bluuebunny/crossref_metadata_2025 huggingface dataset:
Rifampicin kinetics in undernutrition.
Authors: Polasa K , Murthy KJ , Krishnaswamy K
Published: July 2012

Rifampicin 10 mg/kg was administered as a single dose to eight undernourished subjects, 10 well nourished subjects and 10 undernourished patients on continuous antituberculosis therapy as a single dose. The area under plasma time concentration (AUC0‐ infinity) and the peak concentration were significantly reduced in both the undernourished groups. The apparent oral and renal clearances were increased in both the undernourished groups. The (AUC0‐infinity) was reduced in undernourished due to reduced absorption and/or changes in total body clearance or disposition. The plasma protein binding of the drug was significantly reduced in the undernourished resulting in increased free drug concentration. This might be sufficient to ensure adequate therapeutic efficacy. Therefore alteration in dosage regimes are not necessary in the undernourished.
Contribution of prostaglandins to the systemic and renal vascular response to frusemide in normal man.
Authors: Mackay IG , Muir AL , Watson ML
Published: July 2012

In eight normotensive male volunteers indomethacin decreased both the peak urine flow rate and total sodium excreted within 1 h of an intravenous dose of frusemide. Resting effective renal plasma flow and glomerular filtration rate were unchanged by indomethacin, but the increase in both parameters after frusemide was inhibited. The early increase in plasma renin activity after frusemide was inhibited by indomethacin. Indomethacin decreased urinary excretion of PGE by 80% and the increase after frusemide was abolished. The urinary excretion of a metabolite of systemic PGI2 was unaltered in the 40‐60 min period following frusemide. The early haemodynamic effects of frusemide are likely to be prostaglandin mediated, but there was no evidence of any change in systemic PGI2 synthesis after frusemide.
Patients compliance in hypertension‐the importance of number of tablets.
Authors: Asplund J , Danielson M , Ohman P
Published: July 2012

The importance of number of tablets for patient compliance was investigated in 160 patients with mild‐moderate essential hypertension treated with a beta‐adrenoceptor blocker and a thiazide diuretic. Mean BP at entry 146 +/‐ 16/92 +/‐ 8 mm Hg. All patients were given pindolol 10 mg and clopamide 5 mg in one combination tablet or in separate tablets for 4 months respectively. Approximately 90% of the patients took greater than 90% of the prescribed dose throughout the study. Mean BP decreased progressively and heart rate increased slightly. Side effects were more frequently reported during the first month of the study than previously, and 30 patients discontinued the treatment. No differences in this respect were seen between 1 and 2 tablets daily. Approximately 75% of the patients preferred 1 tablet daily, but combining two drugs in one tablet had no effect upon compliance.
Saliva concentrations of isosorbide dinitrate, isosorbide 2‐mononitrate and isosorbide 5‐mononitrate.
Authors: Taylor IW , Major RM , Chasseaud LF , Taylor T
Published: July 2012

Correlations between saliva and plasma concentrations of isosorbide dinitrate (ISDN), and its active metabolites, isosorbide 2‐mononitrate (2‐ISMN) and isosorbide 5‐mononitrate (5‐ISMN) were examined. In the case of 5‐ISMN (r = 0.98, P less than 0.01), saliva concentrations are probably reliable indices of the plasma concentrations of this drug and their measurement should provide a useful non‐invasive procedure to assess compliance during the clinical use of products containing either ISDN or 5‐ISMN: it may also be helpful in assessing the clinical pharmacokinetics of 5‐ISMN. Less satisfactory correlations were obtained for ISDN (r = 0.84) and 2‐ISMN (r = 0.83).
Pharmacokinetics of valproic acid in the elderly.
Authors: Perucca E , Grimaldi R , Gatti G , Pirracchio S , Crema F , Frigo GM
Published: July 2012

The kinetics of a single oral dose of sodium valproate was studied in six healthy elderly patients (age 68‐89 years) and six young control subjects (age 24‐26 years). The profiles of total plasma valproic acid (VPA) concentrations were very similar in the elderly and in the young. Half‐lives (15.3 +/‐ 0.7 s.e. mean in the elderly vs 13.0 +/‐ 1.0 h in the young), volumes of distribution (0.16 +/‐ 0.01 l/kg in the elderly vs 0.14 +/‐ 0.01 l/kg in the young) and clearance (7.5 +/‐ 0.9 ml h‐1 kg‐1 in the elderly vs 7.7 +/‐ 0.6 ml h‐1 kg‐1 in the young) did not differ significantly between the two groups. Free VPA concentrations were significantly increased in the elderly. The clearance of the free drug (intrinsic clearance) was reduced from 127.0 +/‐ 12 ml h‐1 kg‐1 (control value in the young) to 77.7 +/‐ 5.5 ml h‐1 kg‐1 (P less than 0.02). Free VPA fraction was 9.5 +/‐ 0.6% in the elderly and 6.6 +/‐ 0.5% in the young (P less than 0.02). These findings suggest that the pharmacokinetic alterations of VPA in old age are complex and include at least two separate mechanisms: a decrease in plasma protein binding and a reduction of drug metabolizing capacity resulting in decreased clearance of free drug by the liver.
Temazepam's efficacy in patients with sleep onset insomnia.
Authors: Roehrs T , Lamphere J , Paxton C , Wittig R , Zorick F , Roth T
Published: July 2012

The hypnotic efficacy of temazepam capsules (30 mg) was studied in twelve patients who had objective polysomnographic evidence of sleep onset insomnia. Patients slept in the laboratory, retiring at their usual bedtime after taking placebo or temazepam 30 min earlier, and were monitored for 8 h using standard polysomnographic techniques. Acute (nights 5‐7) and chronic (nights 11‐13) temazepam improved the sleep of these patients by reducing sleep latency and increasing sleep time compared to the placebo baseline (nights 2‐4). No detrimental effects on daytime function the following morning were observed using questionnaires and objective tests of performance. No consistent evidence of disturbed sleep after discontinuation of treatment was obtained over three recovery nights.
Aspirin metabolism and efficacy in postoperative dental pain.
Authors: Seymour RA , Williams FM , Ward A , Rawlins MD
Published: July 2012

Aspirin 1200 mg was compared with placebo in a randomised, double‐ blind, crossover study in 15 patients with postoperative pain after removal of impacted lower third molars. Over a 5 h investigation period, patients reported significantly less pain (P less than 0.01) after treatment with aspirin, than after treatment with placebo. Peak concentrations of aspirin occurred at 15 min after dosage. Significant negative correlations were observed between plasma aspirin esterase activity and both AUC aspirin (r = −0.904, P less than 0.001) and AUC analgesia (r = −0.91, P less than 0.001). Similarly, a significant correlation was observed between AUC aspirin and AUC analgesia (r = 0.96, P less than 0.001). Evidence from this study would suggest that an individual's pain relief in postoperative dental pain is determined by the rate of aspirin hydrolysis to salicylate.
Low‐dose acetylsalicylic acid (100 mg/day) after aortocoronary bypass surgery: a placebo‐controlled trial.
Authors: Meister W , von Schacky C , Weber M , Lorenz R , Kotzur J , Reichart B , Theisen K , Weber PC
Published: July 2012

The effect of low‐dose acetylsalicylic acid (100 mg/day) upon bypass patency‐rate and clinical course after aortocoronary bypass surgery was investigated in a randomized, placebo‐controlled clinical trial. Sixty patients with 143 distal anastomoses of bypasses were randomized, 46 underwent repeat angiography after 4 months. Using the intention to treat‐strategy, treatment was superior to placebo as judged by bypass patency rate and occurrence of cardiovascular complications or death. Counting the six drop‐outs as failures, only nine of the 31 patients of the placebo group, but 16 of the 29 patients of the treatment group were considered successes (P less than 0.04). Eighteen patients in the placebo group and eight patients of the treatment group received beta‐ adrenoceptor blockers postoperatively, suggesting again a favourable effect of the treatment. Adverse drug reactions were very rare and minor. Supported by pathophysiological insights and positive trends in similar trials, the positive result justifies the recommendation of prescribing 100 mg of acetylsalicylic acid once daily to all patients without contraindications after aortocoronary bypass surgery. The positive result of this trial warrants further clinical trials of low‐ dose acetylsalicylic acid for other indications in arterial diseases.
Differential transplacental binding of valproic acid: influence of free fatty acids.
Authors: Albani F , Riva R , Contin M , Baruzzi A , Altomare M , Merlini GP , Perucca E
Published: July 2012

The unbound fraction of valproic acid (VPA) was found to be significantly lower in cord serum (6.0 +/‐ 0.8%) than in maternal serum collected before oxytocin (12.2 +/‐ 2.7%) or after delivery (9.9 +/‐ 2.3%). The difference was probably due to the concentration of free fatty acids (acting as displacing agents) being higher in maternal serum. The transplacental binding gradient explains the clinical observation that total VPA levels at delivery are higher in the newborn than in the mother.
Partial reversal of carbamazepine‐induced water intolerance by demeclocycline.
Authors: Ballardie FW , Mucklow JC
Published: July 2012

The anti‐diuretic action of carbamazepine, before and after concurrent treatment with demeclocycline, has been studied in a single epileptic subject, in whom two episodes of status epilepticus had been associated with excessive fluid intake and hyponatraemia. After addition of demeclocyline, free water clearance, plasma arginine vasopressin concentration and serum osmolality (all appreciably reduced after carbamazepine alone) increased but did not revert to normal. The findings are consistent with direct antagonism by demeclocycline of the enhancing effect of carbamazepine on endogenous ADH activity.
Polymorphic metabolism of beta‐adrenoceptor antagonists.
Authors: Silas JH , Lennard MS , Tucker GT , Ramsay LE , Woods HF
Published: July 2012

Most beta‐adrenoceptor blockers undergo extensive oxidative metabolism. The evidence for polymorphism of the debrisoquine type is reviewed. The AUC and half‐life of metoprolol were considerably greater in poor metabolisers (PM) of debrisoquine than in extensive metabolisers (EM). Metoprolol alpha‐hydroxylation is impaired and O‐dealkylation must also be affected. Polymorphism in the former route has been demonstrated in a population of 143 patients to be directly related to debrisoquine phenotype. Bufuralol AUC and half‐life are much higher in PM than EM subjects. Hydroxylation at the 1 and 4 positions are affected. Genetic polymorphism for 1‐hydroxylation has been shown in family and population studies. Propranolol 4‐hydroxylation is defective in PM subjects of debrisoquine but propranolol AUC is not related to phenotype, presumably because other major pathways are unaffected. Oxidation phenotype correlates well with intensity and duration of beta‐ adrenoceptor blockade after metoprolol, PM subjects requiring only once‐ daily dosing. However, in EM subjects twice‐daily dosing is required even if slow release preparations are used, since plasma metoprolol concentrations may remain negligible 24 h after dosing. The beta‐ adrenoceptor blocking effects of propranolol and bufuralol are unlikely to be influenced by oxidation status. Anecdotal reports of toxicity arising in PM subjects taking metoprolol or propranolol need to be substantiated. However, vomiting after the administration of bufuralol often occurs in poor metabolisers. Metabolic interactions with drugs sharing the same enzyme system are discussed. Debrisoquine and bufuralol competitively inhibit each other's metabolism in vitro. (ABSTRACT TRUNCATED AT 250 WORDS)
The interaction between H2‐receptor antagonists and beta‐adrenoceptor blockers.
Authors: Mutschler E , Spahn H , Kirch W
Published: July 2012

The degrees of interactions between the H2‐receptor antagonists, cimetidine and ranitidine, and several beta‐adrenoceptor blockers were investigated in healthy volunteers following 7 days of oral monotherapy with penbutolol, propranolol, metoprolol, pindolol and atenolol, and after co‐administration with each of the H2‐receptor antagonists. The kinetic parameters of unmetabolised penbutolol and penbutolol glucuronide were unaffected, whereas the levels of 4‐hydroxypenbutolol and 4‐hydroxypenbutolol glucuronide were significantly reduced. Furthermore, cimetidine led to a marked increase in propranolol and metoprolol plasma levels. During co‐administration with cimetidine, pindolol plasma levels were only slightly raised, whereas the pharmacokinetics of atenolol were not affected. With regard to pharmacodynamics, the inhibition of exercise‐induced tachycardia by each of the beta‐adrenoceptor blockers was not affected by cimetidine. Ranitidine did not alter atenolol plasma levels, but did raise the peak plasma concentration of metoprolol by about 30%. It is concluded that cimetidine interactions do occur and can be predicted for substances metabolised by the cytochrome P‐450 pathway.
Interaction between the beta‐adrenoceptor blockers metoprolol and atenolol with amitriptyline and their effects on oxidative liver metabolism.
Authors: Kirch W , Spahn H , Kitteringham NR , Hutt HJ , Mutschler E , Ohnhaus EE
Published: July 2012

Neither the kinetics of the hydrophilic beta‐adrenoceptor blocker atenolol nor those of the lipophilic metoprolol were influenced by the concurrent administration of amitriptyline. Compared with placebo, chronic administration (14 days) of atenolol and metoprolol (each as monotherapy) did not significantly reduce oxidative liver metabolism as measured by antipyrine half‐life and by 6‐beta‐hydroxycortisol excretion. Compared with atenolol and metoprolol monotherapy, chronic administration of amitriptyline concurrently with each of the beta‐ adrenoceptor blockers produced an insignificant decrease (circa 10‐20%) in antipyrine half‐life and 6‐beta‐hydroxycortisol excretion. Amitriptyline appears therefore to have little enzyme‐inducing activity.
Enzyme induction and beta‐adrenergic receptor blocking drugs.
Authors: Branch RA , Herman RJ
Published: July 2012

All beta‐adrenergic receptor blockers that require metabolism prior to elimination are potentially subject to drug interactions due to enzyme induction. However, data is only available in man for propranolol, metoprolol and alprenolol. Cross‐sectional population studies suggest that environmental factors, such as smoking in the young, are able to influence the oral clearance of propranolol. Long‐term studies comparing within‐subject clearances of metoprolol, alprenolol and propranolol before and after rifampicin and pentobarbitone, indicate that oral clearance is increased by 50%‐500%. Inducing agents can influence intrinsic clearance, liver blood flow, and protein binding in addition to drug metabolising ability, indicating that changes in pharmacokinetic disposition may be complex. Enzyme induction exhibits both dose and time dependency relationships. The maximal extent of enzyme induction is similar between subjects. The range of intersubject variation in drug metabolism is similar before and after induction. The reduction in steady‐state beta‐adrenergic receptor drug concentration following enzyme induction is sufficiently large that an altered pharmacodynamic response would be expected if no dosage modification is made.
The psychopharmacological effects of premazepam, diazepam and placebo in healthy human subjects.
Authors: Golombok S , Lader M
Published: July 2012

Pharmacological studies of premazepam in animals predicted antianxiety activity without sedation and, in combination with diazepam, a reduction in the sedative effects of the latter. The effects of single doses of premazepam (25 and 50 mg), diazepam (10 mg), premazepam (25 mg) plus diazepam (10 mg), and a placebo on subjective feelings, psychological tests and the EEG were studied in a double‐blind cross‐ over study in 10 healthy subjects. In a repeated dose study in eight subjects, the effects on subjective feelings, psychological tests and the EEG of premazepam (5 and 10 mg twice‐daily), diazepam (5mg twice‐ daily) and a placebo were compared. Premazepam had a different EEG profile from diazepam, producing more slow and less fast wave activity. In the single dose study its effects were similar to diazepam for sedative action and most of the psychological tests, with a tendency towards greater psychomotor impairment. In the repeated dose study, however, premazepam caused less sedation and also tended to produce less psychomotor impairment. The combination dose of premazepam (25 mg) plus diazepam (10 mg) in the single dose study indicated an additive effect rather than an antagonistic one.
Measurement of specific [3H]‐ouabain binding to different types of human leucocytes.
Authors: Boon NA , Oh VM , Taylor EA , Johansen T , Aronson JK , Grahame‐Smith DG
Published: July 2012

We have studied the specific binding of [3H]‐ouabain to intact mononuclear leucocytes (82% lymphocytes) and polymorphonuclear leucocytes. In both types of cells [3H]‐ouabain binding was saturable, confined to a single site of high affinity, slow to reach equilibrium, slow to reverse, temperature‐dependent, competitively antagonized by potassium, and facilitated by the presence of divalent cations. The equilibrium dissociation constants were 2.4 +/‐ 0.7 nmol/l (polymorphs) and 2.4 +/‐ 0.4 nmol/l (mononuclear cells) (NS). The values of maximal specific ouabain binding, measured by Scatchard analysis of concentration vs binding curves (Bmax), were 33.9 +/‐ 6.0 fmol/10(6) cells (polymorphs) and 59.3 +/‐ 11.6 fmol/10(6) cells (mononuclear cells) (P less than 0.02). The corresponding numbers of sites per cell were 20415 +/‐ 3616 and 35712 +/‐ 6986 respectively (P less than 0.02). When the numbers of binding sites were expressed per square micron of cell surface area the difference between the two cell types was proportionately greater (83 and 186 sites per micron 2 respectively). We conclude that the [3H]‐ouabain binding sites on mononuclear and polymorphonuclear leucocytes are similar in nature, but different in both number and density on the cell surface. Measurements of Bmax in mixed cell populations should therefore take account of cell type as well as cell size and number.
The effect of chlormethiazole on the hypoxic drive to breathing in normal man.
Authors: Calverley PM , Carmichael GL , Scott DB
Published: July 2012

We have studied the effects of chlormethiazole infusion on the ventilatory response to progressive isocapnic hypoxia in seven healthy volunteers, during both normocapnia and induced hypercapnia. The dose of chlormethiazole was such that it produced the same degree of hypnosis as would be expected from oral administration of two capsules each containing 192 mg of base in arachis oil. Ventilation did not change significantly during chlormethiazole administration. The ventilatory response to hypoxia was unaffected by chlormethiazole during normocapnia and was enhanced during hypercapnia. In these subjects, giving chlormethiazole intravenously was not associated with depression of the resting ventilation nor the hypoxia ventilatory response.
Dose and concentration dependent effect of ranitidine on procainamide disposition and renal clearance in man.
Authors: Somogyi A , Bochner F
Published: July 2012

The pharmacokinetics of oral procainamide (1 g) were investigated in six healthy subjects during chronic dosing with ranitidine 150 mg twice daily, and in three of the subjects when ranitidine 750 mg was administered over 12 h. The procainamide area under the plasma concentration‐time curve was significantly (PQ0.02) increased by ranitidine (27.761.5 vs 31.561.8 mg l‐1 h) with a significant reduction in renal clearance (379632 vs 309630 ml/min, PQ0.02). There was no change in half‐life. The N‐acetylprocainamide (NAPA) area under the plasma concentration‐time curve was also significantly (PQ0.02) elevated by ranitidine (8.661.2 vs 9.761.3 mg 1‐1 h) due to a reduction in renal clearance from 187630 to 168628 ml/min. The larger dose of ranitidine produced greater alterations in the procainamide and NAPA pharmacokinetics. Ranitidine reduced the absorption of procainamide by 10% and by 24% at the higher dose level. Two‐hourly renal clearance values of procainamide were significantly (PQ0.05) reduced in the 2 to 10 h period and for NAPA between 0 to 6 and 8 to 10 h. The larger ranitidine dose reduced the renal clearances of procainamide and NAPA over the control period at each 2‐hourly time period. The reductions in renal clearance are most likely mediated by competition for the renal tubular cationic secretory pathway. Clinical implications arising from this study suggest a reduction in procainamide dosage may be necessary in a small, select number of patients with high plasma ranitidine concentrations, e.g., the elderly; furthermore, failure of therapeutic response for some drugs may be due to ranitidine‐induced impaired gastrointestinal absorption.
The pharmacokinetics of imipenem (thienamycin‐formamidine) and the renal dehydropeptidase inhibitor cilastatin sodium in normal subjects and patients with renal failure.
Authors: Verpooten GA , Verbist L , Buntinx AP , Entwistle LA , Jones KH , De Broe ME
Published: July 2012

The antibiotic imipenum (thienamycin‐formamidine) is partially hydrolyzed during excretion by a renal brush border dehydropeptidase. The co‐administration of imipenum with the renal dehydropeptidase inhibitor cilastatin results in an increase of the urinary recovery of the antibiotic, both in animals and humans. To study the pharmacokinetics of imipenem and cilastatin, subjects with normal renal function and patients with different degrees of renal insufficiency received intravenously 250 mg imipenum alone and 250 mg imipenem with 250 mg cilastatin. The mean plasma half‐life of imipenem varied from 52 min in subjects with normal renal function to 173 min in subjects with end‐stage renal failure studied while off‐dialysis. The plasma half‐ life of imipenem was not affected by the co‐administration of cilastatin. The mean plasma half‐life of cilastatin varied from 54 min in normals to 798 min in patients with end‐stage renal failure. The co‐ administration of cilastatin resulted in an increase of the urinary concentration and in the urinary recovery of imipenem, the effect being more pronounced in the subjects with normal or only mildly impaired renal function. The plasma clearance of imipenem was decreased when cilastatin was co‐administered, possibly due to inhibition of tubular secretion of imipenem. Elimination studies performed during haemodialysis indicated efficient removal of both imipenem and cilastatin during a 4 h session. In view of the important increase in half‐life of cilastatin as a function of increasing renal failure, a dosage reduction is proposed in patients with severe renal failure. It is recommended that the maximum dose of imipenem/cilastatin would be limited to either 1000/1000 mg twice daily or 500/500 mg four times daily in patients with a creatinine clearance of less than 15 ml/min. Also, a supplementary dose of imipenem and cilastatin after dialysis is recommended.
Naproxen pharmacokinetics in the elderly.
Authors: Upton RA , Williams RL , Kelly J , Jones RM
Published: July 2012

While naproxen pharmacokinetics appear to be altered in the presence of both diminished renal and hepatic function, the degree to which naproxen disposition might be influenced in the elderly by concurrent alteration in these functions is not obvious. Total plasma clearance/bioavailability (CL/F) of naproxen after a single 375 mg oral dose was found to be less in a group of 10 healthy men between 66 and 81 years of age than in 10 healthy men between 22 and 39 years (0.318 +/‐ 0.078, 0.416 +/‐ 0.061 l/h). At steady state (375 mg, 12 hourly), however, CL/F was statistically indistinguishable between the two groups. The fraction of naproxen unbound to plasma protein was doubled in elderly subjects, both at peak and trough drug concentrations. The lowered protein binding tended to obscure a 50% decrement in the intrinsic clearance of naproxen in the elderly as estimated by unbound clearance/bioavailability (213 +/‐ 64, 396 +/‐ 155 l/h). As a result, mean steady‐state plasma concentrations of naproxen were indistinguishable between the elderly and young (64.2 +/‐ 8.5, 58.2 +/‐ 8.1 mg/l) but the elderly generated twice the mean steady‐state unbound plasma drug concentration (0.157 +/‐ 0.039, 0.0859 +/‐ 0.0212 mg/l). Since it is the unbound drug concentration which appears in general to relate more closely to pharmacological and toxic effect, it may be advisable to reduce naproxen doses by half in the elderly, pending plasma drug concentration‐response studies in this age group. If a similar perturbation with age occurs in benoxaprofen protein binding as was observed with naproxen, benoxaprofen intrinsic clearance in the elderly might be only one quarter of that in younger individuals; a factor which may contribute to the toxicity of this drug in the elderly.
Stereoselective binding of propranolol enantiomers to human alpha 1‐ acid glycoprotein and human plasma.
Authors: Albani F , Riva R , Contin M , Baruzzi A
Published: July 2012

The binding of propranolol enantiomers to human albumin (ALB), alpha 1‐ acid glycoprotein (alpha 1‐AGP) and plasma was studied. (‐) propranolol is more bound than (+)propranolol to alpha 1‐AGP (P less than 0.001) and to plasma (P less than 0.05). In solutions containing ALB at a constant concentration (580 mumol/l) and alpha 1‐AGP at increasing concentrations, the binding of both isomers increases but the stereo selectivity is evident throughout the alpha 1‐AGP concentration range examined (25‐100 mumol/l).
Quantification of side‐effects of beta‐adrenoceptor blockers using visual analogue scales.
Authors: Lewis RV , Jackson PR , Ramsay LE
Published: July 2012

We have devised a series of visual analogue scales (VAS) to measure the side‐effects prevalent amongst hypertensive patients taking beta‐ adrenoceptor blockers, and we present the results of a pilot study. These show that the method is suitable for studying side‐effects and suggest that patients on beta‐adrenoceptor blockers experience a greater incidence of tiredness of the legs, (P = 0.001), cold digits (P = 0.005) and vivid dreaming (P = 0.01) when compared to hypertensive patients not taking beta‐adrenoceptor blockers.
The action of prazosin and propylene glycol on methoxamine‐induced bronchoconstriction in asthmatic subjects.
Authors: Black JL , Salome C , Yan K , Shaw J
Published: July 2012

The effect of 1 mg inhaled prazosin on bronchoconstriction induced by methoxamine was investigated in seven asthmatic subjects. Prazosin caused significant inhibition of the methoxamine‐induced bronchoconstriction in six of the seven patients. These findings suggest that methoxamine produces bronchoconstriction in asthmatic subjects via stimulation of alpha‐adrenoceptors. In previous studies propylene glycol has been used as a vehicle for delivery of prazosin. This substance was found to cause significant inhibition of methoxamine effects and to shift the dose response curve to histamine to the right in four of seven patients.
The potentiation of acenocoumarol anticoagulant effect by amiodarone.
Authors: Arboix M , Frati ME , Laporte JR
Published: July 2012

Out of 690 patients (337 males and 353 females) on long‐term acenocoumarol therapy, 80 (35 males and 45 females) were taking amiodarone. Forty patients had started amiodarone treatment while being treated with acenocoumarol. Of these, nine patients had begun amiodarone treatment while taking acenocoumarol. The relation between the daily dose of acenocoumarol and the prothrombin ratio (AC dose/PR ratio) has been considered a useful indicator to study the interaction between amiodarone and acenocoumarol. Differences of acenocoumarol daily dose between takers and non‐takers of amiodarone were statistically significant (t = 5.35; P less than 0.001) for the whole population, for all the age groups, and also among males (t = 2.43; P less than 0.01) as well as among females (t = 5.38; P less than 0.001). Out of 40 patients chronically treated with acenocoumarol in whom amiodarone was instituted, 32 showed a decrease of the AC dose/PR ratio, while in eight patients no change was recorded (paired t‐test, t = 5.82; P less than 0.001). In 15 patients who were being concomitantly treated with acenocoumarol and amiodarone, amiodarone was discontinued. An increase of the AC dose/PR ratio was recorded (paired t‐test, t = 4.01; P less than 0.001). Nine patients had started treatment with amiodarone while receiving acenocoumarol and a decrease of the AC dose/PR ratio was documented; amiodarone was discontinued some months later, and an increase of the AC dose/PR ratio was seen.
An electromyographic method of objectively assessing cough intensity and use of the method to assess effects of codeine on the dose‐response curve to citric acid.
Authors: Cox ID , Wallis PJ , Apps MC , Hughes DT , Empey DW , Osman RC , Burke CA
Published: July 2012

The integrated surface abdominal electromyogram (EMG) has been used as a simple measurement of cough intensity which correlates well with the volume, air flow and noise produced in different coughs. Using the integrated abdominal EMG as a measure of cough intensity, dose response curves to inhaled citric acid can be drawn which are highly reproducible. We have studied the effects of codeine (60 mg) on these curves, and have demonstrated a reduction in cough intensity. It is suggested that this method of testing the effects of an antitussive on such a dose‐response curve may be a useful one.
Theophylline‐rifampicin interaction: non‐selective induction of theophylline metabolic pathways.
Authors: Robson RA , Miners JO , Wing LM , Birkett DJ
Published: July 2012

The effect of rifampicin pre‐treatment (600 mg daily for 6 days) on theophylline disposition at steady state was investigated in six healthy males. Following rifampicin treatment total plasma clearance of theophylline increased by 82%. Theophylline clearance through each metabolic pathway was increased, 1‐demethylation by (116 +/‐ 34%) (mean +/‐ s.e. mean), 3‐demethylation by (91 +/‐ 16%) and 8‐oxidation by (81 +/‐ 17%). Renal clearance of unchanged drug was not altered. Previous studies have suggested that two forms of cytochrome P‐450 are involved in theophylline metabolism, one mediating the N‐demethylations and the other 8‐oxidation. Thus, unlike the selective inductive effect of rifampicin on antipyrine metabolic pathways, rifampicin does not differentially affect those forms of cytochrome P‐450 involved in theophylline metabolism. The extent to which theophylline metabolism is induced by rifampicin is likely to have important clinical consequences.
Oxprenolol placental transfer, plasma concentrations in newborns and passage into breast milk.
Authors: Sioufi A , Hillion D , Lumbroso P , Wainer R , Olivier‐Martin M , Schoeller JP , Colussi D , Leroux F , Mangoni P
Published: July 2012

Thirty‐two pregnant hypertensive patients were treated with oxprenolol administered in combination with dihydralazine as Trasipressol tablets. Before delivery, oxprenolol was demonstrable in the maternal plasma and the amniotic fluid. The free fraction of oxprenolol in the maternal serum (15% +/‐ 7.8; mean +/‐ s.d.; n = 25) was similar to that in normal serum. At the end of delivery, oxprenolol was found in both the maternal and umbilical plasma in most cases. Measurable, but low oxprenolol concentrations were present in the newborn plasma. After delivery, oxprenolol was demonstrable in the maternal plasma and breast milk. An infant weighing 3 kg and consuming 500 ml of breast milk per day would receive a maximum dose 60 times less than the normal daily dose for a hypertensive adult (4 mg/kg).
Influence of food and reduced gastric acidity on the bioavailability of bacampicillin and cefuroxime axetil.
Authors: Sommers DK , van Wyk M , Moncrieff J , Schoeman HS
Published: July 2012

The present study was designed to investigate the effect of food and of a raised intragastric pH on the bioavailability of two prodrug beta‐ lactam, antibiotics, namely bacampicillin and cefuroxime axetil. Six healthy volunteers participated in an intraindividual comparison of absorption of (a) prodrug, (b) breakfast, followed by prodrug, (c) breakfast, ranitidine and sodium bicarbonate followed by prodrug, and (d) ranitidine and sodium bicarbonate, followed by prodrug. All volunteers were dosed with both bacampicillin and cefuroxime axetil under the above regimens. The drug‐free periods between trials were 7 days. Blood samples were obtained before and 20, 40, 60, 90, 120, 150, 180, 210 min and 4, 5, 6, 8 and 10 h after administration. The urine was collected for a period of 10 h after dosing with the antibiotic. An estimation of the relative bioavailability of the drugs under the various regimens was made by comparing the average areas under the serum concentration time curves and also the amounts recovered in the urine. Both food and reduced gastric acidity decreased the bioavailability of bacampicillin (as ampicillin) and these variables had an additive lowering effect on the AUC and percentage urinary recovery. Possibly this ester becomes partially hydrolyzed prior to absorption on raising the intragastric pH. Adsorption onto food components or complexing with proteins may also play a role in the reduced bioavailability of bacampicillin in the presence of food. In contrast, the absorption of the cefuroxime ester was enhanced postprandially. This may be rationalized in terms of delayed gastric emptying and gastrointestinal transit which allows more complete dissolution or prolonged residence at the most favourable site of absorption in the intestine.(ABSTRACT TRUNCATED AT 250 WORDS)
Electrophysiological aspects of benzodiazepine antagonists, Ro 15‐1788 and Ro 15‐3505.
Authors: Gath I , Weidenfeld J , Collins GI , Hadad H
Published: July 2012

The comparative action of two specific benzodiazepine antagonists, Ro 15‐1788 and Ro 15‐3505 was examined in six healthy volunteers. Medication was given i.v. in a double‐blind cross over pattern, and EEG was recorded throughout each experimental session. Ten minutes after the injection of one of the antagonists or placebo, midazolam was injected in incremental doses until first signs of drowsiness appeared in the EEG. The EEG was computer analyzed, using adaptive segmentation and time‐dependent clustering. Continuous power profiles for various frequency bands, as well as power ratios for the physiological frequency bands (e.g. sigma/alpha power ratio) were generated. It has been found that sigma/alpha power ratio was the most sensitive parameter detecting early effects of midazolam on the EEG signal, thus enabling a semi‐quantitative titration of the antagonists by midazolam. Ro 15‐1788 in doses of 5 mg i.v. was counteracted on average by 7.3 mg midazolam. From the EEG analysis it has been found that Ro 15‐3505 was at least 4‐5 times more potent than Ro 15‐1788.
Interaction of isoxicam with acetylsalicylic acid.
Authors: Esquivel M , Cussenot F , Ogilvie RI , East DS , Shaw DH
Published: July 2012

Ten healthy male volunteers were given 200 mg p.o. of isoxicam after an overnight fast and the plasma concentrations over time followed for 96 h by h.p.l.c. Five days later enteric coated acetylsalicylic acid (ASA) 650 mg four times daily was started and continued for 10 days producing steady state trough plasma salicylate of 83 mg/l (range 21‐133). A second 200 mg isoxicam dose was given 5 days after starting ASA and the plasma concentration time‐curve again followed. After ASA, there was no change in lag time (0.54 vs 0.51 h), time to peak concentration (10 vs 10 h), or disappearance t1/2 (28.7 vs 31.0 h) however the peak isoxicam concentration and AUC were reduced 18 and 22% respectively (P less than 0.01). Plasma protein binding of isoxicam studied by equilibrium dialysis was 96 +/‐ 1% in the absence and 86 +/‐ 5% in the presence of ASA. The reduction in binding was unrelated to plasma SA concentrations achieved or observed reductions in AUC for plasma isoxicam. ASA decreased plasma isoxicam binding, peak plasma isoxicam concentrations and AUC without altering the apparent disappearance half‐life of total plasma isoxicam after a single oral dose.
2‐Hydroxylation of ethinyloestradiol in relation to the oxidation of sparteine and antipyrine.
Authors: Back DJ , Maggs JL , Purba HS , Newby S , Park BK
Published: July 2012

The metabolism of [3H]ethinyloestradiol (EE2) was investigated in six male subjects who had been phenotyped with respect to sparteine metabolism (three metabolizers and three non‐metabolizers). Urinary metabolite profiles of EE2 were virtually identical. Following enzyme hydrolysis of sulphate and glucuronide conjugates the major urinary metabolite was 2‐methoxyEE2. The ratio EE2:2‐methoxyEE2 was taken as a measure of EE2 2‐hydroxylation (metabolizers, 2.4 +/‐ 0.3; non‐ metabolizers, 2.5 +/‐ 0.4). Primaquine (45 mg), previously shown to inhibit antipyrine metabolism, had no effect on EE2 2‐hydroxylation. Supporting studies in rats showed that acute administration of primaquine (50 mg/kg) and 1‐methylimidazole (50 mg/kg) inhibited antipyrine but not EE2 metabolism. It is concluded that the cytochrome P‐450 enzyme responsible for 2‐hydroxylation of EE2 is distinct from the enzymes involved in the oxidation of sparteine and antipyrine.
Xipamide: no advantage over bendrofluazide in hypertension.
Authors: Ramsay LE , Freestone S
Published: July 2012

In patients with uncontrolled hypertension addition of xipamide 20 mg daily to bendrofluazide 5 mg daily produced no significant additive antihypertensive effect, and the 95% confidence limits excluded a clinically important response. Xipamide treatment worsened hypokalaemia and increased the blood urea concentration significantly.
Cimetidine does not alter ibuprofen kinetics after a single dose.
Authors: Conrad KA , Mayersohn M , Bliss M
Published: July 2012

Cimetidine does not slow the disappearance of ibuprofen from the serum after a single dose in healthy male volunteers. This suggests that no change in ibuprofen dosing is necessary when cimetidine is co‐ administered.
Pharmacokinetic study of cyclosporin A (Sandimmun) in patients with primary biliary cirrhosis.
Authors: Robson S , Neuberger J , Keller HP , Abisch E , Neiderberger W , von Graffenried B , Williams R
Published: July 2012

The pharmacokinetics of cyclosporin A (CS‐A) were studied in 10 patients with primary biliary cirrhosis (PBC) after oral administration in steady state. Mean values for area under the blood concentration‐ time curve (AUC), time to maximal blood concentration (tmax), maximal blood concentration (Cmax) and elimination half‐life (t1/2,z) were similar to results of previous studies in transplant patients. The variation between patients was large. No significant correlations of pharmacokinetic data with biochemical or histological parameters were found. Because of the high variability of pharmacokinetic parameters, patients with PBC treated with CS‐A need to be regularly controlled for nephrotoxicity by estimation of serum creatinine and bioavailability (trough blood levels).
Ethosuximide in epileptic women during pregnancy and lactation period. Placental transfer, serum concentrations in nursed infants and clinical status.
Authors: Kuhnz W , Koch S , Jakob S , Hartmann A , Helge H , Nau H
Published: July 2012

A total of 10 epileptic mothers treated with ethosuximide (ES) as well as their 13 newborns were included in this study. At birth foetal/maternal serum concentration ratios were 0.97 +/‐ 0.02 (n = 7) and ES half‐lives in three neonates were 32, 37 and 38 h. The breast milk concentrations of ES were similar to those in maternal serum (milk/serum: 0.86 +/‐ 0.08, n = 12) and the nursed infants maintained serum levels between 15 and 40 micrograms/ml. Two major malformations (bilateral clefting, hare‐lip) were observed in two neonates whose mothers received either ES/PB or ES/PMD comedication. The number of minor anomalies was higher in the ES group (6.2, n = 12) than in the pair‐matched control group of infants born to non‐epileptic mothers (2.1, n = 10). Neonatal behaviour complications occurred in seven infants, two of them were severely affected.
Influence of rifampicin treatment on antipyrine clearance and metabolite formation in patients with tuberculosis.
Authors: Teunissen MW , Bakker W , Van der Meerburg‐Torren JE , Breimer DD
Published: July 2012

The influence of an 8‐day therapy with rifampicin (600 mg daily) was studied on antipyrine plasma clearance and metabolite formation in seven patients with tuberculosis (age 18‐79 years), who were also treated with isoniazid and pyrazinamide. After rifampicin treatment the elimination half‐life of antipyrine had decreased in all patients from 12.9 +/‐ 5.0 to 8.8 +/‐ 2.0 h (P less than 0.05). Antipyrine clearance had increased from 2.2 +/‐ 0.9 to 2.9 +/‐ 0.7 l/h (P less than 0.05), while no change in apparent volume of distribution was observed. The increase in antipyrine clearance was primarily due to a selective increase in the rate of formation of norantipyrine by 80% from 6.9 +/‐ 3.4 to 12.4 +/‐ 3.4 ml/min. Rifampicin seems to induce preferentially the cytochrome P‐450 (iso‐) enzyme(s) involved in the demethylation of antipyrine to norantipyrine. Other pathways of antipyrine metabolism were hardly affected. This provides further evidence for the involvement of different iso‐enzymes of the cytochrome P‐450 system in antipyrine metabolism in man.
Initial clinical experience with ICI 141,292 (Visacor), a new selective beta 1‐adrenoceptor blocker with ISA‐a multicentre trial in 59 patients.
Authors: Dahlof B , Danielson M , Andersson O , Thulin T , Ohman P , Morlin C , Boberg J , Karlberg BE , Jern S , Hansson L
Published: July 2012

The objective of this placebo controlled double‐blind multicentre (six centres) trial was to investigate the safety and efficacy of ICI 141,292 (Visacor), a new selective beta 1‐adrenoceptor antagonist with modest intrinsic sympathomimetic activity (ISA), in hypertensive patients. Fifty‐nine patients with mild essential hypertension were randomized to two of five treatment alternatives (placebo, 50 mg, 100 mg 200 mg or 300 mg of ICI 141,292) each given once daily for 2 weeks with a 4 week placebo period before (run in) and in between (wash out) active periods. Thus, each of the five treatments was evaluated in 20‐ 24 patients. After 2 weeks (24 h after last dose) the reduction in recumbent blood pressure for all doses except 50 mg of ICI 141,292 was statistically significant and in the order of 6/4 mm Hg. Standing systolic blood pressure was reduced in a dose‐dependent way but only significant for 200 mg of ICI 141,292 (8 mm Hg). Heart rate changes (delta) less than 4 beats/min) were not statistically significant for any dose. It is concluded that ICI 141,292 was well tolerated and had a significant but weak antihypertensive effect which might be explained by too much beta 1‐adrenoceptor ISA.
Failure of ‘therapeutic’ doses of beta‐adrenoceptor antagonists to alter the disposition of tolbutamide and lignocaine.
Authors: Miners JO , Wing LM , Lillywhite KJ , Smith KJ
Published: July 2012

The effects of separate 1 week pre‐treatments with each of the beta‐ adrenoceptor antagonists, propranolol (80 mg every 12 h), metoprolol (100 mg every 12 h) and atenolol (50 mg once daily), on the disposition of a single i.v. dose of tolbutamide were studied in six healthy volunteers. In addition, the effects of a 1 week pre‐treatment with metoprolol (100 mg every 12 h) and atenolol (50 mg once daily) on the disposition of orally and i.v. administered lignocaine were determined in seven healthy subjects. Tolbutamide clearance, half‐life, volume of distribution and plasma protein binding were not altered by the beta‐ adrenoceptor blocker pre‐treatments. Similarly, neither metoprolol nor atenolol had a significant effect on the systemic clearance, apparent oral clearance or other dispositional parameters of lignocaine. ‘Therapeutic’ plasma concentrations of the beta‐adrenoceptor blockers were confirmed on each study day. It is concluded that the inhibition of oxidative drug metabolism previously reported for lipophilic beta‐ adrenoceptor blockers may be selective for different forms of cytochrome P450 and possible concentration‐dependent.
Effect of migraine attacks on paracetamol absorption.
Authors: Tokola RA , Neuvonen PJ
Published: July 2012

The absorption of effervescent paracetamol (1000 mg) was investigated in nine female patients during a migraine attack and in the same patients when headache free. Migraine attack decreased (P less than 0.05) the areas under the serum paracetamol concentration‐time curves (AUC) of 0‐2 h, 0‐4 h and 0‐6 h and the peak serum concentration. The severity of nausea correlated significantly with the decrease in the AUC values. Our results support findings of delayed gastric emptying in migraine attacks. Both a delay and an impairment of drug absorption may follow.
The effect of posture at the time of administration on the central depressant effects of the new hypnotic zopiclone.
Authors: Channer KS , Dent M , Roberts CJ
Published: July 2012

Nine healthy volunteers swallowed 7.5 mg zopiclone in the standing and lying positions on different occasions. Plasma concentrations of zopiclone and psychometric tests, including simple and complex reaction time, and critical flicker fusion threshold, were performed at regular intervals after drug administration. The results show that when the drug was swallowed in the supine position, there was a significant delay in the onset of the impairment of psychomotor function, with prolongation in time to peak impairment by 30‐40 min (P less than 0.02). The overall impairment in psychomotor performance was found to be significantly less after administration of the drug in the supine position (P less than 0.005). Pharmacokinetic analysis revealed a prolongation in lag time of greater than 20 min before absorption began (P less than 0.002) after supine drug administration, with a significantly lower rate constant of absorption (P less than 0.02). Area under the plasma concentration‐time curve extrapolated to infinity and rate constant of elimination were not significantly different between the two modes of administration. We conclude that to obtain a rapid and complete effect from the hypnotic zopiclone, the tablet should be swallowed in the standing position.
Drug metabolism in diabetic subjects with fatty livers.
Authors: Pirttiaho HI , Salmela PI , Sotaniemi EA , Pelkonen RO , Pitkanen U , Luoma PV
Published: July 2012

The effect of fatty degeneration of liver parenchyma on drug metabolism was investigated in 21 obese non‐insulin‐dependent diabetic subjects by measuring plasma antipyrine kinetics, hepatic cytochrome P‐450, liver size and the extent of fatty infiltration. The hepatic drug metabolising capacity, as measured by total antipyrine clearance and the estimated total amount of cytochrome P‐450, was at the same level as in non‐diabetic control subjects with normal livers. Relative antipyrine clearance (per unit weight of liver) and cytochrome P‐450 concentrations were significantly lower in the diabetics than in controls. The extent of fatty infiltration correlated poorly with the indices of drug metabolism. In non‐insulin‐dependent diabetics, slight to moderate hepatic fatty infiltration, without more serious structural distortion interfering with hepatic blood flow or hepatocellular function, seems to have only a minor influence on drug metabolism.