25 pmol mg⁻¹ protein) for 0.9 ppt of oil exposed M. malcolmsonii and 110±3.11 pmol mg⁻¹ protein (P<0.01 versus control, 63.7±3.24 pmol mg⁻¹ protein) for 2.3 ppt and 95.3±2.63 pmol mg⁻¹ protein (P<0.01 versus control, 61.4±2.82 pmol mg⁻¹ protein) for 0.9 ppt of oil exposed M. lamarrei lamarrei). The enhanced levels of biotransformation enzymes in oil-exposed prawns demonstrate a well-established detoxifying mechanism in crustaceans, and the response offers the possibility of use as a biomarker for the early detection of oil pollution.Special Issue on Biomarkers of Marine Pollution and Bioremediation     

Induction of microsomal enzyme activity by flupenthixol in chronic schizophrenics

The effect of long-term treatment with flupenthixol on hepatic microsomal enzyme activity was studied in 12 chronic schizophrenic outpatients who had been receiving two weekly maintenance doses for at least 6 months. Antipyrine half-life was measured in the 12 patients while they continued to receive the drug. Flupenthixol was then discontinued for 6 weeks and antipyrine half-life was repeated in 7 of the 12 patients. In the 12 patients the plasma antipyrine elimination half-life was 4–24 h (mean 9.73±1.61 h) when receiving flupenthixol and there was a significant negative correlation between antipyrine half-life and the dose of flupenthixol (r=0.582, P<0.05). In the seven patients to whom antipyrine was given on two occasions, antipyrine half-life was 7.33±1.07 h and 12.04±1.87 h on and off flupenthixol treatment respectively. The clearance significantly decreased when flupenthixol was discontinued, but there was no change in the apparent volume of distribution.     

A comparative study of the effects of aspirin and paracetamol (acetaminophen) on platelet aggregation and bleeding time

Summary In a double blind, randomised trial, the effects of 1 g aspirin and 1 g paracetamol were compared on bleeding time and platelet aggregation in 40 volunteers (20 females). Also investigated was the relationship between plasma aspirin esterase activity and both bleeding time and platelet aggregation after aspirin. Following 1 g aspirin there was a significant increase in bleeding time at 24 h (p<0.01). A significant reduction (P<0.01) in platelet aggregation with collagen was observed at 1, 6 and 24 h after aspirin, but no significant reduction (P>0.05) was observed with ADP. Paracetamol had no effect on bleeding time or platelet aggregation. Plasma aspirin esterase activity ranged from 0.26–0.6 µmol/ml/min. A significant negative correlation (R=–0.55, P<0.001) was observed between percentage increase in bleeding time (24 h) and plasma aspirin esterase activity. Further significant correlations were observed between plasma aspirin esterase activity and change in platelet aggregation with collagen at 1 h (R=0.68, P<0.001), 6 h (R=–0.73, P<0.001) and 24 h (R=–0.67, P<0.001). These results suggest that it might be possible to predict an individual's haemostatic response to aspirin from knowledge of their plasma aspirin esterase activity.     

Onset and time course of antidepressant action: psychopharmacological implications of a controlled trial of electroconvulsive therapy

Onset and time course of antidepressant effect were examined in 47 patients with major depressive disorder who had been randomly assigned to twice weekly bilateral, brief pulse electroconvulsive therapy plus one simulated treatment per week (ECT×2) or to a three times weekly schedule of administration (ECT×3). Rapid improvement was observed in the ECT×3 group in whom the number of real ECTs to 30% reduction on the Hamilton Depression Scale (HAM-D) was 3.2±1.90, administered over 7.3±4.43 days and to 60% reduction, 5.9±3.09 real ECTs over 13.7±7.21 days. Among the responders in both groups combined, 24.3±29.58% of the overall improvement in HAM-D was contributed by the first real ECT, 60.9±28.13% by the first four real ECTs and 91.6±25.82% by the first eight. Although 85.3% of the responders had reached 60% HAM-D improvement after eight ECTs, a clinically significant minority (14.7%) responded later in the course (ECT 9–12). However, response was predictable on the basis of symptomatic improvement (30% on the HAM-D) by the sixth real ECT. Thirty-three out of 34 responders would have been correctly identified by this criterion and only 2 out of 13 non-responders mis-identified (P<0.000001). Once achieved, the antidepressant effect was stable, without continuation pharmacotherapy, until 1 week after the last treatment and on lithium carbonate (Li) or Li plus clomipramine for a further 3 weeks. These findings confirm the clinical impression that ECT is a rapidly effective treatment for major depression with a shorter latency than generally reported for antidepressant drugs. Elucidation of its neurobiological mechanisms could contribute to the development of pharmacological agents with a similar profile.     

Intravenous sodium lactate decreases plasma GABA levels in man

Gamma aminobutyric acid (GABA), an inhibitory neurotransmitter, may play an important role in anxiety. We studied changes in plasma GABA levels in nine healthy subjects before and after infusions of sodium lactate and dextrose. Plasma GABA significantly decreased during infusions of sodium lactate (109.3±4.4 versus 91.6±5.1 pmol/ml;P=0.0001) but not during infusions of dextrose.     

Acute effects of a new vasodilator,Ro 12-4713, on blood pressure,plasma renin activity,aldosterone and catecholamine levels,and renal function in hypertensive and normal subjects

Summary Selected cardiovascular and endocrine effects of the new oral vasodilator Ro 12-4713 have been evaluated in an acute single dose study. In five patients with essential hypertension, Ro 12-4713 caused a dose-dependent decrease in supine and upright blood pressure and an increase in heart rate. Initial effects occurred one to 2 h after drug ingestion and maximal effects were noted after five hours and persisted for at least 8 h. Blood pressure was normalized, and the antihypertensive and chronotropic effects persisted for 24 h after a dose of about 300 mg/1.73 m². Plasma and urinary norepinephrine and plasma renin levels tended to be raised, whereas plasma and urinary epinephrine and plasma aldosterone did not change. Changes in supine heart rate were inversely correlated with changes in mean blood pressure (r=–0.60; P<0.02), and positively with those in plasma norepinephrine (r=0.55; P<0.05) and renin (r=0.62, P<0.01); changes in supine plasma renin level were also inversely correlated with those in mean blood pressure (r=–0.65; P<0.01), and positively with those in plasma norepinephrine (r=0.58; P<0.05). 24 h-urinary sodium excretion was significantly (P<0.001) decreased; it was positively correlated with mean blood pressure (r=0.51; P<0.05) and inversely with supine plasma renin activity (r=–0.63; P<0.01). In six normal subjects and six patients with essential hypertension, effective renal plasma flow and the renal clearance of sodium, potassium, calcium and uric acid were not significantly altered five hours after a dose of Ro 12-4713 of about 250 mg/1.73 m²; glomerular filtration rate tended to be slightly decreased, and filtration fraction was significantly (P<0.05) reduced in the hypertensive patients. At the same time blood pressure was decreased and plasma norepinephrine (P<0.01) and renin (ns) were slightly increased in both groups. Ro 12-4713 in a single oral dose of about 300 mg appeared to be a potent, long acting, hypotensive vasodilator.     

Maleate induced fall of glomerular filtration rate

Summary Maleate causes an enhanced excretion of amino acids, glucose, phosphate and bicarbonate. In addition to this inhibition of fluid and electrolyte reabsorption malate decreases glomerular filtration rate (GFR). The present investigation was designed to study the mechanisms of this fall in GFR.In group I (Sprague-Dawley rats;N=8) maleate (2 mmol/kg body weight i.v.) increased the hydrostatic pressure in proximal tubule from 12.6±0.5 to 16.3±0.8 mm Hg (mean+SEM) and stop flow pressure in the first accessible loop of the proximal tubule was unchanged (33.6±0.4 vs 33.1±1.3 mm Hg; n.s.). Directly measured hydrostatic pressure in the glomerular capillaries in Munich-Wistar rats (N=7), however, was reduced by maleate from 47.6±1.6 to 42.4±1.9 mm Hg. In group II (N=8) we determined single nephron filtration rate (SNGFR) from distal and proximal collection sites in the same nephron in a paired fashion under control conditions and after maleate administration to assess the activity of the tubuloglomerular feedback. In the control periods SNGFR (16 nephrons) from distal collection sites was 26.3±1.6 nl/min whereas SNGFR from proximal collection sites was 31.8±2.4 nl/min. Following maleate distal SNGFR (17 nephrons) was 15.2±1.7 nl/min and proximal SNGFR was 24.3±2.2 nl/min. The ratio distal/proximal SNGFR was 1.23±0.07 under control conditions and increased to 1.76±0.1 following maleate indicating enhanced activity of tubuloglomerular feedback.Following maleate (group III;N=8) the chloride concentration in the late proximal tubular fluid fell from 135±4 mmol/l to 121±6 mmol/l (13 tubules), however, in the early distal tubule we found an increase in chloride concentration from 43±3 mmol/l to 62±6 mmol/l (12 tubules). Delivery of chloride to the loop of Henle was 2,107±221 pmol/min in the control periods and decreased to 1,475±200 pmol/min during maleate. Since early distal chloride delivery increased from 199±24 pmol/min to 364±47 pmol/min following maleate inhibition of chloride reabsorption in the loop of Henle has to be assumed. We conclude that maleate decreases glomerular filtration rate first by an elevation of hydrostatic pressure in the proximal tubule which is the result of inhibition of fluid and electrolyte reabsorption, and second by activation of the tubuloglomerular feedback.     

Renal action of adenosine: Effect on renin secretion in the rat

Summary The present study was undertaken to further evaluate the interaction of adenosine and the renin angiotensin system. In 12 sodium-restricted (SR) Sprague-Dawley rats plasma renin activity in the arterial carotid (PRA_a) and the renal venous (PRA_v) blood was measured using a radioimmunoassay for angiotensin I (AI). Renin secretion rate (RS) was calculated from the arteriovenous difference of PRA and renal plasma flow obtained from the reading of an electromagnetic flowmeter and hematocrit. Adenosine infused into the thoracic aorta at a rate of 33 nmol/min·100g body weight, decreased RS from 250±29 ng AI/min in the control periods to 115±17 ng AI/min (P<0.001, n=9). After cessation of the adenosine infusion RS recovered incompletely to 167±21 ng/AI/min. Adenosine reduced glomerular filtration rate (GFR) by 56% (P<0.001) but renal blood flow (RBF) by only 20%. The effects of adenosine were also studied in a group of sodium loaded (SL) rats. In 6 non-laparotomized SL rats (PRA_a=16±5 ng AI/ml·h) GFR was not significantly changed following adenosine infusion (1.54±0.16 vs 1.42±0.09 ml/min). In additional 7 SL rats (PRA_a=39±4 ng AI/ml·h) in which RBF was measured with an electromagnetic flow probe, adenosine reduced GFR by 20% (P<0.01), whereas RBF increased from 13.7±1.2 to 16.5±2.2 ml/min (P<0.05). RS in SL rats was not affected by adenosine infusion (59±16 vs 62±26 ng AI/min). There was a close correlation between the adenosine induced decrease of GFR and PRA_a (r=0.91, n=25) suggesting a higher sensitivity of the renal vasculature to adenosine when the renin-angiotensin system was stimulated. Micropuncture experiments in 9 Sprague-Dawley rats on a normal sodium diet demonstrated that adenosine infused in the low dose of 5 nmol/min·100 g of body weight markedly decreased the superficial nephron GFR from 38.6±2.65 to 20.5±1.67 nl/min (P<0.001) whereas whole kidney GFR was not changed significantly. This disproportionate response of superficial nephron compared to whole kidney GFR indicates that adenosine affects preferentially the superficial nephrons. It is concluded that adenosine depresses the renin secretion in SR rats. This depression was accompanied by a marked fall of the GFR. The renal response to adenosine was nearly abolished in SL rats suggesting that the renal action of adenosine is functionally related to the reninangiotensin system.Supported by Deutsche Forschungsgemeinschaft (Os 42/2)     

Influence of cimetidine on the pharmacokinetics of desmethyldiazepam and oxazepam

Summary The pharmacokinetics of single oral doses of desmethyldiazepam 20 mg or oxazepam 50 mg were studied in 5 healthy volunteers under controlled conditions, before and following a 24 h pretreatment with cimetidine 200 mg×5. Cimetidine significantly impaired (p=0.03) the elimination of desmethyldiazepam, as shown prolongation of its elimination half-life from 51.7±21.9 h to 72.6±39.4 h (mean ± SD), and a decrease in total plasma clearance from 12.0±2.7 ml/min to 8.6±3.3 ml/min. The disposition of oxazepam was not affected. From these results, and recently published data on diazepam and chlordiazepoxide, it is concluded that cimetidine impairs the hepatic elimination of those benzodiazepines which are metabolized by phase I reactions.     

Inhibition of the metabolism of etizolam by itraconazole in humans: evidence for the involvement of CYP3A4 in etizolam metabolism

Objective To clarify the involvement of cytochrome P₄₅₀ (CYP) 3A4 in the metabolism of etizolam.Methods The effects of itraconazole, a potent and specific inhibitor of CYP3A4, on the single oral dose pharmacokinetics and pharmacodynamics of etizolam were examined. Twelve healthy male volunteers received itraconazole (200 mg/day) or placebo for 7 days in a double-blind randomized crossover manner, and on the 6th day they received a single oral 1-mg dose of etizolam. Blood samplings and evaluation of psychomotor function using the Digit Symbol Substitution Test and Stanford Sleepiness Scale were conducted up to 24 h after etizolam dosing. Plasma concentration of etizolam was measured by means of high-performance liquid chromatography.Results Itraconazole treatment significantly increased the total area under the plasma concentration–time curve (AUC; 213±106 ngh/ml versus 326±166 ngh/ml, P<0.001) and the elimination half-life (12.0±5.4 h versus 17.3±7.4 h, P<0.01) of etizolam. The 90% confidence interval of the itraconazole/placebo ratio of the total AUC was 1.38–1.68, indicating a significant effect of itraconazole. No significant change was induced by itraconazole in the two pharmacodynamic parameters.Conclusion The present study suggests that itraconazole inhibits the metabolism of etizolam, providing evidence that CYP3A4 is at least partly involved in etizolam metabolism.     

Pharmacokinetic interaction of chloroquine and methylene blue combination against malaria

Objective The combination of chloroquine and methylene blue is potentially effective for the treatment of chloroquine-resistant malaria caused by Plasmodium falciparum. The aim of this study was to investigate whether methylene blue influences the pharmacokinetics of chloroquine.Methods In a randomized, placebo-controlled, parallel group design, a 3-day course of therapeutic oral doses of chloroquine (total 2.5 g in male, 1.875 g in female participants) with oral co-administration of placebo or 130 mg methylene blue twice daily for 3 days was administered to 24 healthy individuals. Chloroquine, desethylchloroquine, and methylene blue concentrations were determined by means of HPLC/UV or LC/MS/MS assays in whole blood, plasma, and urine for 28 days after the last dose.Results During methylene blue exposure, the area under the chloroquine whole blood concentration–time curve normalized to body weight (AUC_{0-24 h}/BW) yielded a trend of reduction (249±98.2 h g l^–1 kg^–1 versus 315±65.0 h g l^–1 kg^–1, P=0.06). The AUC_{0-24 h}/BW of desethylchloroquine was reduced by 35% (104±40.3 h g l^–1 kg^–1 versus 159±66.6 h g l^–1 kg^–1, P=0.03), whereas the metabolic ratio between chloroquine and desethylchloroquine remained unchanged (2.25±0.49 versus 1.95±0.42, P=0.17). The renal clearance of chloroquine and the ratio between chloroquine in whole blood and plasma remained unchanged (P>0.1).Conclusion Oral co-administration of methylene blue appears to result in a small reduction of chloroquine exposure which is not expected to be clinically relevant and thus represents no concern for further development as an anti-malarial combination.     

Alpidem and lorazepam in the treatment of patients with anxiety disorders: Comparison of efficacy and rebound

Alpidem, a novel imidazo-pyridine anxiolytic, was compared with lorazepam for efficacy and withdrawal effects in 23 (17 male) anxious psychiatric out-patients of mean age 35.3 years with a mean Hamilton Anxiety Rating Scale (HAM-A) total score of 26.4. Treatment was double blind for 4 weeks with doses built up to a mean of 112.5 mg alpidem and 3.5 mg lorazepam per day. Assessment were made for a further 2 weeks after abrupt withdrawal. There were no differences in scores between the groups before treatment. The HAM-A, Hospital Anxiety and Depression Scale, Sleep Rating Scale and other measures showed both drugs to be equally effective for psychic and somatic anxiety, depression and insomnia. Despite the small numbers, lorazepam produced greater improvement in the anxious mood, fear and insomnia items of the HAM-A. After stopping treatment serious rebound in mood and somatic scores was experienced by the lorazepam group in contrast to those patients on alpidem who maintained their improvement. Neither group was troubled by side effects; dropouts were few and due to inefficacy (1 alpidem) or withdrawal problems (2 lorazepam). Alpidem seemed to offer effective anxiolysis without the risk of rebound associated with lorazepam use.     

Absorption kinetics and pharmacodynamics of two oral dosage forms of flecainide in patients with an episode of paroxysmal atrial fibrillation

Objectives The objectives were to study the absorption kinetics and pharmacodynamics of two oral formulations of flecainide in patients with atrial fibrillation (AF) and to assess the relationship between pharmacokinetic parameters and the efficacy in restoring sinus rhythm. Methods The data of 54 patients included in a randomised, open, parallel-group study were used. Patients received an oral solution containing 300 mg flecainide and 20 mg cisapride or three tablets each containing 100 mg flecainide. The pharmacokinetic profile of flecainide was fitted using a one-compartment model with lag-time and first-order absorption. Results The tablets gave a maximum concentration (C _{max\ fit}) of 0.43±0.14 mg/l at 2.37±1.20 h. The oral solution resulted in a much faster peak concentration at 1.05±0.71 h (P<0.0001). The C _{max\ fit} of the oral solution of 0.60±0.17 mg/l was higher (P=0.0002) than that of the tablets, and interindividual variabilities of C _{max\ fit} were 28% and 33%, respectively. The absorption rate constant (ka) of the oral solution was twofold larger (P<0.0001). A higher ka (P=0.04) and a duration of AF less than 24 h (P=0.006) increased the probability of cardioversion. If atrial fibrillation lasted less than 24 h, only ka (P=0.016) was obtained as a significant variable in multivariate analysis. The linear models of QRS interval changes versus flecainide concentrations of both formulations had similar slopes with similar interindividual variabilities. Conclusions The probability of cardioversion after an oral loading dose of flecainide in patients with AF is dependent on ka. Rapid loading of the effect compartment, i.e. the atria, appears to be critical to reach cardioversion. Higher flecainide serum concentrations and a more rapid absorption does not increase interindividual variability of pharmacokinetics and pharmacodynamics, which is important when safety is considered.