bluuebunny/crossref_metadata_2025 huggingface dataset:
The influence of age, smoking and hyperthyroidism on plasma propranolol steady state concentration.
Authors: Feely J , Crooks J , Stevenson IH
Published: July 2012

1 Plasma propranolol steady state concentration (Css) was determined during chronic dosage (160 mg/day) in 22 hyperthyroid patients (aged 16‐ 75 years, 11 smokers, 11 non‐smokers) and again following treatment when euthyroid. 2 There was a positive correlation between plasma propranolol Css and age in patients both when hyperthyroid (r = 0.74, P less than 0.01) and when euthyroid (r = 0.58, P less than 0.05). 3 Plasma propranolol Css in hyperthyroid patients were lower (P less than 0.05) in smokers than in non‐smokers. 4 Following correction of hyperthyroidism there was a significant increase (P less than 0.01) in both the plasma propranolol Css and degree of plasma protein binding of propranolol. 5 Hyperthyroidism and smoking are known to increase the rate of drug metabolism and it is suggested that these variables may give rise to or accentuate an age related reduction in propranolol clearance.
A study of pethidine kinetics and analgesia in women in labour following intravenous, intramuscular and epidural administration.
Authors: Husemeyer RP , Cummings AJ , Rosankiewicz JR , Davenport HT
Published: July 2012

1 Epidural administration of opiates for analgesia has recently generated widespread interest and would theoretically be advantageous as a method for relief of pain in labour. 2 Plasma pethidine concentrations were measured after intravenous, intramuscular and epidural administration of pethidine to women in labour and after epidural administration to non‐pregnant female surgical patients. 3 Kinetic parameters were derived from the plasma concentration data in each group of subjects and the relationship between plasma kinetics and analgesia in labour were examined. 4 Absorption of pethidine from the epidural space in pregnant women in rapid and excepting the lower initial values, the average plasma concentration and area under the plasma concentration v time curve did not differ significantly (P less than 0.01) from those obtained with intravenous dosage, but were significantly higher (P less than 0.01) during the first 2 h after dosage than the results after intramuscular administration. The analgesia provided by the epidural route of administration was greater than with intravenous or intramuscular administration. 5 It is postulated that the analgesic efficacy of epidural pethidine in women in labour is due to a combination of systemic and local effects and that the local effect is attributable to the local anaesthetic properties of pethidine rather than a selective anti‐nociceptive action on the spinal cord.
Comparison of prorenoate potassium and spironolactone after repeated doses and steady state plasma levels of active metabolites.
Authors: McInnes GT , Shelton JR , Harrison IR , Perkins RM , Palmer RF
Published: July 2012

1 After repeated single daily doses, the aldosterone antagonists prorenoate potassium and spironolactone were compared with regard to renal antimineralocorticoid activity, plasma potassium concentration and steady state plasma levels of their active metabolites, prorenone and canrenone respectively, in a balanced crossover study of twelve healthy subjects. 2 Following challenge with the mineralocorticoid, fludrocortisone, best estimates of the potency of prorenoate potassium relative to spironolactone were 3.6 (95% confidence limits 1.6‐10.4) for urinary sodium excretion and 3.4 (95% confidence limits 2.0‐6.5) for urinary log10 10Na/K. Estimates with respect to urinary potassium excretion and plasma potassium concentration were imprecise, confirming the limitations of the fludrocortisone model in the evaluation of aldosterone antagonists at steady state. 3 Both compounds exhibited directly proportional relationships between daily dose and steady state plasma levels of active metabolites. The approximate mean terminal elimination half‐life of prorenone at steady state was 32.6 h (range 18‐ 80 h).
Ethanol‐induced increase in procainamide acetylation in man.
Authors: Olsen H , Morland J
Published: July 2012

1 The effect of ethanol on procainamide pharmacokinetics was studied in humans by two different experimental designs. In one, ethanol was given 1.5 h after taking the drug followed by hourly drinks, while in the other ethanol was given 2 h before and subsequently after taking the drug. 2 In both studies, ethanol caused a significant reduction of T1/2 and a significant increase in total clearance of procainamide, while the apparent volume of distribution of procainamide, as well as the renal clearance of both procainamide and N‐acetylprocainamide were unaffected by ethanol treatment. 3 Ethanol treatment increased the percentage of N‐acetylprocainamide measured in blood and urine and the ratio of AUCNAPA/AUCPA significantly. 4 The T1/2 and total clearance of procainamide was significantly different in slow and rapid acetylators.
Antihypertensive action of acebutolol (Sectral) when used concomitantly with hydrochlorothiazide.
Authors: Mitenko PA , McKenzie JK , Brossard JJ
Published: July 2012

1 In a placebo‐controlled study, the respective anti‐hypertensive effects of hydrochlorothiazide and hydrochlorothiazide plus the beta‐ adrenoceptor blocker acebutolol were assessed in 18 patients with moderately severe essential hypertension. 2 Hydrochlorothiazide 100 mg daily decreased the mean supine blood pressures from 163/107 mmHg to 150/103 mmHg. Addition of acebutolol in a single‐blind fashion in doses up to 800 mg daily reduced mean supine pressure to 137/95 mmHg. Further increases in acebutolol dosage to a maximum of 2000 mg daily in 13 patients whose hypertension was not well controlled on lower doses resulted in a mean supine blood pressure of 132/92 mmHg.
Oxprenolol, methyldopa and lipids in diabetes mellitus.
Authors: Benfield GF , Hunter KR
Published: July 2012

1 Twelve‐week courses of oxprenolol and methyldopa were administered in a randomised, double‐blind cross over study to ten insulin dependent hypertensive diabetics. 2 Prior to treatment, and at the end of each period of drug administration, fasting levels of high density lipoprotein, triglycerides, free fatty acids and cholesterol were measured. 3 Neither preparation altered levels of high density lipoprotein and cholesterol, but both drugs significantly reduced the free fatty acids. 4 Whereas oxprenolol did not alter triglyceride levels, methyldopa significantly elevated triglycerides above pre‐ treatment values. 5 Oxprenolol does not appear to influence lipoprotein fractions affecting the relative risks of coronary heart disease, but methyldopa seems to have potentially detrimental effects of triglyceride levels.
Comparison of two recently published algorithms for assessing the probability of adverse drug reactions.
Authors: Busto U , Naranjo CAU , Sellers EM
Published: July 2012

1 A simple valid and reliable method for estimating the probability of adverse drug reactions (adverse drug reactions probability scale, APS) has been recently described (Naranjo et al., 1981a). 2 The results using APS were compared to those obtained with another more detailed algorithm (adverse reactions scoring system, ASS) described by Kramer et al. (1979). 3 Sixty‐three randomly selected adverse drug reactions (ADRs) were rated by two observers, using APS and ASS one year apart. The cases were ordered in a random sequence. Between‐raters reliability using APS (R(est) = 0.96 and ASS (R(est) = 0.86), was very high. 4 ADR scores obtained with both methods were highly correlated (r = 0.82, P less than 0.001). However, time spent using ASS was significantly longer (paired t‐test, t = 1.70, P less than 0.05). 5 These results suggest that while ASS is somewhat more complex than APS both are equally reliable and will give very similar conclusions regarding the probability of ADRs. Such algorithms must be used if the clinical assessment of ADRs is to become acceptably reliable.
Relative potency and structure activity relationships of aldosterone antagonists in healthy man: correlation with animal experience.
Authors: McInnes GT , Shelton JR , Ramsay LE , Harrison IR , Asbury MJ , Clarke JM , Perkins RM , Venning GR
Published: July 2012

1 The renal antimineralocorticoid potency of single doses of thirteen compounds with properties in animals compatible with competitive aldosterone antagonism was compared to that of spironolactone in healthy men. 2 Twelve compounds showed significant activity when compared to placebo but only one, prorenoate potassium, was significantly more potent than spironolactone on a weight basis. 3 The results allowed ranking of the compounds in order of potency relative to spironolactone and general observations on structure activity relationships in man. 4 Animal bioassays and in vitro aldosterone binding studies are unreliable predictors of the human activity of competitive mineralocorticoid antagonists.
Tachyphylaxis after repeated dosage of decamethonium in anaesthetized man.
Authors: Hughes R , Al‐Azawi S , Payne JP
Published: July 2012

1 The tetanic and single twitch responses to the adductor pollicis muscle were used to study the neuromuscular effects of repeated dosage of decamethonium in nine anaesthetized patients. 2 In two of three patients who received the same total dose of decamethonium in three separate series of injections, blockade of the tetanic response was less after the third administration. In the third patient tachyphylaxis was evident after the second series of injections. 3 In three other patients, tachyphylaxis occurred after the second series of injections when the total dose of decamethonium administered was at least twice that given on the first occasion. 4 In terms of tachyphylaxis the single twitch response followed a similar pattern to that of the tetanic response. 5 Once tachyphylaxis had developed, neuromuscular block of the tetanic response by decamethonium was antagonised by neostigmine (2.5 mg) and enhanced by 2% halothane. 6 In contrast, in three patients who were not exposed to more than one series of injections of decamethonium, and presumably therefore before tachyphylaxis had developed, neuromuscular block of the tetanic response was potentiated by neostigmine. Under these circumstances recovery was unaffected by halothane. 7 Thus, when tachyphylaxis occurs with decamethonium the characteristics of the block change to resemble those of the competitive neuromuscular blocking agents; these findings could be of importance in clinical anaesthesia.
Antihypertensive effects of lofexidine in patients with essential hypertension.
Authors: Fagan TC , Bloomfield SS , Cowart TD , Corns‐Hurwitz RH , Lipicky RJ , Conradi EC , Hsu CY , Grossman WJ , Harmon GE , Degenhart WJ , Sinkfield AW , Gaffney TE
Published: July 2012

1 Single oral doses of lofexidine, 0.1, 0.3, and 0.6 mg produced dose related decreases in supine and standing arterial pressure and heart rate in nineteen patients with essential hypertension. 2 A mean oral antihypertensive threshold dose of less than 0.1 mg was estimated. 3 Lofexidine decreased mean urinary noradrenaline excretion 28% and caused significant retention of sodium and water. 4 The most prominent side effects were sedation and orthostatic dizziness. 5 Lofexidine is pharmacologically similar to, but apparently less potent than clonidine as an antihypertensive agent.
Disopyramide pharmacokinetics during recovery from myocardial infarction.
Authors: Bryson SM , Cairns CJ , Whiting B
Published: July 2012

1 Previous pharmacokinetics studies of disopyramide in patients with ischaemic heart disease include unexplained reports of poor bioavailability and extremely long elimination half‐lives which undermine accepted dosage recommendations. 2 Disopyramide pharmacokinetics were investigated after intravenous and oral administration to nine such patients. 3 Mean elimination half‐life (6.82 h) and bioavailability (79.8%) were consistent with findings from a previous study in young healthy volunteers. 4 Volume of distribution was reduced by 25%: the mean +/‐ s.d. value was 0.61 +/‐ 0.17 l/kg. Total body clearance was significantly reduced: the mean +/‐ s.d. value was 1.02 +/‐ 0.16 ml min‐1 kg‐1. 5 These figures indicate that, in this patient group, if renal function is not significantly impaired, a standard loading dose of 2 mg/kg should be followed by the appropriate maintenance dose administered three or four times daily.
Bioavailability of diazepam after intravenous, oral and rectal administration in adult epileptic patients.
Authors: Dhillon S , Oxley J , Richens A
Published: July 2012

1 The absorption of single doses of diazepam in six adult epileptic subjects following intravenous, oral and rectal administration were studied in order to evaluate the usefulness of the latter in emergency situations in the adult. 2 Diazepam tablets (Valium, Roche) and rectal solution (Valium solution for intravenous administration) produced similar peak serum concentrations after delays of 15‐90 min. 3 Two suppository formulations showed statistically significant differences in absorption characteristics. 4 Serum diazepam levels above 400 ng ml‐ 1 (suggested to be necessary for a satisfactory anticonvulsant effect) were reached in only a few subjects after rectal doses of 10‐20 mg of solution, and then usually after a delay of over 2 h.
A comparison of triprolidine and cyclizine on histamine (H1) antagonism, subjective effects and performance tests in man.
Authors: Hamilton M , Bush M , Bye C , Peck AW
Published: July 2012

1 The effects of triprolidine and cyclizine on the histamine skin response, performance tests and subjective effects were examined in a controlled, double‐blind study in eight healthy volunteers. 2 Triprolidine was considerably more potent that cyclizine in inhibiting the skin response to histamine. Significant inhibition of flare size occurred at 1, 2 an 4 h after triprolidine 2.5 mg. A smaller but significant reduction occurred at 2 and 4 h after cyclizine 100 mg but not after the 50 mg dose. 3 Cyclizine 100 mg produced a significant increase in reaction time at 4.5 h compared with lactose. Smaller though non significant increases followed triprolidine and cyclizine 50 mg. 4 Subjective effects were seen only after cyclizine 100 mg when subjects were significantly more drowsy, feeble, muzzy, lethargic and dreamy than after lactose dummy. No significant changes followed triprolidine 2.5 mg or cyclizine 50 mg. 5 It was concluded that while cyclizine has antihistamine properties, these are weak compared with triprolidine, and are not seen with doses sufficiently low to avoid central nervous system impairment.
An assessment of beta‐adrenoceptor blockade in man by prizidilol hydrochloride.
Authors: Pitcher DW , Curry PV , Trounce JR
Published: July 2012

1 Prizidilol hydrochloride (SK&F 92657) is a new compound which causes both arteriolar dilatation and beta‐adrenoceptor blockade. The effect of a single oral dose on the responses of heart rate and blood pressure to isoprenaline infusion has been studied in healthy volunteers. 2 Isoprenaline heart rate dose‐response curves showed parallel shifts to the right after oral prizidilol, indicating antagonism by this compound at beta‐adrenoceptors in the heart. 3 Isoprenaline dose‐response curves for decreases in diastolic blood pressure also showed shifts to the right after oral prizidilol, providing evidence of beta‐adrenoceptor antagonism by this drug in peripheral resistance vessels. 4 The peak effect of a 40 mg dose of propranolol was greater than that of a 200 mg dose of prizidilol but both drugs caused persistent beta‐adrenoceptor blockade for at least 7 h after ingestion.
Studies of the haemodynamic effects of creatine phosphate in man.
Authors: Hurlow RA , Aukland A , Hardman J , Whittington JR
Published: July 2012

1 The haemodynamic effects of intravenous creatine phosphate 1000 mg have been studied. 2 During the first 60 min following drug administration heart rate and blood pressure did not change but cardiac output fell significantly by approximately 18%. Calculated total peripheral resistance showed a corresponding significant rise, the maximum increase being approximately 24%. All these changes were beginning to diminish within 90 min after the injection. 3 Total limb blood flow measured in both arm and leg (using venous occlusion strain‐ gauge plethysmography) showed no appreciable changes following injection of creatine phosphate. 4 There was a progressive reduction in leg muscle blood flow (Xe133 clearance method) following injection which was statistically significant with respect to the initial level and reached a minimum (46% reduction) 50 min after the injection. 5 Skin blood flow, estimated by infra‐red photoplethysmography, showed changes complementary to those seen with muscle flow. There was a progressive and significant rise to a peak (73% increase) 30 min after the injection. 6 No adverse reactions to the injections were noted. 7 Reduced cardiac output in the absence of altered total limb blood flow presumably reflects a reduction in visceral blood flow, which was not measured in this study. Within the limbs, creatine phosphate appears to result in a redistribution of blood flow from muscle to skin. Thus, these preliminary results suggest that intravenous creatine phosphate could be clinically useful in situations where short term improvement in skin blood flow would be advantageous and that further controlled studies would be justified.
Labetalol in general practice: a review.
Authors: Kane JA
Published: July 2012

1 The results of the treatment of 8573 hypertensive patients with labetalol in general practice, for periods between 1 month and 5 yr, are reviewed. 2 The data reviewed were obtained from the published literature together with our own published (Kane et al., 1976; Kane et al., 1979) and more recent (unpublished) work. 3 Between 60% and 80% of severe (diastolic blood pressure greater than 120 mmHg) and previously uncontrolled hypertensives responded satisfactorily to the drug, as did up to 88% of mild to moderate hypertensives. 4 The anti‐hypertensive effect of labetalol was not dependent on the frequency of administration, twice and three times daily treatment regimes being equally effective. 5 The withdrawal rate attributable to side‐effects was between 6% and 13%. Tiredness, dizziness, headache and upper gastro‐ intestinal symptoms were the four principal side‐effects, but they were usually transient when labetalol treatment was continued. 6 No drug interactions or adverse haematological or biochemical changes were seen.
The acute and chronic hypotensive effect of labetalol and the relationship with pretreatment plasma noradrenaline levels.
Authors: Agabiti‐Rosei E , Alicandri CL , Beschi M , Castellano M , Fariello R , Montini E , Muiesan ML , Romanelli G , Muiesan G
Published: July 2012

1 Labetalol 100 mg was given intravenously to 27 patients with essential hypertension (12 males, 15 females; WHO I‐II; age range 30‐66 yr; on average, a significant reduction of blood pressure was observed within 5 min (P less than 0.001). Average heart rate was also reduced significantly (P less than 0.01). 2 In 18 patients haemodynamic measurements were performed (dye‐dilution or thermodilution technique): blood pressure reduction was related to peripheral vasodilatation, as cardiac index remained unmodified. 3 The absolute and percentage decrease of blood pressure, heart rate and total peripheral resistance after labetalol 100 mg intravenously, was significantly greater in the patients with higher baseline plasma noradrenaline concentration values. 4 In 12 out of 27 patients labetalol was given orally for 2 months (dose range 300‐1200 mg); the pattern of blood pressure and heart rate changes after oral therapy were comparable to those observed after acute administration of the drug. 5 The degree of blood pressure and heart rate reductions after oral labetalol was also significantly related to pretreatment basal noradrenaline concentration.
Intravenous labetalol in severe hypertension.
Authors: Palu Dal C , Pessina AC , Semplicini A , Hlede M , Morandin F , Palatini P , Sperti G , Rossi GP
Published: July 2012

1 Labetalol was administered by intravenous infusion or by the combination of intravenous bolus injection plus infusion to 15 patients with severe essential hypertension and to one with phaeochromocytoma. 2 With the infusion alone the reduction of arterial pressure was slow to develop and limited in degree, but with the combination of the bolus injection plus the infusion the reduction in pressure was more prompt, more pronounced and longer lasting. Apart from an uncomplicated syncopal attack in one patient, no serious side–effects were encountered. 3 Subsequent treatment with oral labetalol usually required the addition of a diuretic to control the blood pressure probably due to sodium and fluid retention during treatment with labetalol alone.
Alternatives to beta‐blockade in therapy of hypertension with angina pectoris: role of nifedipine or of labetalol.
Authors: Opie LH , White D , Lee J , Lubbe WF
Published: July 2012

1 Patients with combined hypertension and angina pectoris may represent a therapeutic dilemma, with the angina being refractory to conventional beta‐blockade. 2 The added benefit of peripheral vasodilation in control of blood pressure is documented in the case of nifedipine. 3 Improved blood pressure control by added nifedipine may not be accompanied by decreased severity of angina pectoris, emphasizing the complex causation of the angina in such patients. 4 The clinically proven added alpha‐blocking activity of labetalol distinguishes labetalol from other beta‐blockers. However, the suggested benefits of the added alpha‐activity in patients with hypertension and angina remain to be proven by further trials in patients.
Renal haemodynamics after chronic treatment with labetalol and propranolol.
Authors: Malini PL , Strocchi E , Negroni S , Ambrosioni E , Magnani B
Published: July 2012

1 Effective renal plasma flow (ERPF) and glomerular filtration rate (GFR) were measured in two groups of 12 patients both at rest and during sub‐maximal cycloergometer exercise while on placebo and after 3 months of treatment with either labetalol or propranolol. 2 ERPF increased and renal vascular resistance decreased both at rest and during exercise after labetalol treatment, compared with placebo; the opposite was observed after propranolol treatment. 3 GFR increased after labetalol and decreased after propranolol both at rest and during exercise, compared with placebo, but these changes were not statistically significant. 4 Labetalol and propranolol resulted in the same decrease in blood pressure and a comparable incidence of side effects.
The evaluation of labetalol in the treatment of hypertension complicating pregnancy.
Authors: Michael CA
Published: July 2012

1 Eighty‐five women with severe hypertension complicating pregnancy were treated with oral labetalol (Trandate). Six of these had a twin pregnancy and 54 had proteinuria. 2 Effective control of the blood pressure was achieved in all but six patients. The maximum dose of labetalol prescribed was 1200 mg daily. There were no significant maternal or foetal side‐effects. 3 Foeto‐placental function was carefully monitored in all patients. Twenty‐four of the 89 infants born alive showed evidence of intra‐uterine growth retardation, the highest incidence occurring in the group of patients with essential hypertension complicated by pregnancy induced hypertension. 4 The low perinatal mortality of 4.4% was a reflection of the meticulous control of the blood pressure. 5 There were no congenital malformations or evidence of oculotoxicity in any of the infants delivered. 6 The efficient hypotensive action of orally administered labetalol together with the absence of maternal and foetal side effects and consequent improved perinatal mortality confirms that it is an eminently suitable drug for the treatment of hypertension complicating pregnancy.
The use of labetalol in anaesthesia.
Authors: Scott DB
Published: July 2012

1 Observed and possible roles for the use of labetalol in anaesthesia are reviewed. 2 When used together with halothane inhalation anaesthesia, satisfactory conditions are achieved for safe hypotensive anaesthesia: (a) Labetalol and halothane have additive hypotensive effects. (b) The usual dose of labetalol is 25 mg intravenously together with 1% halothane. (c) The duration of hypotension can be controlled in the presence of halothane; withdrawal leads to rapid recovery of pre‐surgery blood pressure. (d) High doses of halothane (3%) with labetalol predispose to the myocardial depressant effects of halothane and undesirable reductions in myocardial performance. 3 As it is now seen to be important to reduce the blood pressure before anaesthesia and surgery in hypertensive patients, then labetalol is likely to be satisfactory either by the intravenous route for immediate reduction or for less urgent reduction of raised arterial pressure by the oral route. 4 It is known that anaesthesia (for example, laryngoscopy) and surgery provoke hypertensive responses which are particularly undesirable in the patient with pre‐existent myocardial ischaemia. In such cases it is likely that previous treatment with labetalol will satisfactorily modify unwanted hypertensive and cardiovascular responses.
Comparison of the effects of propranolol, pindolol, oxprenolol and acebutolol on atrioventricular conduction in unanaesthetized dogs.
Authors: Kantelip JP , Duchene‐Marullaz P , Delaigue‐Fabry R , Eschalier A
Published: July 2012

1 Atrio‐ventricular conduction (AVC) in the unanaesthetized dog (17 animals) was studied using atrial pacing at progressively increasing frequencies applied via electrodes implanted in the right atrium. In animals habituated to the experimental conditions, beta‐adrenoceptor blocking drugs devoid of intrinsic sympathomimetic activity (ISA) modified neither heart‐rate (HR) nor AVC, though 4 mg/kg i.v. propranolol transiently raised HR and facilitated AVC. Due to their ISA, pindolol and oxprenolol raised HR and facilitated AVC at high doses. 2 Thus, when not under anaesthesia, the resting dog, in contrast to man, possesses no tonic adrenergic influence which might be suppressed by beta‐adrenoceptor blockings drugs. 3 After atropine or pentobarbitone, which considerably increased HR, beta‐adrenoceptor blocking effects became clearly visible, and the hitherto reported depressant effects on HR and AVC were observed. However, the ISA of oxprenolol, and especially of pindolol, can partly or completely mask their beta‐adrenoceptor blocking action at high doses under these experimental conditions.
Intrinsic sympathomimetic activity and coronary blood flow.
Authors: Berdeaux A , Giudicelli JF
Published: July 2012

1 The effects of four beta‐adrenoceptor blocking agents, propranolol, pindolol, practolol and atenolol, used in doses inducing the same degree of beta 1‐adrenoceptor blockade, have been investigated on regional myocardial blood flow (microspheres) and coronary vascular resistance in the normal and ischaemic myocardium of the anaesthetized dog. 2 In the ischaemic and non‐ischaemic myocardial areas, transmural blood flow was significantly reduced by propranolol and atenolol which are devoid of intrinsic sympathomimetic activity (ISA) while it remained unaffected by beta‐adrenoceptor blocking drugs endowed with ISA, whether cardioselective (practolol) or not (pindolol). In non‐ ischaemic areas, only propranolol and atenolol increased coronary vascular resistance. 3 Regarding coronary blood flow distribution between the epicardium and endocardium, only propranolol and pindolol induced a favourable redistribution towards the endocardium increasing the endo/epi flow ratio, while practolol and atenolol were ineffective. 4 These results suggest that ISA is of major importance in maintaining coronary flow especially in the ischaemic myocardium but that it is not involved in the mechanisms underlying coronary blood flow redistribution between the different myocardial layers.
Effects of age and smoking on the pharmacokinetics of pindolol and propranolol.
Authors: Hitzenberger G , Fitscha P , Beveridge T , Nuesch E , Pacha W
Published: July 2012

1 Pharmacokinetic investigations were carried out in a group of 32 ambulant normal male volunteers in order to determine the effect of age and smoking on steady‐state plasma levels of pindolol and propranolol. There were four groups of 8: young non‐smokers (YNS), young smokers (YS), old non‐smokers (ONS) and old smokers (OS). Each subject received, in a randomized cross‐over sequence, 5 mg pindolol and 80 mg propranolol three times daily for 2 days with an interval of at least 14 days between the two treatment periods. 2 Neither age nor smoking was shown to have any influence on the time to reach a peak plasma level after pindolol or propranolol. Age, on the other hand, significantly increased the peak plasma levels and the areas under the plasma concentration time curves, and decreased the elimination rate constants, the differences between the age groups being more pronounced for propranolol than for pindolol. No effect of smoking on these parameters was observed. 3 Differences were found between pindolol and propranolol in respect of time to reach a peak plasma level, peak plasma levels and area under the plasma concentration time curves in the groups ONS and YS when related to the YNS control group. Changes observed (with the exception of the time to reach a peak level) tended to be less for pindolol and were considered to be of little clinical relevance.
Effects of propranolol and pindolol on plasma lignocaine clearance in man.
Authors: Svendsen TL , Tango M , Waldorff S , Steiness E , Trap‐Jensen J
Published: July 2012

1 Steady state concentrations and clearance of lignocaine were determine in eight healthy volunteers during 360 min continuous lignocaine infusion (2 mg/min). Before the infusion propranolol (0.18 mg/kg i.v.), pindolol (0.023 mg/kg i.v.) or placebo were administered in a random double‐blind, cross over design. 2 During the infusion of lignocaine heart rate, cardiac output and arterial blood pressure were measured every 60 min. 3 Propranolol decreased heart rate and cardiac output significantly by 10–20%, while pindolol or lignocaine did not change cardiac output or heart rate significantly. None of the drugs changed the arterial blood pressure. 4 Propranolol pretreatment decreased lignocaine significantly by 14.7% and the steady state concentration was increased by 22.5%. Pindolol produced no significant change in steady state concentration or clearance of lignocaine.
Influence of intrinsic sympathomimetic activity (ISA) during beta‐ adrenoceptor blockade in asthmatics.
Authors: Dorow P
Published: July 2012

1 Ten patients suffering from extrinsic bronchial asthma were examined. 2 In the pretreatment period, the histamine concentration required to produce a 20% decrease of forced expiratory volume in one second (FEV1) was 7.71 mg/ml. 3 Histamine provocation was repeated 2 h after administration of placebo, propranolol 40 mg, pindolol 5 mg or metoprolol 50 mg. After pindolol and metoprolol the histamine concentrations were slightly, but not significantly, lower than after placebo. After propranolol only 3.16 mg/ml histamine was necessary to reduce FEV1 by 20%. 4 This indicates that in equipotent cardiac beta‐ adrenoceptor blocking doses, in contrast to propranolol, neither pindolol nor metoprolol increased sensitivity to the bronchoconstrictor effects of inhaled histamine.
The effect of intrinsic sympathomimetic activity on beta‐receptor responsiveness after beta‐adrenoceptor blockade withdrawal.
Authors: Walden RJ , Bhattacharjee P , Tomlinson B , Cashin J , Graham BR , Prichard BN
Published: July 2012

1 Heart rate (HR) and blood pressure (BP) changes supine, at 60 degrees tilt and in response to increasing exercise loads, and HR responses to Valsalva's manoeuvre and to isoprenaline bolus injections were studied in 19 healthy volunteers to assess the response to abrupt withdrawal of atenolol n = 6, propranolol n = 6 and pindolol n = 7. 2 The dosage of each drug administered double‐blind was gradually increased over a period of 2 weeks and the dose to produce maximum inhibition of exercise‐induced tachycardia was continued for one further week. 3 Plasma renin activity, plasma noradrenaline and serum free thyroid hormones were measured during control periods, maximum dosage and withdrawal periods. 4 An increased sensitivity to isoprenaline injections was seen on Day 5 after withdrawal in the atenolol treated group whereas the pindolol treated group showed decreasing hyposensitivity to isoprenaline for the 13 days of observation after withdrawal and propranolol showed an intermediate effect. 5 There was no overshoot in HR or BP measurements at rest or in response to tilting, Valsalva's manoeuvre or exercise with atenolol or propranolol and with pindolol the HR response to tilt only was significantly higher on the third day post‐drug. 6 Plasma noradrenaline and serum free T3 were reduced on drug treatment and further reduced in the early withdrawal period but there were no consistent changes in plasma renin activity.
The influence of beta‐adrenoceptor blocking drugs with and without intrinsic sympathomimetic activity on the hormonal responses to hypo‐ and hyperglycaemia.
Authors: Schluter KJ , Aellig WH , Petersen KG , Rieband HC , Wehrli A , Kerp L
Published: July 2012

1 The effects of oral doses of pindolol (15 mg), metoprolol (200 mg) and propranolol (160 mg) on the response to insulin‐induced hypoglycaemia and an oral glucose load were investigated. 2 Serum insulin and serum C‐peptide secretion in response to a glucose load were inhibited (2P less than 0.01) by metoprolol and propranolol but not by pindolol. 3 During hypoglycaemia metoprolol and propranolol inhibited the clearance of insulin (2P less than 0.01) and caused a delay of glucose nadirs. 4 Adrenaline secretion during hypoglycaemia was markedly increased by metoprolol and propranolol but not by pindolol. 5 The counterregulatory response of growth hormone, ACTH and cortisol was increased following metoprolol and propranolol but not after pindolol. 6 The hypoglycaemic symptoms and signs showed a prevalence of sweating and prolonged changes in skin conductivity whereas palpitations were not observed during beta‐adrenoceptor blockade. Asymptomatic hypoglycaemia did not occur. 7 The absence of unphysiological rises in adrenaline, growth hormone, ACTH and cortisol supports the use of a beta‐adrenoceptor blocker with intrinsic sympathomimetic activity.
Effects of beta‐adrenoceptor blockade on carbohydrate metabolism during exercise‐comparison of pindolol and metoprolol.
Authors: Dorow P
Published: July 2012

1 The influence of equipotent cardiac beta‐adrenoceptor blocking doses of pindolol (10 mg daily) and metoprolol (200 mg daily) was studied in ten healthy male subjects. 2 The subjects were studied at rest and during exercise before and after 3 days' treatment with pindolol or metoprolol. 3 At rest and during exercise, there were no significant differences in the blood glucose levels between the metoprolol and pindolol treatments when compared with control values.
Ranitidine upon meal‐induced gastric secretion: oral pharmacokinetics and plasma concentration effect relationships.
Authors: Mignon M , Chau NP , Nguyen‐Phuoc BK , Sauvage M , Leguy F , Bonfils S
Published: July 2012

1 Ranitidine oral kinetics and plasma concentration‐effect relationships upon meal‐induced gastric secretion were investigated in normal subjects. Four oral doses of ranitidine (50, 100, 150 or 200 mg) and placebo were tested. 2 Oral ranitidine showed a terminal half‐life of about 2 h 25 min. Maximal plasma level was about 240 ng/ml for a 100 mg dose, and occurred about 1 h after dose. From the range of 50 to 200 mg dose, no indication of non‐linearity was observed in the drug kinetics. 3 Ranitidine administration resulted in a dose‐related reduction in meal‐stimulated acid secretion reaching, 46, 70, 82 and 92%, respectively. Mean ranitidine plasma concentrations producing 50 and 80% inhibition of acid secretion were 73 and 180 ng/ml, respectively, with great inter‐individual variability. 150 and 200 mg ranitidine oral doses maintained IC50 for at least 4.5 and 5.5 h, respectively. Upon oral administration, ranitidine exerted no effect on gastric emptying of the meal but slightly decreased the gastrin response to the meal.
Digitoxin accumulation.
Authors: Ochs HR , Pabst J , Greenblatt DJ , Hartlapp J
Published: July 2012

1 Nine healthy volunteers received single 1 mg intravenous doses of digitoxin, following which serum digitoxin concentrations were measured at multiple points in time over the next 14 days. 2 Mean kinetic variables for digitoxin were: volume of distribution, 0.76 l/kg; elimination half‐life, 8 days; total clearance, 0.049 ml min‐1 kg‐1. 3 After a drug‐free interval of at least 4 months, subjects took 0.07 mg of oral digitoxin daily for 28 consecutive days. Serum digitoxin concentrations were measured during the period of dosage and in the 21 day post‐dosage washout. 4 Digitoxin accumulation was slow, proceeding with a mean half‐life (7.9 days) that was nearly identical to the single‐dose half‐life. However, the two were not significantly correlated. 5 Mean observed steady‐state serum concentrations (15.4 ng/ml) also were nearly identical to those predicted from the single‐ dose study (15.3 ng/ml), but again the two were not significantly correlated. 6 Steady state is very slowly attained after initiation of maintenance therapy with digitoxin. The kinetic data suggest that a loading dose on the average should be 12 times the maintenance dose.
Relative potency of spironolactone, triamterene and potassium chloride in thiazide‐induced hypokalaemia.
Authors: Jackson PR , Ramsay LE , Wakefield V
Published: July 2012

1 The influence of spironolactone 50 mg and 100 mg daily, triamterene 100 mg and 200 mg daily, potassium chloride 32 mmol and 64 mmol daily and placebo on plasma potassium and other variables was examined in a random crossover study of nine hypertensive patients taking bendrofluazide 10 mg daily. 2 Spironolactone and triamterene had significant and parallel dose‐response curves for plasma potassium, with a relative potency for triamterene:spironolactone of 0.25:1, significantly lower than the accepted 0.5:1 ratio. These drugs also lowered serum sodium, bicarbonate and body weight, and increased serum urea and creatinine. 3 Potassium chloride increased plasma potassium above placebo values, but the dose‐response was not significant and was not parallel with those of the potassium‐sparing drugs. Seven of nine patients remained hypokalaemic despite treatment with 64 mmol potassium chloride daily. 4 The relative expense, convenience and toxicity of the potassium‐sparing drugs should be assessed at equivalent doses, namely spironolactone 50 mg:triamterene 200 mg:amiloride 20 mg. Potassium chloride does not correct moderate diuretic‐induced hypokalaemia even at doses of 64 mmol daily.
Predictive indices for chlorpromazine therapy in schizophrenics.
Authors: Dixon PA , Oforah E , Makanjuola R
Published: July 2012

1 Response to chlorpromazine therapy was studied in 24 schizophrenics and 75% reduction in Brief Psychiatric Rating scale (BPRS) within 4 weeks of treatment was taken to indicate good response. 2 Test oral dose of CPZ (200 mg) was administered and serial blood samples and total urine excreted in 6 h were taken for analyses of CPZ and its metabolites. 3 Area under the plasma time curve (AUC) showed an inverted U‐shaped relationship with % reduction in BPRS. 4 Three groups of patients were identified, responders, l‐ and h‐group non‐responders. 5 l‐ and h‐groups respond on further treatment with haloperidol (30 mg daily) and ECT respectively. 6 Responders showed threshold metabolic molar fraction MMFHO‐CPZ greater than or equal to 3.0 x 10(‐5) and MMFHO‐CPZ/MMFCPZ‐SO greater than 1.
A clinical and pharmacokinetic study of indomethacin in standard and slow release formulations.
Authors: Adams KR , Halliday LD , Sibeon RG , Baber N , Littler T , Orme ML
Published: July 2012

Fifteen patients with rheumatoid arthritis received indomethacin in three treatment schedules; indomethacin retard 75 mg twice daily; indomethacin capsules 50 mg three times daily; and indomethacin 100 mg suppository at night with 50 mg by mouth each morning. The study was a double‐blind, double‐dummy one with each treatment being given for 2 weeks after a washout period of 3 days. After the washout period, and at the end of each 2 week active treatment period, blood samples were taken during a dosage interval for assay of indomethacin concentrations in plasma. Clinical assessments were also performed. All three treatment period produced significant clinical improvements in the assessments compared with the placebo washout period. However, no differences were seen between the treatments. Side effects occurred with equal frequency in all three periods, and the anticipated reduction in central nervous system side effects during the indomethacin retard period was not seen. Plasma concentrations of indomethacin were significantly higher during indomethacin retard therapy with a peak concentration of 2500 +/‐ 25 ng ml‐1 during indomethacin retard therapy (mean +/‐ s.d.) and 1900 +/‐ 200 ng ml during conventional oral therapy. Indomethacin retard is as effective as the other formulations of indomethacin but appears to offer no significant advantages.
Cimetidine does not increase the anticoagulant effect of phenprocoumon.
Authors: Harenberg J , Staiger C , De Vries JX , Walter E , Weber E , Zimmermann R
Published: July 2012

In patients on oral warfarin, nicoumalone and phenindione an increase of the anticoagulant effect has been described during concomitant treatment with cimetidine. Therefore we have investigated the effect of cimetidine on the steady state dynamics of phenprocoumon in ten outpatients. No changes in the anticoagulant effect and the plasma phenprocoumon levels were observed during and after 2 weeks application of cimetidine. The data show that cimetidine does not interact with the metabolism of phenprocoumon in contrast to warfarin.
Phenytoin: an inhibitor and inducer of primidone metabolism in an epileptic patient.
Authors: Porro MG , Kupferberg HJ , Porter RJ , Theodore WH , Newmark ME
Published: July 2012

The interaction between primidone and phenytoin was studied in an epileptic patient treated with primidone only and primidone plus phenytoin for 3 months. Plasma and urine levels of drugs and metabolites were monitored daily by GC and GC‐MS. The addition of phenytoin to the regimen increased steady‐state plasma levels of phenobarbitone and phenylethylmalonamide (PEMA), metabolites of primidone, and decreased levels of primidone and unconjugated p‐ hydroxyphenobarbitone (p‐OHPB), a metabolite of phenobarbitone. After withdrawal of phenytoin, plasma phenobarbitone and primidone levels slowly returned to previous steady‐state levels, PEMA rapidly decreased to lower levels than before, and p‐OHPB levels rose rapidly. Urinary excretion of primidone and its metabolites paralleled the changes in their plasma levels after the addition of phenytoin but the percentage of unconjugated p‐OHPB in urine was unchanged during the course of the study. In conclusion phenytoin initially induces the conversion of primidone to PEMA and phenobarbitone, although each to a different extent, but it appears to inhibit the hydroxylation of phenobarbitone. Thus, two apparently contradictory phenomena seem to be involved in the primidone‐phenytoin interaction. The net effect is an enhanced increase in plasma phenobarbitone levels.
Azo reduction of sulphasalazine in healthy volunteers.
Authors: Houston JB , Day J , Walker J
Published: July 2012

1 A comparison of total sulphapyridine saliva concentrations resulting from administration of sulphapyridine and sulphasalazine at equimolar doses has been carried out. It is concluded that the extent of azo reduction of sulphasalazine to release sulphapyridine is complete in healthy volunteers. 2 An ampicillin course of treatment alters the azo reduction of sulphasalazine. The extent of cleavage is reduced by one third on average. There is no change in the rate of absorption of the release sulphapyridine. 3 An ampicillin course of treatment does not alter the disposition of sulphapyridine. The changes noted in acetyl conjugate plasma concentrations are entirely consistent with reduced availability of sulphapyridine.
Altered disposition and availability of cimetidine in liver cirrhotic patients.
Authors: Gugler R , Muller‐Liebenau B , Somogyi A
Published: July 2012

1 The pharmacokinetics and bioavailability of cimetidine were studied after 200 mg oral and intravenous doses in 14 patients with liver cirrhosis, and results were compared to a control group of 12 ulcer patients. 2 In cirrhotic patients, the volume of the central compartment (0.41 +/‐ 0.06 v 0.19 +/‐ 0.09 1/kg) and the volume of distribution at steady‐state (1.02 +/‐ 0.17 v 0.80 +/‐ 0.24 1/kg) were significantly increased. No differences were observed in the area volume of distribution, the total systemic plasma clearance and renal clearance. The non‐renal clearance was significantly decreased from 191 +/‐ 46 to 123 +/‐ 102 ml/min. 3 The bioavailability of cimetidine (area method) was significantly increased from 60 +/‐ 23% to 77 /+‐ 18% in the cirrhotic patients. Also increased was the time during which plasma levels exceeded 0.5 microgram/ml. 4 Urinary excretion of cimetidine was increased in liver cirrhosis by 32% after intravenous and by 36% after oral administration, while the amount of the sulphoxide metabolite decreased accordingly. Creatinine clearance in the cirrhotic patients was highly correlated with the renal clearance of cimetidine as well as its total plasma clearance.
Beta 2‐adrenoceptor agonists and thyroid hormones.
Authors: Kampmann JP , Svendsen TL , Skovsted L , Hansen Molholm JE
Published: July 2012

The potential influence of the selective beta 2‐adrenoceptor agonist terbutaline on the serum concentration of the thyroid hormones in humans was studied in 11 healthy euthyroid subjects. Five served as a control group without medication while six received 5 mg terbutaline three times daily for 2 weeks. No significant differences were found between the two groups by measuring the serum concentrations of thyroxine, triiodothyronine, reverse triiodothyronine and resin‐ triiodothyronine uptake. The use of a beta 2‐adrenergic receptor stimulating drug is relatively contraindicated in untreated thyrotoxicosis. This recommendation is based upon a summation of clinical adverse reactions and not due to an effect on the serum concentrations of thyroid hormones.
Alteration of plasma prednisolone levels by indomethacin and naproxen.
Authors: Rae SA , Williams IA , English J , Baylis EM
Published: July 2012

Eleven patients with stable rheumatoid disease (RD) who were receiving regular corticosteroid therapy (CS) were investigated to discover the effect on plasma prednisolone levels of additional therapy with the non‐ steroidal anti‐inflammatory (NSAI) drugs, indomethacin and naproxen. There was a highly significant (P less than 0.001) increase in free prednisolone levels after concurrent therapy with either indomethacin or naproxen for 2 weeks. Total prednisolone levels were unchanged. These results could provide an explanation for clinical reports that these two NSAI drugs possess a steroid‐sparing effect.