Showing papers in "European Journal of Clinical Pharmacology in 1985"
TL;DR: Caffeine clearance, previously reported to be a specific marker of cytochrome P-448 activity in man, is decreased by chronic OCS use, which suggests that OCS may cause significant impairment of this enzyme activity as assessed in vivo.
Abstract: The effect of chronic (>3 months) administration of low-dose oestrogen-containing (<50 µg oestrogen) oral contraceptives (OCS) on the pharmacokinetics of caffeine has been examined in a treated females matched with 9 non-smoking, drug-free, healthy control females of similar age, weight and ethnic origin. Each subject received 162 mg caffeine base orally after an overnight fast. OCS subjects had a prolonged elimination half-life of caffeine, (mean 7.88 h vs 5.37 h in the controls). This was the result of marked impairment of the plasma clearance of caffeine (1.05 vs 1.75 ml/min/kg, respectively) with no change in apparent volume of distribution (0.685 in OCS vs 0.750 l/kg in the control group). The absorption parameters determined were peak plasma caffeine concentration (3.99 vs 4.09 µg/ml) and time to peak concentration after drug administration (1.52 vs 0.79), which was moderately prolonged in OCS users. Thus, caffeine clearance, previously reported to be a specific marker of cytochrome P-448 activity in man, is decreased by chronic OCS use. This suggests that OCS may cause significant impairment of this enzyme activity as assessed in vivo. With chronic caffeine consumption, OCS users are predicted to have an increased steady-state plasma caffeine concentration as compared to non-OCS users.
174 citations
TL;DR: β-Adrenoreceptor antagonists are liable to produce behavioural side-effects such as drowsiness, fatigue, lethargy, sleep disorders, nightmares, depressive moods, and hallucinations, which indicate that β-Blockers affect not only peripheral autonomic activity but also some central nervous mechanisms.
Abstract: β-Adrenoreceptor antagonists are liable to produce behavioural side-effects such as drowsiness, fatigue, lethargy, sleep disorders, nightmares, depressive moods, and hallucinations. These undesirable actions indicate that β-Blockers affect not only peripheral autonomic activity but also some central nervous mechanisms. In experimental animals β-Blockers have been found to reduce spontaneous motor activity, to counteract isolation-, lesion-, stimulation-and amphetamine-induced hyperactivity, and to produce slow-wave and paradoxical sleep disturbances. Furthermore, central effects such as tranquillizing influences are used for the treatment of conditions such as anxiety. Several different mechanisms of action could be responsible for these CNS effects: (1) Centrally mediated specific actions on centrally located β-adrenergic receptors, known to exist downstream from, and at the terminals of, ‘vigilance-enhancing’ central noradrenergic pathways. (2) Centrally mediated specific actions on centrally located receptors of the non-adrenergic type; an affinity of some β-Blockers towards 5-HT-receptors is well documented. (3) Centrally mediated non-specific actions on centrally located neurones, owing to the membrane-stabilizing effects of β-Blockers. (4) Peripherally mediated actions whereby β-Blockers induce changes in the autonomic activity in the periphery, which are relayed to the CNS to induce changes in activity of a variety of central systems. It can be assumed that with any one of the β-Blockers all these mechanisms come into play, yet with varying degrees depending on characteristics of the drugs such as lipophilicity and hydrophilicity, the ratio of antagonist versus (partial) agonist properties, affinity to ‘alien’ receptor sites, strength of membrane-stabilizing activity, stereospecific affinity, and potency.
95 citations
TL;DR: The study indicates that some of the prevailing practices in the area are unhealthy, and the high self medication rate, faulty prescribing habits of physicians and liberal dispensing methods of pharmacist need to be viewed with concern.
Abstract: An attempt has been made to quantitate drug consumption in a conurbation. The prescribing habits of physicians, self medication rate and therapeutic classes of drugs purchased have been evaluated. The study indicates that some of the prevailing practices in the area are unhealthy. The high self medication rate, faulty prescribing habits of physicians and liberal dispensing methods of pharmacist need to be viewed with concern. The wide gap between the precepts and practices prevailing among practitioners, the use of potent medicines without proper medical advice and the uninhibited sale of scheduled drugs over the pharmacy counter require careful consideration. If such unhealthy trends persist iatrogenic problems may surface in the near future. The physician, pharmacist and the public need to cooperate to create the proper pattern of drug usage.
85 citations
TL;DR: The relationship between improvement and serum level of citalopram indicated a lower limit of effect in endogenous depression at about 100 nM, corresponding to an average dose of 15 mg, and no significant correlation was found between serum drug level and the few reported side effects.
Abstract: Three dose levels (5, 25, and 50 mg once daily) of the selective serotonin uptake inhibitor citalopram were compared in a four-week, double-blind trial in depressed patients. Serum levels of citalopram and desmethylcitalopram, and the inhibitory effect of serum on serotonin uptake by fresh platelets, were assessed once weekly during the trial. The serum concentrations of citalopram were highly correlated with inhibition of serotonin uptake. Less of the metabolite was found, it being detected only in the higher dose groups. Steady state levels of citalopram, attained after 1 week, were linearly related to dose. The relationship between improvement (percentage reduction in total score on the Montgomery-Asberg Depression Rating Scale) and serum level of citalopram indicated a lower limit of effect in endogenous depression at about 100 nM, corresponding to an average dose of 15 mg. Marked improvement was seen in ten patients with steady state levels in the range 70 to 335 nM. The ten nonendogenously depressed patients had steady state levels from 15 to 620 nM; complete remission was seen in the three with the lowest levels (15–25 nM). No significant correlation was found between serum drug level and the few reported side effects.
80 citations
TL;DR: The plasma pharmacokinetics of adriamycin have been studied in 21 cancer patients (31-85 years old) without liver tumours after short (3.00 min) and prolonged (45 min-16h) i.v. infusions as mentioned in this paper.
Abstract: The plasma pharmacokinetics of adriamycin has been studied in 21 cancer patients (31–85 years old) without liver tumours after short (3.00 min) and prolonged (45 min-16h) i.v. infusions.
79 citations
TL;DR: Atenolol is significantly less likely to provoke nightmares and hallucinations than are the lipophilic β-Blockers, metoprolol and propranolol, and it seems likely that this finding is due to the differences in hydrophilicity amongst these drugs.
Abstract: Previous investigations have suggested that hydrophilic beta-blockers, which appear at low concentrations in brain tissue, are less likely to produce CNS-related side-effects than are lipophilic beta-blockers, which occur at higher concentrations in the brain. The validity of this hypothesis was tested in a double-blind crossover study in which the hydrophilic beta-blocker atenolol was compared with the lipophilic agents metoprolol and propranolol, in 14 patients with a previous history of nightmares or hallucinations when treated with lipophilic beta-blockers. Nightmares or hallucinations were reported by all patients receiving lipophilic beta-blockers but by only three patients receiving atenolol. The total number of episodes was significantly lower (p less than 0.01) for patients receiving atenolol (8) than for those receiving lipophilic beta-blockers (54). It is concluded that atenolol is significantly less likely to provoke nightmares and hallucinations than are the lipophilic beta-blockers, metoprolol and propranolol. It seems likely that this finding is due to the differences in hydrophilicity amongst these drugs.
78 citations
TL;DR: Analysis of the subjective questionnaires showed that recollection of dreaming and awakening in the night was increased by the three lipophilic drugs, propranolol, metoprolol, and pindolol, contrary to those expected from considering the effects of noradrenaline on sleep.
Abstract: The effects on sleep of four β-Blockers, atenolol, propranolol, metoprolol and pindolol, were studied in a placebo-controlled trial. Drugs were administered in random order to 10 female volunteers who acted as their own controls. Subjects were tested five times, each test period lasting 10 nights (2 baseline, 2 low dose, 4 high dose, and 2 withdrawal). A questionnaire concerning subjective appreciation of the quality of the previous night's sleep was completed each morning. Night recordings of muscle tension, eye movement, heart rate and electroencephalogram were recorded on paper and magnetic tape. Analysis of the subjective questionnaires showed that recollection of dreaming and awakening in the night was increased by the three lipophilic drugs, propranolol, metoprolol, and pindolol. These results confirm reports in the literature but are contrary to those expected from considering the effects of noradrenaline on sleep. Analysis of physiological records confirmed subjects' reports that waking was increased by the lipophilic drugs. Dreaming (rapid eye movement sleep, REM) was reduced, as predicted from knowledge of the effect of noradrenaline on sleep. Increased awakening leads to an increase in remembered dreaming which explains the otherwise paradoxical results. Although atenolol had no effect on subjective measures of sleep this hydrophilic drug also reduced REM frequency, suggesting that either it has some central effect, or that REM reduction is due to a peripheral ‘shielding’ effect.
75 citations
TL;DR: Plasma levels of the ester and triamcinolone acetonide were measured and pharmacokinetic parameters were calculated and no unchanged ester was found in the urine, indicating complete conversion of the pro-drug.
Abstract: Triamcinolone acetonide in the form of its phosphate ester was given intravenously in two different doses (10 mg/kg and 80 mg) Plasma levels of the ester and triamcinolone acetonide were measured and pharmacokinetic parameters were calculated The pharmacokinetics both of the phosphate and the free alcohol were dose-dependent No unchanged ester was found in the urine, indicating complete conversion of the pro-drug Triamcinolone was not a major metabolite of triamcinolone acetonide in humans Renal clearance was low and independent of the dose Only about 1% of the dose was found in the urine as triamcinolone acetonide
70 citations
TL;DR: Rifampicin is an inducer of hepatic metabolism in PBC-patients, ameliorates the pruritus and can lower serum concentrations of alkaline phosphatase and bile acids.
Abstract: Six patients with primary biliary cirrhosis (PBC) were treated with a daily oral dose of 600 mg rifampicin for 2 weeks to induce the hepatic metabolism of drugs and bile acids. On rifampicin 5 of 6 patients experienced a pronounced decrease of their pruritus. In all patients the oxidative cytochrome P-450 dependent drug metabolism was induced as shown by an increase of antipyrine-clearance from 36.3±8.8 to 80.6±20.1 ml/min and an enhanced urinary excretion of 6-β-hydroxycortisol from 454±1.99 to 1607±362 µg/24 h. Furthermore, in all 6 patients the serum alkaline phosphatase declined. In the 3 cholestatic patients (bilirubin>1.0 mg/dl) the serum concentration of total and conjugated bile acids was strikingly reduced. Thus, rifampicin is an inducer of hepatic metabolism in PBC-patients, ameliorates the pruritus and can lower serum concentrations of alkaline phosphatase and bile acids.
70 citations
TL;DR: It is concluded that the receptor interaction of propranolol together with its plasma concentration Kinetics can fully explain the time course of effects after a single oral dose, and so receptor interaction will be the missing link in the correlation between concentration kinetics and effect kinetics of proPRanolol in man.
Abstract: In a double-blind, placebo-controlled study in 6 healthy volunteers, the correlation between beta-adrenoceptor binding, the time course of the effect and plasma concentration kinetics was investigated from 0 to 48 h after a single oral dose of propranolol 240 mg. First, the in vitro beta-adrenoceptor interaction of propranolol was investigated. Propranolol inhibited beta-adrenoceptor binding to rat parotid (beta1) and reticulocyte (beta2) membranes in the presence of pooled human plasma with a Ki of about 8 ng/ml plasma. After oral administration of 240 mg propranolol, concentration kinetics in plasma could be described by a Bateman function with a fictive concentration at time 0 of 275 ng/ml plasma, and a mean elimination half-life of 3.5 h. Using the concentration kinetics of propranolol in plasma together with its in vitro beta-adrenoceptor binding characteristics in the presence of placebo plasma from each individual, the time course of antagonism against beta-adrenoceptor mediated effects was predicted. The latter was in agreement with the time course of propranolol-induced inhibition of tachycardia due to orthostasis. After bicycle ergometry, however, the time course of inhibition of tachycardia was shorter than was predicted. Plasma sampled at various times after propranolol administration inhibited beta-adrenoceptor binding of the radioligand 3H-CGP 12177 to rat reticulocyte membranes in a fashion reflecting the time course of inhibition of exercise tachycardia observed in the volunteers. A direct, linear relation was shown between the in vitro inhibition of beta-adrenoceptor binding by the plasma samples withdrawn after propranolol administration and the inhibition of exercise tachycardia observed in parallel. The results show that the concentrations of antagonist present in plasma are representative of the concentrations in the effect compartment. Deep compartments of drug distribution appear irrelevant to the effects of the drugs. The relation between the plasma concentration of propranolol and the reduction in heart rate at various levels of physical effort shows no significant inhibition at rest and increasing IC50-values from orthostasis to 2 min and to 4 min of ergometry. IC50-values after orthostasis are in the range of the Ki-values from in vitro receptor binding studies, whereas the IC50-values after exercise are shifted 2-to 3-fold to the right relative to the Ki-values. This finding is in agreement with increased beta-adrenoceptor stimulation with increasing effort (release of endogenous noradrenaline), which shifts the antagonist concentration-effect curve to the right. Furthermore, the rightward shift can explain why with increasing effort the time course of the inhibitory effect of propranolol becomes shorter. Release of propranolol from presynaptic stores during exercise is irrelevant, since this would result in opposed effects on the concentration-effect relationship (leftward shift) and the time course of antagonism (longer effect) with increasing work load. It is concluded that the receptor interaction of propranolol together with its plasma concentration kinetics can fully explain the time course of effects after a single oral dose, and so receptor interaction will be the missing link in the correlation between concentration kinetics and effect kinetics of propranolol in man. In general, this mode of correlation should be expandable to any drug exerting its effects according to the law of mass action via receptors in the extracellular space. This approach provides a rational basis for the comparison of different drugs from one group irrespective of their receptor affinity and concentration kinetics.
69 citations
TL;DR: Memory as assessed using the Sternberg technique was found to be significantly improved following treatment with vinpocetine 40 mg when compared to placebo and results suggested a localised effect of the drug on the serial comparison stage of the reaction process.
Abstract: Twelve healthy female volunteers received pre-treatments with vinpocetine 10, 20, 40 mg and placebo (t.d.s.) for two days according to a randomised, double-blind crossover design. On the third day of treatment and 1 h following morning dosage, subjects completed a battery of psychological tests including Ciritcal Flicker Fusion (CFF), Choice Reaction Time (CRT), Subjective Ratings of Drug Effects (LARS) and a Sternberg Memory Scanning Test. No statistically significant changes from placebo were observed on CFF, CRT or subjective ratings of drug effects. However, memory as assessed using the Sternberg technique was found to be significantly improved following treatment with vinpocetine 40 mg when compared to placebo and results suggested a localised effect of the drug on the serial comparison stage of the reaction process.
TL;DR: Cotinine concentrations in plasma were shown to be linearly and directly related to nicotine intake and can be used as an epidemiological marker of nicotine intake if it is measured around the time of the last cigarette of the day.
Abstract: Measurement of plasma cotinine, the major metabolite of nicotine, is usually done to determine nicotine-intake in smokers. Cotinine is used instead of nicotine because it has a much longer half-life than the mother substance and its plasma concentrations are therefore less dependent on the exact times of blood sampling. However, the linearity of the relationship between nicotine-intake and cotinine level in plasma has never been proven. Therefore cotinine was measured in 6 healthy volunteers infused over 4 days with several doses of nicotine i.v. up to 480 µg/kg/day. Cotinine concentrations in plasma were shown to be linearly and directly related to nicotine intake. The concentration of cotinine showed little variation during and for up to 2 h after the last dose of nicotine. Therefore, cotinine can be used as an epidemiological marker of nicotine intake if it is measured around the time of the last cigarette of the day.
TL;DR: The mechanism of the amiodarone-warfarin interaction is pharmacokinetic through dose — and concentration — dependent inhibition of warfarin elimination as well as through its actions on the dose and plasma concentration of warFarin.
Abstract: Potentiation of the anticoagulant-effect of warfarin by amiodarone was studied in 30 patients. Thirteen received both drugs concurrently, and 17 received warfarin alone and the combination sequentially. Warfarin doses were adjusted to maintain the prothrombin time between 25-30% of control and its kinetics were compared to those in 20 control patients who received warfarin alone. Potentiation occurred in 28/30 patients, presenting as a 35%-65% reduction in the required dose of warfarin, and was correlated with the dose of amiodarone (r = 0.77, p less than 0.01). The free warfarin fraction was not affected by amiodarone (1.8% vs 1.6% in the controls). Warfarin clearance was lower in amiodarone-treated patients than in the controls (1.4 vs 3.1 ml/min, p less than 0.01) with similar plasma concentrations (1.5 vs 1.2 micrograms/ml) despite administration of lower doses (23.3 vs 39 mg/week respectively). The amiodarone concentration was significantly correlated with the warfarin concentrations independent of the effect of amiodarone on the dose of warfarin. Amiodarone hat no effect on prothrombin other than through its actions on the dose and plasma concentration of warfarin. The mechanism of the amiodarone-warfarin interaction is pharmacokinetic through dose - and concentration - dependent inhibition of warfarin elimination.
TL;DR: The systemic availability of midazolam and the AUC for 1-hydroxymethylmidazol am appeared to be greater than that anticipated from the lower doses, possibly due to saturation of midAZolam first-pass metabolism.
Abstract: The pharmacokinetics of midazolam and 1-hydroxymethylmidazolam were investigated following oral administration of 7.5, 15 and 30 mg doses of midazolam in solution to 12 healthy subjects. Compared to the 7.5 mg dose, the Cmax and AUC parameters of both midazolam and 1-hydroxymethylmidazolam increased proportionally after the 15 mg dose and more than proportionally after the 30 mg dose. The t1/2 for midazolam remained relatively constant between the 7.5 and 15 mg doses whereas it increased slightly but significantly after the 30 mg dose. These data indicated that the pharmacokinetics of midazolam and 1-hydroxymethylmidazolam were linear between the 7.5 and 15 mg oral dose range. However, after the 30 mg dose, the systemic availability of midazolam and the AUC for 1-hydroxymethylmidazolam appeared to be greater than that anticipated from the lower doses, possibly due to saturation of midazolam first-pass metabolism. This ist not expected to have any clinical significance under the conditions of therapeutic use.
TL;DR: Serum and cerebrospinal fluid concentrations of ketoprofen have been measured in 36 patients hospitalised for sciatica and ketop rofen rapidly crossed the blood-brain barrier and was detected in CSF 15 min after its administration.
Abstract: Serum and cerebrospinal fluid (CSF) concentrations of ketoprofen have been measured in 36 patients hospitalised for sciatica. Diagnostic lumbar puncture was done 15 min to 13 h after a single 100 mg intramuscular dose of ketoprofen. Serum and CSF were sampled at the same time. Free serum concentrations were determined by equilibrium dialysis. Total and free concentrations were assayed by a highly sensitive and specific HPLC method. Ketoprofen rapidly crossed the blood-brain barrier and was detected in CSF 15 min after its administration. The rapid diffusion can be explained by the high lipid solubility of the drug. The CSF level was in equilibrium with the free serum concentration from the second to the 13th hours.
TL;DR: On repeated administration of bupropion there was little accumulation of the parent drug and no evidence for induction of its own metabolism, andSaliva secretion was significantly reduced during the multiple dosing period but there were no complaints of dry mouth.
Abstract: The pharmacokinetics of bupropion and 3 of its basic metabolites were determined in 8 young, healthy, male volunteers after single and multiple oral doses of bupropion. Plasma profiles were obtained: 1) after a single 100 mg oral dose of bupropion hydrochloride, 2) following administration of 100 mg 8-hourly for 14 days and 3) again after a single 100 mg dose 14 days later. Plasma concentrations of the parent drug and metabolites were determined by high-performance liquid chromatography. Saliva secretion and pupil diameters were measured, subjective assessments of sleep made using visual analogue scales and side effects, blood counts and biochemistry were monitored. After the first dose mean elimination half lives (t1/2) of bupropion, and metabolites I and II were 8, 19 and 19 h respectively. On repeated administration there was little accumulation of the parent drug and no evidence for induction of its own metabolism. Accumulation of I was consistent with its rate of elimination after single doses while that of II was greater than predicted with prolongation of t1/2 to 35 h. Metabolite III was barely detectable after single doses but its accumulation on multiple dosing was consistent with its long half life (35 h) determined on occasion 2. Saliva secretion was significantly reduced during the multiple dosing period but there were no complaints of dry mouth. Subjective assessments of sleep were not significantly altered though one subject reported vivid dreams. There were no other adverse reactions.
TL;DR: Thiamine kinetics were studied in plasma and urine from 8 men after intravenous and oral doses of 50, 100 and 200 mg thiamine hydrochloride, demonstrated by plotting the fractional amount of Thiamine excreted unchanged in urine against the corresponding area under the plasma concentration — time curve.
Abstract: A sensitive assay for thiamine suitable for clinical use has been developed. It is based on precolumn oxidation of thiamine to thiochrome followed by HPLC-separation and fluorescence detection. The assay is applicable to various biological materials, including human plasma.
TL;DR: This study appears to confirm the association between CNS-related side-effects and the lipophilicity of β-Blockers.
Abstract: Vivid and bizarre dreams, hallucinations, sleep disturbance and psychosis have all been described following treatment with beta-blockers. It has been suggested that these central nervous system (CNS) side-effects are related to the degree of lipophilicity of the beta-blocker. A randomized double-blind crossover study was performed to compare the incidence of CNS side-effects with atenolol and metoprolol in hypertensive patients who had reported CNS side-effects with lipophilic beta-blockers. Eleven women and six men completed the study, in which a 30-item psychiatric questionnaire was used to detect changes in psychological status and possible CNS side-effects. Discontinuation of the original lipophilic beta-blocker produced a significant improvement in quality of sleep, dreams, concentration, memory, energy, and anxiety. No significant CNS side-effects were reported with atenolol, but introduction of metoprolol caused a significant increase in the incidence of sleep disturbance (p less than 0.01) and restless nights (p less than 0.05), as well as failure to achieve satisfactory sexual intercourse (p less than 0.05). When compared with atenolol, metoprolol was associated with a significantly higher incidence of restless disturbed nights (p less than 0.05). Blood pressure control was identical for both beta-blockers. This study appears to confirm the association between CNS-related side-effects and the lipophilicity of beta-blockers.
TL;DR: Only glibenclamide improved insulin sensitivity and was slightly more active than glipizide on fasting blood glucose levels, which may be consequences of the pharmacokinetics, but differences in pharmacodynamics cannot be excluded.
Abstract: Fifteen Type 2 diabetics were treated for 4-week periods with once daily (10 mg) glibenclamide, glipizide and placebo according to a double-blind cross-over protocol Post-dose glipizide concentrations were three times higher than those of glibenclamide, due to the incomplete bioavailability of the latter On the other hand, pre-dose drug levels were similar, as an expression of the slower absorption and/or elimination of glibenclamide Both active treatments reduced postprandial blood glucose concentrations and 24-hour urinary glucose excretion to a similar degree, but fasting blood glucose concentrations were slightly lower during glibenclamide treatment Both active treatments enhanced fasting and postprandial insulin and C-peptide concentrations, the C-peptide response being greater after glipizide than after glibenclamide Plasma glucagon and GIP concentrations were not significantly affected Insulin sensitivity was increased by glibenclamide but not by glipizide Neither therapy affected insulin binding to erythrocytes It appears that both glibenclamide and glipizide improved glucose metabolism by sustained stimulation of insulin secretion, which was most pronounced with glipizide Only glibenclamide improved insulin sensitivity and was slightly more active than glipizide on fasting blood glucose levels The differences may be consequences of the pharmacokinetics, but differences in pharmacodynamics cannot be excluded
TL;DR: Budesonide had marginal effects on plasma cortisol and white blood cell counts either after i.v. or nasal administration, and the systemic effects after this clinically recommended nasal dose were negligible.
Abstract: Budesonide, a topically potent glucocorticoid, was administered to 4 healthy volunteers by i.v. infusion and by nasal instillation of 100 micrograms tritium-labelled drug. Plasma was analyzed by liquid chromatography plus scintillation counting of collected fractions. After i.v. administration the plasma clearance was 0.921/min and the apparent volume of distribution was 2.81/kg. After nasal administration, the time to reach the peak plasma level was approximately 30 min, and the systemic availability was 102%. Budesonide had marginal effects on plasma cortisol and white blood cell counts either after i.v. or nasal administration. Thus, nasally instilled budesonide in solution is rapidly and completely absorbed from the nasal mucosa. The systemic effects after this clinically recommended nasal dose were negligible.
TL;DR: The brain is buffered from peak blood concentrations of atenolol, and this may account for the low incidence of CNS-related side-effects with this hydrophilic β-blocker.
Abstract: Patients with subarachnoid haemorrhage (SAH) have been shown to benefit from beta-blockade. SAH patients who came to surgery were investigated if they had been receiving chronic (approximately one week) oral treatment with either hydrophilic atenolol (100 mg/day) or one of the following lipophilic beta-blockers: propranolol (80 mg b.i.d.), oxprenolol (80 mg b.i.d.), or metoprolol (100 mg b.i.d.). Cerebrospinal fluid concentrations of beta-blockers did not reflect their concentrations in the brain. Brain concentrations of the three lipophilic beta-blockers were 10-20 times higher than those of atenolol. The approximate brain/plasma concentration ratios were 26 for propranolol, 50 for oxprenolol, 12 for metoprolol, and 0.2 for atenolol. The brain is thus buffered from peak blood concentrations of atenolol, and this may account for the low incidence of CNS-related side-effects with this hydrophilic beta-blocker.
TL;DR: The pharmacokinetics of a new, potent H2-receptor antagonist, famotidine, 20 mg i.v. was studied in 7 subjects with normal renal function and in 24 patients with varying degrees of renal impairment, and the cumulative urinary excretion and renal clearance offamotidine were correspondingly reduced in patients with impaired kidney function.
Abstract: The pharmacokinetics of a new, potent H2-receptor antagonist, famotidine, 20 mg iv was studied in 7 subjects with normal renal function and in 24 patients with varying degrees of renal impairment The volume of distribution at steady state was 114 l/kg in normal subjects and was not altered in renal failure The half-life of elimination was 259 h in normal subjects and was unchanged in mild renal failure (creatinine clearance, CLCR 90–60 ml/min/148 m2) but was increased to 472 h in moderate renal failure (CLCR 60–30 ml/min/148 m2), and to 1207 h in severe renal failure (CLCR below 30 ml/min/148 m2) The cumulative urinary excretion and renal clearance of famotidine were correspondingly reduced in patients with impaired kidney function In normal subjects and in patients with mild to moderate renal failure, about 70% of famotidine was excreted through the kidney, mainly by tubular secretion In patients with a CLCR above 60 ml/min/148 m2 the normal daily dose of famotidine can be employed, but in those with a CLCR between 60 and 30 ml/min/148 m2 the dose should be reduced by half, and in patients with a CLCR below 30 ml/min/148 m2 a reduction by three quarters of the normal dose is recommended
TL;DR: The data suggest that famotidine, in contrast to cimetidine, does not affect the pharmacokinetics of diazepam (hepatic elimination) or procainamide (tubular secretion), and appears to be devoid of an interaction potential for either type of drug elimination.
Abstract: In 8 healthy male volunteers the pharmacodynamic responses to a single dose of diazepam and a single dose of procainamide were assessed before and after pre-treatment with the H2-receptor antagonist famotidine in a randomized crossover study. The pharmacokinetics of diazepam and procainamide were also studied, and the binding of famotidine to human liver microsomes was also measured. Cimetidine induced binding changes with a spectral dissociation constant (Ks) of 0.87 mM, whereas famotidine produced no measurable spectral alteration in concentrations up to 4 mM. The elimination half-life (t1/2: 45.6 h) and total plasma clearance (CL: 0.28 ml/min/kg) of diazepam were not significantly altered by famotidine (t1/2 = 39.0 +/- 11.4 h; CL = 0.31 +/- 0.08 ml/min/kg). Similarly, there was no enhancement of the sedative effect of diazepam by famotidine. The pharmacodynamics and pharmacokinetics of procainamide and N-acetylprocainamide (NAPA), too, were not significantly changed by famotidine: procainamide t1/2 2.9 vs 3.0 h under famotidine and renal clearance (CLR) 436 vs 443 ml/min; and NAPA CLR 195 vs 212 ml/min under famotidine. The data suggest that famotidine, in contrast to cimetidine, does not affect the pharmacokinetics of diazepam (hepatic elimination) or procainamide (tubular secretion). This new H2-receptor antagonist appears to be devoid of an interaction potential for either type of drug elimination.
TL;DR: Simulations based on mean data suggest that increased drowsiness in the elderly was probably not due to changes in the drug's pharmacokinetic behaviour.
Abstract: A double blind crossover trial of baclofen against placebo in elderly stroke patients was discontinued because the drug produced an unacceptably high level of drowsiness In a subsequent study baclofen 10 mg was given orally to 12 elderly stroke patients, and drug concentrations measured from a series of plasma samples A group of healthy subjects given the same dose in a previous study were used as controls Elderly patients took longer to achieve peak plasma baclofen concentrations, but healthy controls had higher peak values and eliminated the drug more rapidly; areas under the curve were similar in the two groups Simulations based on mean data suggest that increased drowsiness in the elderly was probably not due to changes in the drug's pharmacokinetic behaviour
TL;DR: The time course of the haemodynamic changes suggested that the sulphone metabolite contributed to the overall hypotensive response and BTS 49465 was well tolerated in terms of haematological and biochemical parameters and subjective side-effects.
Abstract: The pharmacokinetic and haemodynamic effects of a 200 mg oral dose of BTS 49465 (7-fluoro-1-methyl-3-methylsulphinyl-4-quinolone) were investigated in a double-blind placebo controlled study. BTS 49465 was rapidly absorbed and cleared from the systemic circulation with a half-life of 1.6 h by oxidation to the sulphone metabolite. The metabolite was cleared with a half-life of 37.6 h. Saliva concentrations of both BTS 49465 and its metabolite correlated well with the plasma concentrations. Compared to placebo, BTS 49465 produced statistically significant reductions in blood pressure and increases in heart rate both supine and after a 60° head up tilt. The time course of the haemodynamic changes suggested that the sulphone metabolite contributed to the overall hypotensive response. Plasma Renin Activity was only marginally elevated and there was no evidence of acute fluid retention. BTS 49465 was well tolerated in terms of haematological and biochemical parameters and subjective side-effects.
TL;DR: Early β-blockade benefits patients with subarachnoid haemorrhage, in terms of fewer neurological deficits, for up to one year, and possible mechanisms for this protective effect of propranolol may include a Reduction in plasma renin activity, a reduction in pulmonary oedema, prevention of myocardial infarcts, and a reduced in cerebral oxygen requirements.
Abstract: Previous studies have shown that ECG changes following a subarachnoid haemorrhage are associated with increased catecholamine levels, necrotic myocardial lesions, and a poor prognosis. Furthermore, β-blockade using propranolol reverses some of the ECG changes and prevents necrotic myocardial lesions. This study was established to assess the affects of adrenergic blockade on morbidity and mortality following subarachnoid haemorrhage. Patients were admitted to the randomized double-blind between-patients study if they presented at the neurosurgical unit within 48 hours of a subarachnoid haemorrhage confirmed by lumbar puncture. Of 224 patients, the first 118 received an α-blocker, phentolamine 20 mg three-hourly, and either the β-blocker propranolol 80 mg eight-hourly, or placebo. The last 106 patients received either propranolol or placebo. Treatment was continued for three weeks. Assessment at four weeks revealed significant improvements in the treated group for neurological deficit (p=0.003) and death (p=0.02). More treated patients underwent operation and those that did had a better outcome (p=0.01). Assessment at one year showed that although patients had improved in both groups, patients in the treated group had significantly fewer neurological deficits (p=0.003). There were fewer deaths in the treated group but this difference was not significant (p=0.09). Possible mechanisms for this protective effect of propranolol may include a reduction in plasma renin activity, a reduction in pulmonary oedema, prevention of myocardial infarcts, and a reduction in cerebral oxygen requirements. It is concluded that early β-blockade benefits patients with subarachnoid haemorrhage, in terms of fewer neurological deficits, for up to one year.
TL;DR: Hydroxychloroquine 3.2 µg was detected in breast milk from a woman given 800 mg over 48 hour and it was found to be in excess of the legal limit for H2O in a breastfeeding woman.
Abstract: Hydroxychloroquine 3.2 micrograms was detected in breast milk from a woman given 800 mg over 48 hour.
TL;DR: In this paper, the interaction of phenylbutazone and diazepam with smectite was studied in in-vivo and invitro in healthy subjects.
Abstract: The interaction of phenylbutazone and diazepam with smectite were studied in in-vivo and in-vitro. The kinetics of both drugs were investigated in healthy subjects after oral administration as monotherapy or in association with smectite. Smectite did not substantially alter the kinetics of phenylbutazone, whereas the peak plasma concentration of diazepam was reduced to 91%, and the time of peak concentration was prolonged by 153% of the control values. The in-vitro investigations were conducted at pH 5.5 and 8 and showed that there was no interaction between phenylbutazone and smectite, but that it adsorbed diazepam. The findings suggest that smectite delays the absorption of basic drugs and does not alter the absorption kinetics of acidic drugs.
TL;DR: The oxidative polymorphism was only significant for substances that had a high hepatic first pass metabolism, such as metoprolol, and must be taken into account when assessing the relation between the plasma concentration and effect of these drugs, which are often administered as racemic mixtures.
Abstract: Ten healthy subjects whose genetic oxidative phenotype had been determined (6 extensive and 4 poor metabolizers of the debrisoquine-sparteine type of polymorphism) received single oral doses of 3 beta-blockers: atenolol, bopindolol and metoprolol. The plasma concentrations and the extent of the decrease in exercise-induced tachycardia were determined. The oxidative polymorphism was only significant for substances that had a high hepatic first pass metabolism, such as metoprolol. The metabolic pathway under genetic control was highly stereoselective. This observation must be taken into account when assessing the relation between the plasma concentration and effect of these drugs, which are often administered as racemic mixtures.
TL;DR: In 31 depressive patients, treated daily with 150 mg AT for 3 weeks, free and total plasma AAG were determined, as well as the AAG polymorphic forms and variants, and free AT and NT were strongly correlated with the S form (but not the F form) of AAG variants.
Abstract: Alpha1-acid glycoprotein (AAG) is one of the plasma proteins that bind basic drugs, like amitriptyline (AT) and its metabolite nortriptyline (NT). Two types of genetic polymorphism have been described for AAG: polymorphic forms which, on electrophoresis of the native protein, give four patterns with 5, 6, 7 or 8 bands, and the variants which on by electrophoresis of the desialysed protein, give three patterns with 2 bands, FF, FS and SS. In 31 depressive patients, treated daily with 150 mg AT for 3 weeks, free and total plasma AT and NT were determined, as well as the AAG polymorphic forms and variants. There was only a weak negative correlation between the free fractions of AT and NT and total plasma AAG, but free AT and NT were strongly correlated with the S form (but not the F form) of AAG variants. The differences in binding might be the expression of a further genetic factor determining the steady-state plasma levels of tricyclic drugs.