bluuebunny/crossref_metadata_2025 huggingface dataset:
Short‐term effects of felodipine, a new dihydropyridine, in hypertension.
Authors: Andersson O , Bengtsson C , Elmfeldt D , Haglund K , Hedner T , Seideman P , Sjoberg KH , Stromgren E , Aberg H , Ostman J
Published: July 2012

Felodipine, a dihydropyridine, is a new vasodilating calcium antagonist which lowers blood pressure (BP) by selective action on vascular smooth muscle, especially in the resistance vessels. The effects on BP, heart rate (HR) and tolerance of different single oral doses of felodipine were studied in two series of hypertensive patients. When felodipine was given as single drug to 14 previously untreated hypertensives in a single‐blind manner, BP was rapidly reduced by about 15% while HR increased by 25%. Felodipine given in a double‐blind manner to eight patients on chronic beta‐adrenoceptor blockade reduced BP by some 15‐ 20% compared to placebo, while HR did not change. There was a significant correlation between the pre‐treatment mean arterial BP (MAP) and the maximal relative change in MAP, i.e. the higher the initial BP the greater the reduction after felodipine. A significant correlation was also found between the plasma concentration of felodipine and the relative change in MAP. Felodipine was generally well tolerated. When given alone felodipine caused the side effects expected from a pure vasodilator, i.e. headache, flushing and palpitations. When given together with a beta‐adrenoceptor blocker, the side effects were much less apparent.
Bopindolol: a new long acting beta‐receptor antagonist; its effects on haemodynamics, and on the renin response to tilting.
Authors: Turner DR , Goodwin FJ , Knight AR , Littlejohns DW , Sharman VL , Vere DW
Published: July 2012

Oral administration of single doses of bopindolol (1‐4mg) caused significant reductions in the rises of systolic blood pressure and heart rate produced by exercise; only the reduction in the rise of heart rate was significantly dose‐related. Resting heart rate was reduced by bopindolol. There were small effects on resting blood pressure. Bopindolol caused a significant attenuation of the rise in plasma renin activity produced by passive head‐up tilting to 75‐85 degrees. Bopindolol produced a dose‐related attenuation of the increase in pulse rate evoked by passive tilting. All effects 1‐4 were maintained for at least 24 h. There was no measurable effect on plasma potassium concentration, peak flow rate or forced expiratory volume (FEV1).
The effect of ascorbic acid on the sulphate conjugation of ingested noradrenaline and dopamine.
Authors: Dunne JW , Davidson L , Vandongen R , Beilin LJ , Tunney AM , Rogers PB
Published: July 2012

Changes in the plasma concentration of free and conjugated noradrenaline (NA) and dopamine (DA) following oral administration of these catecholamines were examined in four normal males before and after treatment with ascorbic acid. The marked increase in plasma conjugated DA and NA was considerably reduced after ascorbic acid treatment, presumably due to competitive inhibition of sulphate conjugation. In one subject where there was a considerable delay in the appearance of sulphates, an early rise in free NA and DA concentration occurred. There were no changes in plasma free NA in the other subjects, although DA increased in two after ascorbic acid treatment. These findings emphasise the importance of sulphate conjugation in the gut or liver in inactivating endogenous amines in foods and indicate that interference of this protective mechanism may arise from high doses of ascorbic acid and other related compounds which compete for sulphation.
The psychological side effects of acebutolol and atenolol.
Authors: Lewis MJ , Jones DM , Dart AM , Henderson AH
Published: July 2012

We have measured the psychological effects of acebutolol and atenolol in sixteen patients with essential hypertension. The drugs were administered in a randomized, placebo‐controlled, double‐blind manner, in single daily doses of 100 mg atenolol, 400 mg acebutolol or placebo for periods of 6 weeks, each drug period being separated by a placebo period. At each 2 weekly clinic visit, a questionnaire designed for assessment of state anxiety and state arousal was administered for self‐ completion. Arousal was significantly reduced by atenolol over the whole 6 weeks of administration. It was not affected by acebutolol. Anxiety was significantly reduced by acebutolol but only at the first of the three 2 weekly assessments on treatment. It was not affected by atenolol. Differences in the psychological effects of these two beta‐ adrenoceptor blockers are discussed in terms of their lipid solubility and haemodynamic effects.
Increased forearm vascular resistance after dopamine blockade.
Authors: Mannering D , Bennett ED , Mehta N , Kemp F
Published: July 2012

The peripheral haemodynamic effects of a 40 mg intravenous injection of domperidone (a dopamine antagonist) have been studied in 10 normal subjects. In four subjects domperidone was infused directly into the brachial artery and the effects on forearm blood flow were measured. When administered systemically, domperidone significantly decreased forearm blood flow by 9% (P less than 0.01) and significantly increased calculated forearm vascular resistance by 11% (P less than 0.01). The drug produced no measurable changes in forearm blood flow at any dose when infused directly into the brachial artery. A further study was carried out into the effects of a systemic injection of domperidone on peripheral sympathetic tone. Reduction of sympathetic tone in the forearm was achieved by passively raising the legs of eight recumbent subjects. Before domperidone administration, passive leg elevation significantly increased forearm blood flow by 39% and decreased forearm vascular resistance by 13%. After drug administration the absolute values of vascular resistance increased and the changes between the supine and elevated position values when compared with those of the corresponding values prior to drug administration were significantly lower. These results suggest that the role of domperidone in increasing peripheral vascular tone is unlikely to be mediated by a direct local effect on peripheral resistance vessels. Any effect the drug may have is suggested to be mediated via a central control mechanism.
A simple test for acetylator phenotype using caffeine.
Authors: Grant DM , Tang BK , Kalow W
Published: July 2012

A method is presented for the use of caffeine, in the forms commonly ingested by a large proportion of the world's population, to test for the clinically important acetylation polymorphism. Each of 146 subjects provided a spot sample of urine between 2 and 6 h after coffee, tea or cola soft drink consumption, and the molar ratio of 5‐acetylamino‐6‐ formylamino −3‐methyluracil (AFMU) to 1‐methylxanthine (1X) was determined by a simple h.p.l.c. assay. The ratio afforded segregation of three apparent modes of acetylation capacity in this population, in concordance with a standard sulphamethazine phenotyping procedure and with other methods using controlled caffeine intake and urine collections. The day‐to‐day consistency of the method was established in eight selected subjects.
Comparison of the absorption and metabolism of sulphasalazine and acrylic‐coated 5‐amino salicylic acid in normal subjects and patients with colitis.
Authors: Dew MJ , Ebden P , Kidwai NS , Lee G , Evans BK , Rhodes J
Published: July 2012

Serum levels of 5‐amino salicylic acid (5ASA) and acetyl 5ASA have been measured in volunteers after ingestion of sulphasalazine (6 g) and compared with levels after an equivalent dose of acrylic coated 5ASA (2.4 g). The serum levels of both 5ASA and acetyl 5ASA were similar after each preparation apart from an early peak of 5ASA following acrylic coated 5ASA . Serum and urinary levels for 5ASA and acetyl 5ASA have been measured in colitic patients following equivalent doses of sulphasalazine and acrylic coated 5ASA . Serum levels were similar; 25% of the calculated ingested 5ASA was excreted in the urine after sulphasalazine compared with 20% following acrylic coated 5ASA .
Pharmacokinetics of phosphomycin during haemofiltration.
Authors: Fernandez Lastra C , Marino EL , Dominguez‐Gil A , Tabernero JM , Grande Villoria J
Published: July 2012

The pharmacokinetics of phosphomycin were studied in 10 adult patients with terminal renal impairment during a 4 h haemofiltration session. A single i.v. dose of 30 mg/kg of the antibiotic was administered to each patient at the beginning of the haemofiltration session. The half‐life of the slow disposition phase (t 1/ 2z) showed an average value of 4.05 +/‐ 1.77 h, much lower than that established in patients who did not undergo any purification techniques. Serum phosphomycin concentrations at the input and the output of the haemofilter at the end of the session were, respectively, 26.65 and 19.13 micrograms/ml. During haemofiltration, 64.90% of the original dose was eliminated. In this kind of patient we recommend a dose of 30 mg/kg at the beginning and at the end of each haemofiltration session for interfiltration periods of 48 h.
Effects of lormetazepam and of flurazepam on sleep.
Authors: Adam K , Oswald I
Published: July 2012

Nine poor sleepers of mean age 61 years took part in a double‐blind, balanced order study in which, during three periods of 3 weeks, each took lormetazepam 1 mg, lormetazepam 2.5 mg, and flurazepam 30 mg. Using electrophysiological measures, sleep was found to increase by 0.75 h with each treatment condition, mainly through more of stage 2 sleep. The treatments reduced the delay to sleep and led to fewer and shorter awakenings, with little difference among the three treatments. Slow‐wave sleep was reduced by flurazepam and by lormetazepam 2.5 mg. After flurazepam intake ceased, there was evidence of persisting drug effects for as long as 7 nights. In contrast, when lormetazepam 2.5 mg ceased, there was significant rebound reduction of sleep duration below baseline for up to 3 withdrawal nights, and there was a similar though non‐significant trend after lormetazepam 1 mg had ceased. Wakefulness in the final 2 h of nocturnal recording during the third week of drug intake was significantly reduced below baseline by flurazepam, but was little affected by lormetazepam. The differences among the treatment conditions could be attributed to the long‐persistence of flurazepam vs the more rapid elimination of lormetazepam.
Plasma concentrations of unbound phenytoin in the management of epilepsy.
Authors: Kilpatrick CJ , Wanwimolruk S , Wing LM
Published: July 2012

In 46 epileptic patients the range of the unbound fraction of phenytoin in plasma measured by ultrafiltration (at 37 degrees C) and tracer‐ labelling with [14C]‐phenytoin was 6.7%‐33.3% with a median of 11.9%. The total and unbound phenytoin plasma concentrations were significantly correlated (r = 0.93, P less than 0.001), but in six patients the unbound concentration fell on or outside the 90% predictability limits for a single value. In all patients the unbound concentration reflected the clinical status of the patient equally or better than the total concentration. An inverse relationship was found between the plasma albumin concentration (within the normal reference range) and the phenytoin unbound fraction (r = −0.83, P less than 0.001) indicating that plasma albumin concentration is one of the important overall determinants of phenytoin protein binding. Saliva and plasma unbound phenytoin concentrations were significantly correlated (r = 0.98, P less than 0.001) but both collection of plasma samples and preparation of plasma ultrafiltrate using the Amicon micropartition system are simpler than collection and processing saliva, and interpretation of plasma unbound concentration does not require allowance for potential contamination. The additional value of the unbound phenytoin concentration in a clinically significant number of individuals would justify routine measurement of unbound phenytoin concentration in monitoring therapy, once available simplified methodology has been adequately characterised.
Comparison of the clinical pharmacokinetics and concentration‐effect relationships for medroxalol and labetalol.
Authors: Elliott HL , Meredith PA , Sumner DJ , Reid JL
Published: July 2012

The pharmacokinetics of medroxalol are described in normal subjects and compared with those of labetalol. Both drugs were administered in doses of 400 mg orally and 1 mg/kg intravenously. The data for both drugs was most appropriately described by a two compartment model. For oral medroxalol the clinical pharmacokinetic parameters were a terminal elimination half‐life (t 1/2,Z) of 15.6 h, a peak level of 450 ng/ml and a time to peak of 2‐3 h. Following intravenous medroxalol the bioavailability was calculated as 64%, the plasma clearance was 948 ml/min and the t 1/2,Z was 7.3 h. The t 1/2,Z following intravenous administration was significantly shorter than that following oral administration. The significant differences between medroxalol and labetalol were in time to peak, respectively 2.3 and 1.1 h; oral t 1/2,Z, 15.6 and 5.5 h; clearance 948 and 1560 ml/min; and bioavailability, 64 and 20%. Despite the pharmacokinetic differences a similar plasma concentration‐hypotensive effect relationship was described for each drug.
Comparative effects of long‐acting and conventional propranolol on stress‐induced angina pectoris and on frequency of ventricular premature beats.
Authors: Hansteen V , Endresen K , Hellemann H , Eriksen II , Brorssen O , Ekeli T , Day M , Baber NS
Published: July 2012

Ten male patients with chronic stable angina pectoris completed a randomized, double‐blind cross‐over study, with matched placebo run‐in period (P), to compare the effects of a long‐acting preparation of propranolol (LA, 160 mg once a day) with that of conventional propranolol (CP, 40 mg four times a day) each given for 14 days. Response was assessed by symptom‐limited bicycle ergometry, degree of ST segment depression, daily anginal attack rate and glyceryl trinitrin consumption (GTN). Heart rate and ventricular extra‐systolic frequency (VES) were recorded by 24 h Holter monitor. Bicycle ergometry was performed and a trough blood sample taken for propranolol estimation on day 14 prior to the morning dose. Both formulations increased total work capacity (P 3412, LA 4095, CP 3697 kpm/min), reduced rate‐pressure product (P 21896, LA 16011, CP 15609 mm Hg beats/min), and degree of ST segment depression (P 4.53, LA 2.48, CP 2.43), but without differences between the formulations. Daily anginal attack rate was reduced from 30 (placebo) to 7.5 (CP) and 14.5 (LA) (P less than 0.05 between treatment groups). There was a reduction in daily GTN consumption by both treatments. The heart rate and total number of VESs during 24 h was similar in the two treatment groups and was reduced in comparison with placebo. Both formulations were well tolerated. Long‐acting propranolol is an effective and well‐tolerated alternative to conventional propranolol in the treatment of chronic stable and stress‐induced angina, and in reducing VES frequency.
Lack of effect of ibopamine, a dopamine pro‐drug, on renal function in normal subjects.
Authors: Harvey JN , Worth DP , Brown J , Lee MR
Published: July 2012

The effects of two single oral doses of ibopamine (150 and 600 mg) on heart rate, blood pressure, urine flow, sodium, potassium and creatinine excretion were studied in normal volunteers. No significant change was observed in urine flow, sodium, potassium or creatinine excretion at either dose. No significant change was observed in heart rate or blood pressure except that systolic blood pressure was transiently elevated after the 600 mg dose (P less than 0.05).
The relationship between debrisoquine oxidation phenotype and the pharmacokinetics and pharmacodynamics of propranolol.
Authors: Lennard MS , Jackson PR , Freestone S , Tucker GT , Ramsay LE , Woods HF
Published: July 2012

The pharmacokinetics and pharmacodynamics of propranolol (80 mg by mouth) were studied in seven extensive and four poor metabolisers of debrisoquine. Evidence for impairment of the 4′‐hydroxylation of propranolol was found in poor metabolisers. However, no significant difference was detected in the oral clearance of unchanged drug between the two groups of debrisoquine oxidation phenotypes. Poor metabolisers of debrisoquine did not experience more intense or more prolonged beta‐ adrenoceptor blockade than extensive metabolisers of debrisoquine.
Differential blockade of alpha‐adrenoceptors by indoramin.
Authors: Nicholls DP , O'Connor PC , Harron DW , Leahey WJ , Shanks RG
Published: July 2012

The effect of equihypotensive single oral doses of indoramin (mean dose 67 mg), phenoxybenzamine (mean dose 50 mg), hydralazine (mean dose 133 mg) and placebo on arterial pressure and heart rate in the supine and standing position was studied in six normal volunteers. Observations were made before and at 2 and 4 h after drug administration. Plasma noradrenaline (NA) was measured at each time interval in the supine position, and after 4 min of standing. Plasma renin activity (PRA) was measured at each time interval after 30 min in the standing position. The three active drugs reduced systolic arterial pressure in the standing position to a similar extent (indoramin, −24 mm Hg; phenoxybenzamine, −23.4 mm Hg; hydralazine, −30.4 mm Hg). The maximum effect of indoramin and phenoxybenzamine was observed at 4 h, and of hydralazine at 2 h after drug administration. The reductions of arterial pressure in the standing position were accompanied by increases in heart rate, plasma NA and PRA. Small increases were observed after indoramin (heart rate, + 9.2 beats min‐1; plasma NA, + 126 pg/ml; PRA, + 0.33 ng angiotensin 1 ml‐1 h‐1), greater increases after phenoxybenzamine (heart rate, + 20; plasma NA, + 210; PRA, + 0.47), and the greatest increases after hydralazine (heart rate, + 26; plasma NA, + 250; PRA, + 1.16). In the supine position, indoramin and phenoxybenzamine produced no effect on arterial pressure, heart rate or plasma NA. Hydralazine produced small reductions in diastolic pressure, which were accompanied by an increase in heart rate of 25.5 beats min‐1 (P less than 0.01 when compared to placebo) and in plasma NA of 223 pg ml‐1 (P less than 0.05). Plasma NA, PRA and heart rate increased together and may be regarded as three interdependent indices of sympathetic activity. Indoramin reduced the degree of increase of plasma NA, PRA and heart rate per unit fall in pressure, when compared to phenoxybenzamine and hydralazine. The effect of phenoxybenzamine and hydralazine on the degree of increase was similar. The results are consistent with the hypothesis that indoramin produces selective postsynaptic alpha 1‐adrenoceptor blockade in man, and therefore produces relatively less tachycardia and NA increase than does a non‐ selective alpha‐adrenoceptor antagonist (phenoxybenzamine) or an arteriolar vasodilator (hydralazine).
The effects on left ventricular performance of nifedipine and verapamil in exercise‐induced angina pectoris.
Authors: Silke B , Verma SP , Nelson GI , Ahuja RC , Hussain M , Taylor SH
Published: July 2012

The differences between slow calcium blocking agents with respect to effects on heart rate, myocardial contractility and atrioventricular conducting time are well described; the relevance of such differences to the treatment of patients with impaired left ventricular function due to coronary heart disease is uncertain. The haemodynamic effects of equivalent hypotensive doses of nifedipine and verapamil were therefore compared in 20 patients with severe angina pectoris associated with angiographically documented coronary artery disease. The plasma concentrations of nifedipine (mean 57 +/‐ 19; range 27‐77 ng/ml) and verapamil (mean 147 +/‐ 14; range 117‐260 ng/ml) at the time of the haemodynamic measurements were of an order usually associated with substantial pharmacodynamic activity. Sitting at rest nifedipine resulted in reduction in systemic arterial pressure (P less than 0.05) and vascular resistance (P less than 0.01); both the heart rate (P less than 0.01) and cardiac output (P less than 0.05) increased without any significant change in the left heart filling pressure. In contrast, verapamil, which similarly reduced systemic blood pressure (P less than 0.05) and vascular resistance (P less than 0.01), increased cardiac output (P less than 0.05) and left heart filling pressure (P less than 0.05) without any change in heart rate. During upright bicycle exercise both drugs attenuated the angina induced in all subjects during the control exercise period. Despite reductions in systemic blood pressure and vascular resistance the cardiac output was unaltered on either drug at the same workload as in the control assessment. The reduction in exercise blood pressure following nifedipine induced a reflex tachycardia; this was not present, despite the similar hypotensive action, after verapamil.(ABSTRACT TRUNCATED AT 250 WORDS)
Reductions in portal pressure by selective beta 2‐adrenoceptor blockade in patients with cirrhosis and portal hypertension.
Authors: Bihari D , Westaby D , Gimson A , Crossley I , Harry J , Williams R
Published: July 2012

In order to elucidate the mechanisms by which beta‐adrenoceptor blockade leads to a reduction in portal pressure, we have measured portal pressure, heart rate and cardiac index in 17 patients with cirrhosis and portal hypertension following the oral administration of the selective beta 2‐adrenoceptor blocking agent, ICI 118551, in the two dosage ranges 10‐20 mg and 50‐100 mg. There was a fall in portal pressure in 14 of the 17 patients from a median of 17 mm Hg to a median of 15 mm Hg, P less than 0.01, that occurred only at 60 min following administration of the drug. Although there were early systemic haemodynamic changes, with a significant fall in heart rate and cardiac index from before to 30 min after the ingestion of ICI 118551 (median heart rates 86 and 80 beats/min respectively, P less than 0.01, median cardiac indices 3.5 and 3.31 min‐1 m‐2, P less than 0.05), these occurred before the fall in portal pressure and were unrelated to changes in portal pressure. This reduction in portal pressure independent of systemic haemodynamic changes is consistent with beta 2‐ adrenoceptor blockade within the splanchnic and hepatic arterial circulations; subsequent increases in splanchnic and hepatic arterial resistances with a concomitant fall in portal blood flow and hepatic portal resistance may lead to the reduction in portal pressure.
Pharmacokinetics and pharmacodynamics of verapamil in combination with atenolol, metoprolol and propranolol.
Authors: Warrington SJ , Holt D , Johnston A , Fitzsimons TJ
Published: July 2012

Treatment of angina pectoris with beta‐adrenoceptor antagonists and verapamil in combination is effective and increasingly common. The study reported here was designed to show whether the pharmacokinetics of verapamil are influenced by concurrent treatment with three different beta‐adrenoceptor blockers, and whether there is any pharmacodynamic interaction between these drugs. Twelve healthy volunteers (eight men, four women) aged 21‐25 years and weighing 48‐82 kg consented to participate in the study. They received verapamil 50 mg three times daily for four 1‐week periods, each separated by a 1 week ‘washout’ period. During three of the four treatment periods, the subjects took either atenolol 100 mg once daily, metoprolol 100 mg twice daily or propranolol 80 mg twice daily; in the remaining period they took verapamil alone. The concentration/time curve and plasma elimination half‐life of verapamil and norverapamil, its major metabolite, were not influenced by 1 weeks co‐administration atenolol, metoprolol or propranolol. As expected, co‐administration of each of the beta‐adrenoceptor blockers significantly reduced exercise heart rate when compared with verapamil alone.
The effect of cimetidine on the relative cardioselectivity of atenolol and metoprolol in asthmatic patients.
Authors: Ellis ME , Hussain M , Webb AK , Barker NP , Fitzsimons TJ
Published: July 2012

The effects of chronic cimetidine therapy on the pharmacodynamic properties of atenolol and metoprolol were assessed in eight asthmatic patients using a placebo‐controlled trial. When atenolol and metoprolol were administered at doses which achieved an equivalent degree of beta1‐ adrenoceptor blockade, metoprolol caused a significantly greater reduction in mean forced expiratory volume in one second (FEV1). This demonstrates the greater cardioselectivity of atenolol. The reductions in mean FEV1 induced by either atenolol or metoprolol were each unaffected by cimetidine. Plasma levels of each of the beta‐ adrenoceptor blockers were not affected by the addition of cimetidine. The FEV1 in one patient was further reduced when cimetidine was administered with metoprolol, although there was no corresponding change in plasma levels of drug. In this patient there was no such further reduction in FEV1 with atenolol. This study has not provided evidence for a pharmacodynamic interaction between cimetidine and either atenolol or metoprolol, but further studies are indicated.
The influence of indomethacin and sulindac on some pharmacological actions of atenolol in hypertensive patients.
Authors: Salvetti A , Pedrinelli R , Alberici P , Magagna A , Abdel‐Haq B
Published: July 2012

Indomethacin and sulindac were used as tools to study the role of renal and/or systemic prostaglandins in the pharmacological response to atenolol. Patients receiving chronic treatment with atenolol 100 mg received indomethacin 50 mg twice daily or sulindac 200 mg twice daily in a randomised crossover trial. Indomethacin significantly reduced the antihypertensive action of atenolol while sulindac had no effect. The role that systemic and/or renal prostaglandins may play in the antihypertensive action of atenolol is discussed with reference to renal PGI2 production and inhibition of platelet cyclo‐oxygenase.
Paracetamol metabolites in the neonate following maternal overdose.
Authors: Roberts I , Robinson MJ , Mughal MZ , Ratcliffe JG , Prescott LF
Published: July 2012

A case of paracetamol overdose in a 36 week pregnant woman is described. The baby was delivered by Caesarian section 6 h after the overdose. The mother but not the baby was treated with N‐acetylcysteine and neither suffered liver damage. The plasma paracetamol half‐life was prolonged to 10 h in the neonate compared to 2.5 h in the mother and was unaffected by a two volume exchange transfusion. The pattern of urinary metabolites in the neonate was similar to that observed in the mother, but there was a marked delay in the time taken to reach peak plasma concentrations of metabolites. This is consistent with a very slow biotransformation of the drug and may explain the relative resistance of very young children to the hepatotoxicity of paracetamol. There was no evidence of limited or decreasing capacity in sulphate conjugation nor was sulphation the major metabolic pathway. In retrospect both the obstetrical intervention and the exchange transfusion were unnecessary.
Pinacidil monotherapy for hypertension.
Authors: Ward JW
Published: July 2012

Ten patients with mild to moderate hypertension were treated for 9 weeks with a tablet formulation of pinacidil. Mean supine blood pressure fell from 174/100 to 148/84 mm Hg and mean supine pulse increased by 3 beats/min. Daily dosage was 40‐100 mg, given in two or three divided doses. Plasma urea increased significantly and mean weight increased by 1.1 kg. Side effects were frequent but mild, in the main being those typically associated with potent vasodilator drugs. No patient withdrew from the study, and all achieved target blood pressure.
Maintenance therapy after i.v. administration of disopyramide with an oral sustained release preparation, a pharmacokinetic study.
Authors: Liem KL , Hollander JM
Published: July 2012

The blood levels in 20 patients were studied during the change from parenteral administration of disopyramide to an oral sustained release preparation containing the same active substance. From this study it is concluded that 100 mg i.v. bolus injection of disopyramide can safely be followed by the immediate administration of one sustained release tablet containing 250 mg disopyramide. In case of an i.v. infusion (0.4 mg kg‐1h‐1) it seems wise not to start earlier with the administration of the sustained release preparation than at the moment of stopping the infusion.
Effect of indapamide on the renin‐aldosterone system, and urinary excretion of potassium and calcium in essential hypertension.
Authors: Danielsen H , Pedersen EB , Spencer ES
Published: July 2012

The effect of indapamide, 2.5 mg daily, on blood pressure, electrolyte balance and the renin‐aldosterone system was studied in 11 patients with essential hypertension. During indapamide treatment blood pressure decreased and the renin‐aldosterone system was stimulated. A moderate hypokalaemia seen during indapamide treatment was not correlated to changes in plasma aldosterone concentration. Fractional excretion of potassium was unchanged during treatment, while renal calcium excretion was reduced. No effect on calcium in serum was observed.
Antipyrine absorption after delayed oesophageal capsule transit.
Authors: Channer KS , Roberts CJ
Published: July 2012

Twenty fasted patients were given hard gelatin capsules containing antipyrine and barium, and in ten patients the capsule arrested and disintegrated in the oesophagus. Plasma antipyrine was assayed at 10 min intervals for 1 h, then 30 min intervals for a further 3 h. The plasma concentration‐time curves for the patients in whom the capsule entered the stomach rapidly, and for those in whom the capsule lodged in the oesophagus, were compared. The absorption in the first hour was calculated from the area under the plasma concentration‐time curve and found to be significantly lower if the capsule disintegrated in the oesophagus (P less than 0.0005). The time to peak plasma concentration was delayed by an average of 46 min (P less than 0.01) and the peak plasma concentration was significantly lower (P less than 0.05) if delayed capsule transit occurred. Delayed capsule transit through the oesophagus significantly changed the pharmacokinetic profile of antipyrine.
Vagal activity is increased during intravenous isoprenaline infusion in man.
Authors: Arnold JM , McDevitt DG
Published: July 2012

Eight healthy normal subjects (19‐23 years) received graded intravenous isoprenaline infusions PRE‐ and POST‐atropine, 0.04 mg/kg i.v. The adequacy of atropinization was tested with bolus intravenous injections of phenylephrine. PRE‐atropine, isoprenaline caused an increase in heart rate and systolic pressure, but a decrease in diastolic pressure with little change in mean pressure (+32.8 +/‐ 3.0 beats/min, +18.9 +/‐ 3.0 mm Hg, ‐13.5 +/‐ 1.9 mm Hg, ‐2.7 +/‐ 1.9 mg Hg respectively at isoprenaline 2 micrograms/min). POST‐atropine, the increase in heart rate was enhanced, the rise in systolic pressure abolished and the falls in diastolic and mean pressures exaggerated (+47.0 +/‐ 2.8 beats/min, ‐8.9 +/‐ 2.9 mm Hg, ‐27.3 +/‐ 2.1 mm Hg, ‐21.1 +/‐ 1.9 mm Hg, respectively at isoprenaline 2 micrograms/min). During an isoprenaline infusion, when the heart rate and blood pressure changes are stable, there is an increase rather than a decrease in cardiac vagal tone.
Effects of cholestyramine and colestipol on the plasma concentrations of propranolol.
Authors: Hibbard DM , Peters JR , Hunninghake DB
Published: July 2012

The effect of equivalent hypolipidaemic doses of cholestyramine (8 g) or colestipol (10 g) on the plasma concentrations of propranolol and 4′‐ hydroxypropranolol was studied in 12 normal volunteers following the oral administration of 120 mg of normal release propranolol tablets. When two doses of either cholestyramine or colestipol were administered prior to the propranolol, the peak plasma concentrations and area under the curve for both propranolol and the metabolite 4′‐hydroxypropranolol were reduced significantly (P less than 0.05). We conclude that the drug interaction between cholestyramine or colestipol and propranolol leads to significant reductions in plasma concentrations of propranolol and 4′‐hydroxypropranolol which may cause a clinically diminished effect for a given dosage. Therefore, patients should be observed when either of these resins are added to or deleted from a therapeutic regimen.
Disposition of betamethasone in parturient women after intramuscular administration.
Authors: Petersen MC , Ashley JJ , McBride WG , Nation RL
Published: July 2012

When betamethasone phosphate equivalent to 8 mg betamethasone was administered intramuscularly in solution (Celestone Injection) to pregnant women, a large proportion of this ester was absorbed unchanged. Bioavailability of betamethasone from the phosphate ester was as high as after intravenous injection. When pregnant patients received the equivalent of either 6 or 12 mg betamethasone in a formulation containing 3.1 mg/ml betamethasone acetate suspended in a solution of 4 mg/ml betamethasone phosphate (Celestone Chronodose), much of the phosphate ester was absorbed intact but betamethasone acetate was not detected in plasma. Availability of betamethasone from Celestone Chronodose was much lower than from Celestone Injection. After administration of either formulation, maternal plasma cortisol concentrations fell towards a basal level but were rising again within 2 to 3 days of the last dose. We conclude that Celestone Chronodose does not provide prolonged release of betamethasone and offers no advantage over Celestone Injection.
Comparative bioavailability of trazodone formulations using stable isotope methodology.
Authors: Gammans RE , Mackenthun AV , Russell JW
Published: July 2012

The bioavailability of trazodone, a new antidepressant, from 50 mg dividose (A) or film‐sealed (B) tablets relative to an oral solution was determined in six healthy male subjects using 50 mg of D4‐trazodone as a stable isotope labelled standard. Concentrations of trazodone and D4‐trazodone were measured by GCMS. The pharmacokinetics of trazodone and D4‐trazodone were identical indicating no isotope effect. For formulation A, B and solution, the relative (trazodone/D4‐trazodone) Cmax values were 0.84 +/‐ 0.09, 0.90 +/‐ 0.05 and 1.05 +/‐ 0.04. The relative bioequivalence of the dosage formed with a power of 85% (power by conventional ANOVA was 54%). Among subjects % relative standard deviations (RSD) for the D4‐trazodone AUC values, a measure of intra‐ subject variability, were 6 to 38% while the % RSDs by period, a measure of inter‐subject variability, were 26 to 55%.
The role of sulphate conjugation in the metabolism and disposition of oral and intravenous paracetamol in man.
Authors: Clements JA , Critchley JA , Prescott LF
Published: July 2012

The effects of paracetamol dose (5 and 20 mg/kg) and route of administration (intravenous and oral) on the urinary excretion of paracetamol and its glucuronide, sulphate, cysteine and mercapturic acid conjugates were studied in five healthy subjects. The fractional urinary excretion of unchanged paracetamol and its conjugates was independent of the route of administration at both dose levels, suggesting that the gastrointestinal tract is not an important site for paracetamol metabolism. The percentage of the dose excreted as the sulphate conjugate was significantly higher after 5 than after 20 mg/kg (37.7% and 33.3% respectively) and this is consistent with saturation of sulphate conjugation. No significant effect of paracetamol dose upon the area under the plasma concentration‐time curve (AUC), corrected for dose, was found for the sulphate or glucuronide conjugates. The total plasma clearance of paracetamol and the renal clearance of the sulphate conjugate were significantly higher after the 5 than the 20 mg/kg dose (331 +/‐ 42 ml/min and 295 +/‐ 48 ml/min; 273 +/‐ 74 ml/min and 205 +/‐ 46 ml/min respectively). The oral systemic availability of paracetamol was 80% and independent of dose.
An evaluation of possible interactions between ethanol and trazodone or amitriptyline.
Authors: Warrington SJ , Ankier SI , Turner P
Published: July 2012

The pharmacodynamic effects of single doses of trazodone (100 mg), amitriptyline (50 mg) or placebo either alone or with ethanol (0.5 ml/kg) were investigated in six healthy volunteers in a double‐blind crossover study. Plasma concentrations of the drugs and ethanol were also measured. Pharmacodynamic tests were critical flicker fusion frequency threshold (CFF), choice reaction time (CRT), manual dexterity, a digit span test and visual analogue scales. Blood ethanol concentrations were not influenced by the co‐administration of either antidepressant. tmax for trazodone was prolonged by ethanol but the other pharmacokinetic parameters for trazodone and amitriptyline were not influenced by ethanol. Trazodone and amitriptyline caused the expected profound depressant effects on CFF, CRT, manual dexterity and on the rating scales for drowsiness, ‘clear‐headedness’, aggression and disinhibition. Ethanol alone impaired manual dexterity, increased drowsiness, reduced ‘clear headedness’ and also tended to reduce feelings of aggression. In combination with either trazodone or amitriptyline, ethanol caused little additional effect except in the case of manual dexterity which was further impaired. This result may reflect the profound effects of the antidepressants alone and does not suggest that it is safe for patients receiving antidepressant medication to take ethanolic drinks.
Unchanged peripheral sympathetic activity following withdrawal of chronic metoprolol treatment. A study of noradrenaline concentrations and kinetics in plasma.
Authors: Olsson G , Daleskog M , Hjemdahl P , Rehnqvist N
Published: July 2012

Noradrenaline plasma kinetics were assessed in 17 male patients, who had been treated with metoprolol 100‐200 mg daily (n = 8) or placebo for 3 years after an acute myocardial infarction, before and 1 week after gradual withdrawal (during 1 week) of the study treatment. Endogenous noradrenaline concentrations in plasma were measured by high performance liquid chromatography. Noradrenaline spillover rate, plasma clearance and the t1/2 for the rapid removal from plasma were determined by radio‐tracer methodology. During treatment the plasma noradrenaline concentrations and noradrenaline plasma kinetic variables were similar in the two groups. Venous plasma noradrenaline concentrations were more closely correlated to the spillover rates of noradrenaline to plasma than to the clearance of noradrenaline from plasma, but the spillover rates were correlated to the clearance rates. Following the withdrawal of metoprolol noradrenaline clearance from plasma increased slightly (by 18 +/‐ 5%, P less than 0.05), but the plasma concentrations and spillover rates of noradrenaline were unchanged. In the placebo group withdrawal did not result in any significant changes. Our results indicate that a generalised increase in sympathetic nerve activity is not the cause of so‐called rebound phenomena following withdrawal of chronic beta‐adrenoceptor blockade.
Effects of xamoterol (ICI 118,587) in asthmatic patients.
Authors: Lofdahl CG , Svedmyr N
Published: July 2012

To study the cardioselectivity of xamoterol, eight asthmatic patients took part in a randomised, double‐blind, cross‐over study, in which xamoterol or saline were infused, followed by four increasing doses of terbutaline i.v. Circulatory studies showed a significant increase of systolic blood pressure after xamoterol 0.1 mg/kg compared to saline (P less than 0.05), and heart rate tended to increase. Diastolic blood pressure did not show any significant changes after the different treatments. Skeletal muscle tremor measurements with terbutaline stimulation did not show any differences after pre‐treatment with either xamoterol or saline. Mean values of FEV1 did not reveal any significant difference before or after terbutaline stimulation between xamoterol and saline pre‐treatments. However, in one patient, FEV decreased 60% after xamoterol, an effect which was reversed by terbutaline. Xamoterol did not have any effect on beta‐adrenoceptor mediated skeletal muscle tremor and no significant effect on beta‐ adrenoceptor mediated bronchodilation in doses which gave a significant increase of systolic blood pressure. Thus, xamoterol was shown to be a selective beta 1‐adrenoceptor agonist in man.
Delayed release peppermint oil capsules (Colpermin) for the spastic colon syndrome: a pharmacokinetic study.
Authors: Somerville KW , Richmond CR , Bell GD
Published: July 2012

Excretion of menthol (as glucuronide) from orally ingested peppermint oil contained in Colpermin was compared with oil contained in two soft gelatine capsules. Total 24 h urinary excretion of menthol was similar in the two formulations in healthy volunteers, but peak menthol excretion levels were lower and excretion delayed with Colpermin. Menthol excretion was reduced in ileostomy patients who took Colpermin and moderate amounts of unmetabolised menthol were recovered from the ileostomy effluent. This is consistent with Colpermin being a delayed‐ release form of peppermint oil.
Antipyrine clearance and metabolite formation in patients with alcoholic cirrhosis.
Authors: Teunissen MW , Spoelstra P , Koch CW , Weeda B , van Duyn W , Janssens AR , Breimer DD
Published: July 2012

The effect of liver cirrhosis on plasma clearance and metabolite profile of i.v. administered antipyrine was studied in 23 patients with alcoholic liver cirrhosis (age 37‐70 years) and 17 healthy subjects (age 28‐55 years). Liver volume was also measured and was found to be larger in patients than in controls, mean values being 1.86 and 1.36 l respectively. The elimination half‐life of antipyrine in patients with alcoholic liver cirrhosis was significantly longer than in the healthy subjects (P less than 0.001). Mean values were 39.9 and 10.1 h respectively. Alcoholic liver cirrhosis had no effect on the apparent volume of distribution of antipyrine, but antipyrine plasma clearance was substantially reduced in the patients. Mean clearance values (ranges) were 13.5 (9.3‐22.8) ml/min in the patients and 49.3 (31.1‐ 103) ml/min in healthy subjects. Normalization of antipyrine plasma clearance for liver volume resulted in an only slightly increased distinction between patients and healthy subjects, mean values (ranges) being 7.8 (3.3‐13.0) ml min(‐1) 1(‐1) and 36.1 (21.9‐35.9) ml min(‐1) 1(‐1) respectively. The cumulative renal excretion of 4‐ hydroxyantipyrine (OHA) and norantipyrine (NORA) was significantly lower in patients with alcoholic liver cirrhosis than in healthy subjects, as was the total recovery of antipyrine and major metabolites from urine. Mean values were 15.0, 8.4 and 41.2% of dose in the patients respectively and 24.3, 25.8 and 68.9% of dose in the control subjects. Excreted amounts of total and unconjugated 3‐ hydroxymethylantipyrine (HMA) and of unchanged antipyrine were the same in the two groups.(ABSTRACT TRUNCATED AT 250 WORDS)
Stereoselective first‐pass metabolism of highly cleared drugs: studies of the bioavailability of L‐ and D‐verapamil examined with a stable isotope technique.
Authors: Vogelgesang B , Echizen H , Schmidt E , Eichelbaum M
Published: July 2012

The pharmacokinetics of dextro(+)‐ and levo(‐)‐verapamil were studied in five healthy volunteers following oral administration of pseudoracemic verapamil containing equal amounts of unlabelled (‐)‐ and dideuterated (+)‐isomer. (+)‐verapamil exhibited approximately five times greater Cmax (+): 240 +/‐ 81.1 ng/ml, (‐): 46.1 +/‐ 15.7 ng/ml, P less than 0.0001) and AUC than (‐)‐verapamil. The apparent oral clearance (CLo) for (+)‐verapamil was significantly smaller than that for (‐)‐verapamil (+): 1.72 +/‐ 0.57 l/min, (‐): 7.46 +/‐ 2.16 l/min, P less than 0.001). The bioavailability of (+)‐verapamil (50%) was 2.5 times greater than that of (‐)‐verapamil (20%), P less than 0.005). Thus following oral administration verapamil exhibited a stereoselective first‐pass metabolism. Neither tmax nor the elimination t1/2,z were different between the isomers. The elimination of t1/2,z for each verapamil isomer obtained following oral administration (+): 4.03 h, (‐): 5.38 h) were similar to those previously obtained following intravenous administration (+): 4.15 h, (‐): 5.38 h, respectively. Whereas the (+)‐ to (‐)‐verapamil plasma concentration ratio following oral administration was 4.92 +/‐ 0.48, the ratio following i.v. administration was approximately 2. (‐)‐verapamil has been demonstrated to possess 8 to 10 times more potent negative dromotropic effect on AV conduction than (+)‐verapamil. Therefore, following oral administration the same concentration of plasma verapamil consisting of a two to three times smaller proportion of the more potent (‐)‐isomer appeared to be less potent than that following i.v. administration with regard to the negative dromotropic effects on the AV conduction.
Influence of chronic renal failure on captopril pharmacokinetics and clinical and biological effects in hypertensive patients.
Authors: Giudicelli JF , Chaignon M , Richer C , Giroux B , Guedon J
Published: July 2012

The pharmacokinetic parameters of unchanged plasma captopril and the kinetics of the drug effects on plasma converting enzyme activity (PCEA), plasma renin activity (PRA), plasma aldosterone (PA) and mean blood pressure (MBP) were studied over 24 h after oral administration in three groups of hypertensive patients: with normal renal function (group 1, plasma creatinine less than 110 mumol/l, n = 10), with moderate chronic renal failure (group 2, 135 less than plasma creatinine less than 450 mumol/l, n = 10) and with severe chronic renal failure (group 3, plasma creatinine greater than 500 mumol/l, n = 10). Renal impairment had no effect on plasma captopril Cmax, CLtot and relative bioavailability (AUC). In contrast, captopril kel decreased while T1/2 increased progressively from group 1 to group 3. PCEA blockade (T1/2 and AUC) was increased significantly and proportionally to the degree of renal impairment. However, there were no differences between the three groups regarding captopril‐induced modifications of PRA and PA. Although the maximal reduction in MBP was identical in the three groups, the overall antihypertensive effect (AUC) of captopril increased significantly and progressively from group 1 to group 3, especially in duration. There was no correlation between basal plasma creatinine values and unchanged captopril relative bioavailability (AUC) and between unchanged captopril relative bioavailability (AUC) and the drug effects (AUC) on PCEA, PRA, PA and MBP. However there was a correlation between basal plasma creatinine values and plasma captopril T1/2, PCEA blockade (AUC) and overall antihypertensive effect (AUC). The apparent discrepancy between the lack of effects of chronic renal failure on plasma unchanged captopril bioavailability and its potentiating effects on PCEA blockade and MBP reduction may be accounted for by the renal impairment‐induced accumulation of captopril metabolites.
Tissue extraction of amiodarone and N‐desethylamiodarone in man after a single oral dose.
Authors: Berdeaux A , Roche A , Labaille T , Giroux B , Edouard A , Giudicelli JF
Published: July 2012

The hepatic extraction of amiodarone and N‐desethylamiodarone has been investigated in seven patients following catheterization of the portal and hepatic veins under general anaesthesia. Amiodarone (600 mg) was administered orally 4 h before regional blood sampling. Concentrations of amiodarone and N‐desethylamiodarone, determined by h.p.l.c., were about twice as high in the portal vein compared with those in the hepatic vein, the calculated hepatic extraction ratios of both compounds being 0.39 +/‐ 0.07 and 0.34 +/‐ 0.03, respectively. The presence of N‐desethylamiodarone in the portal vein in higher concentrations than in the hepatic vein strongly suggests that N‐ dealkylation of amiodarone occurs in the gut wall or lumen, a finding which might account for the low and highly variable intersubject amiodarone bioavailability.