bluuebunny/crossref_metadata_2025 huggingface dataset:
The effects and dose‐response relationship of xamoterol in patients with ischaemic heart disease.
Authors: Molajo AO , Bennett DH , Marlow HF , Snow HM , Bastain W
Published: July 2012

1. In a double‐blind placebo controlled four‐way crossover study the effects and dose response relationships of xamoterol were studied in nine patients with angina and dyspnoea secondary to chronic left ventricular dysfunction. The duration of exercise on a treadmill and heart rate were measured at the end of each phase of the study at 2 h and 24 h after dosing. 2. Xamoterol at 200 mg and 400 mg orally once daily had no effect on the mean resting heart rate but there was a small (5.7 beats min‐1) but significant reduction in resting heart rate on 600 mg at 2‐2.5 h after dosing. All three doses of xamoterol significantly reduced the maximum exercise heart rate at 2‐2.5 h after dosing. 3. Xamoterol at all three doses significantly increased exercise duration at 2‐2.5 h after dosing but not at 24 h. 4. Mean plasma xamoterol concentration at both 2‐2.5 h and 24 h after dosing were dose related. The EC50 for xamoterol is 33.5 ng ml‐1, where EC50 is the effective plasma concentration required to produce 50% of the maximum effect on exercise heart rate.
The effect of famotidine on renal function in patients with renal insufficiency.
Authors: Abraham PA , Opsahl JA , Halstenson CE , Chremos AN , Matzke GR , Keane WF
Published: July 2012

The effect of famotidine, a new histamine H2‐receptor antagonist, on renal tubular creatinine secretion was evaluated in twelve patients with reduced renal function (creatinine clearance 10‐60 ml min‐1). Creatinine and inulin clearances were determined at baseline and for 4 h after a 10 mg intravenous dose of famotidine. Famotidine renal clearance exceeded inulin clearance by an average of 152%, indicating that renal tubular secretion of famotidine occurred. No significant changes in the clearances of creatinine or inulin, or the fractional clearance of creatinine were observed after famotidine administration. These data suggest that famotidine, unlike cimetidine, does not inhibit renal tubular secretion of creatinine. Thus, famotidine does not affect creatinine‐dependent measurements of renal function and is unlikely to alter the renal elimination of basic drugs.
A method for estimating the potency of angiotensin‐converting enzyme inhibitors in man.
Authors: Wellstein A , Essig J , Belz GG
Published: July 2012

Dose‐response curves of the effect of angiotensin I (A‐I) infusion on diastolic blood pressure were constructed before and 3 h following single oral doses of the angiotensin‐converting enzyme (ACE) inhibitor cilazapril (1.25 to 30 mg) in six normal male subjects. Cilazapril shifted the A‐I dose‐response curves dose dependently rightward; Schild‐ plot analysis indicated a competitive antagonism by cilazapril with an apparent Ki‐dose of about 0.6 mg.
The effect of nedocromil on weal reactions in human skin.
Authors: Humphreys F , Shuster S
Published: July 2012

1. Nedocromil 2% iontophoresed into human skin had no effect on wealing produced by intradermal histamine, 48/80 or house dust mite antigen. 2. Iontophoresis of 0.002‐2% nedocromil itself resulted in dose‐related wealing. 3. This wealing was reduced by 62 +/‐ 8% s.e. mean by the H1‐ receptor antagonist terfenadine which decreased histamine wealing by 68 +/‐ 2% s.e. mean. 4. Nedocromil may therefore act as a weak agonist on a skin mast cell receptor concerned with histamine release.
Sedative and cardiovascular effects of medetomidine, a novel selective alpha 2‐adrenoceptor agonist, in healthy volunteers.
Authors: Scheinin M , Kallio A , Koulu M , Viikari J , Scheinin H
Published: July 2012

1. Single intravenous doses (25, 50 and 100 micrograms) of medetomidine (MPV‐785, an imidazole derivative), a selective alpha 2‐adrenoceptor agonist, were administered to eight healthy male volunteers in a double‐ blind, placebo‐controlled study. 2. The following dose‐related effects, all of which were compatible with an agonistic action of the drug at alpha 2‐adrenoceptors, were noted: reductions of systolic and diastolic blood pressure (maximum 18/11 mm Hg), heart rate (maximum 10 beats min‐ 1), saliva secretion (maximum 84%) and noradrenaline levels in plasma (maximum 70%). 3. Dose‐dependent sedation or impairment of vigilance was also observed, both by subjective and objective (critical flicker fusion threshold) assessments, with the highest dose actually inducing sleep in five of the subjects. 4. The observed effects were in general agreement with those previously seen after intravenous administration of the centrally acting antihypertensive alpha 2‐adrenoceptor activating drug, clonidine, but of a shorter duration. 5. The relative importance of alpha 2‐adrenoceptors located in peripheral tissues and in the central nervous system for the drug's cardiovascular effects could not be determined, but the high lipid solubility of the compound and the rapid onset of sedation are in favour of a major central component. 6. Medetomidine may be a useful tool for the investigation of the physiology and pharmacology of alpha 2‐adrenoceptors in man. In addition, the therapeutic and diagnostic uses of the compound should be investigated in pathological conditions related to increased sympathetic neuronal activity.
Buspirone pharmacokinetics in patients with cirrhosis.
Authors: Dalhoff K , Poulsen HE , Garred P , Placchi M , Gammans RE , Mayol RF , Pfeffer M
Published: July 2012

The pharmacokinetics of a single oral dose of buspirone (20 mg) were determined in 12 patients with cirrhosis and 12 normal subjects. The mean AUC of buspirone was 55 +/‐ 38 s.d. ng ml‐1 h in cirrhotics and 3.5 +/‐ 2.4 s.d. ng ml‐1 h in normals. The time until maximum concentration (tmax) attained was similar in the two groups (0.6 vs 0.7 h), but mean maximum concentration Cmax was higher in patients (18.8 +/‐ 16.3 s.d. ng ml‐1) than in normals (1.2 +/‐ 0.8 s.d. ng ml‐1). Mean elimination half‐life of buspirone was greater in cirrhotics, but this difference was marginally significant statistically (cirrhotics, 6.1 +/‐ 3.5 s.d. h, normals 3.2 +/‐ 1.5 s.d. h, P = 0.05). Eight of 12 patients and seven of 12 normal subjects had a second peak in the plasma concentrations of buspirone. In patients this occurred at 10.8 +/‐ 7.4 s.d. h after the dose, and its mean concentration was 3.1 +/‐ 6.6 ng ml‐ 1. In normal subjects the second peak occurred at 4.3 +/‐ 2.1 h after the dose and its mean concentration was 0.5 +/‐ 0.3 ng ml‐1. On the kinetic evidence buspirone should be used with caution in liver disease.
The assessment of the beta‐adrenoceptor blocking activity and cardioselectivity of Koe 3290 in normal subjects.
Authors: Pringle TH , McNeill AJ , Riddell JG , Shanks RG
Published: July 2012

1. The beta‐adrenoceptor antagonist activity, cardioselectivity and antilipolytic properties of Koe 3290 were investigated in healthy subjects. 2. Koe 3290 12.5, 25, 50 and 100 mg, atenolol 25, 50 and 100 mg and placebo were given in double‐blind randomised order to eight subjects. All doses of both Koe 3290 and atenolol reduced supine, standing and exercise heart rate (P less than 0.02). From 2 to 8 h after administration the exercise heart rate after Koe 3290 100 mg was similar to that for atenolol 50 mg. 3. The cardioselectivity of Koe 3290 and atenolol was compared. Koe 3290 50, 100 and 150 mg, atenolol 50 and 100 mg and placebo were given to six subjects in a double‐blind random order. Isoprenaline dose‐response curves were constructed for cardiovascular parameters and finger tremor. 4. For doses which were equipotent at the beta 1‐adrenoceptor (Koe 3290 100 mg and atenolol 50 mg) atenolol caused less attenuation of heart rate, diastolic blood pressure, forearm blood flow and finger tremor (P less than 0.02). 5. There was no difference in the isoprenaline‐induced changes in serum free fatty acids, blood glucose, plasma lactate or potassium after Koe 3290 and atenolol. Koe 3290 attenuated the rise in serum insulin more than atenolol (P less than 0.02). 6. Koe 3290 is an effective beta‐ adrenoceptor blocking drug in man. It is not as cardioselective as atenolol and does not possess specific antilipolytic properties.
Comparison of ketanserin and slow‐release nifedipine added to the treatment of hypertensive patients uncontrolled by a thiazide diuretic plus beta‐adrenoceptor blocker.
Authors: Waller PC , Solomon SA , Ramsay LE
Published: July 2012

1. Ketanserin or slow‐release nifedipine were added to the treatment of 24 patients with hypertension uncontrolled by a thiazide diuretic plus beta‐adrenoceptor antagonist in an observer‐blind, randomised parallel‐ group study of 6 months duration. 2. At 6 months the mean falls in supine blood pressure were for ketanserin (mean daily dose 77 mg) 7/5 mm Hg and for nifedipine (mean daily dose 62 mg) 27/10 mm Hg. The difference between the treatments was significant for systolic blood pressure (P less than 0.02) and mean arterial pressure (P less than 0.05). Six nifedipine‐treated patients reached target blood pressure, compared with one patient with ketanserin (P less than 0.02). 3. One patient taking nifedipine, and none taking ketanserin withdrew because of side‐effects. The tolerability of the two drugs was broadly similar. 4. Ketanserin treatment was associated with significant changes in supine pulse rate (‐8 beats min‐1, P less than 0.05) and corrected QT interval (+27 ms, P less than 0.05). Nifedipine treatment had no effect on these variables. The change in pulse rate was significantly different between the groups. 5. In patients treated with a diuretic and beta‐adrenoceptor blocker who required additional treatment ketanserin was significantly inferior to nifedipine.
Acute and chronic ketanserin in essential hypertension: antihypertensive mechanisms and pharmacokinetics.
Authors: Donnelly R , Elliott HL , Meredith PA , Reid JL
Published: July 2012

1. In nine patients with essential hypertension, following single and multiple doses of ketanserin, assessments were made of blood pressure and heart rate, QT interval, and pressor responses to phenylephrine and angiotensin II. 2. Significant reductions in blood pressure occurred for 6 h after the first dose, on average 23/14 mm Hg supine, and there was a comparable antihypertensive effect after 1 month's treatment. 3. There were small but significant rightward shifts (1.5 to 2‐fold) in the phenylephrine pressor‐response curves but no changes in the responsiveness to angiotensin II. 4. The QT interval (QTc) was significantly increased after 1 month's treatment: at 1 h after dosing 334 +/‐ 32 ms after 1 month of ketanserin compared with 302 +/‐ 31 ms after placebo. 5. The elimination half‐life and AUC for ketanserin were both significantly increased at steady state compared with the first dose: respectively 13.4 vs 4.3 h for half‐life and 830 vs 437 ng ml‐1 h for AUC. 6. Ketanserin had no significant effects on baroreflex function, plasma renin activity, aldosterone, catecholamines and 24 h urinary excretion.
Pharmacokinetics and pharmacodynamics of two formulations of verapamil.
Authors: Hla KK , Henry JA , Latham AN
Published: July 2012

The pharmacokinetics and pharmacodynamics of sustained release verapamil were compared with the conventional formulation in 10 healthy adult volunteers after single and multiple dosing. The mean time of maximum plasma concentrations of verapamil were significantly prolonged and the absorption rate constants significantly reduced after sustained release verapamil on both day 1 and day 10. On day 10 there was no significant difference between formulations in the relative bioavailability of verapamil. However, the area under the plasma concentration‐time curve and maximum concentration (Cmax) for both formulations increased significantly with repeat dosing. On day 10, the difference in Cmax between formulations was significant. The day 10 mean peak/trough plasma verapamil concentration ratio was significantly less following the sustained release dose form. The mean PR interval was significantly prolonged by both formulations on day 1 and day 10. There were no differences between formulations other than a significantly longer PR interval following the conventional formulation 2 h after dosing on day 10.
Polymorphism of dextromethorphan oxidation in a French population.
Authors: Larrey D , Amouyal G , Tinel M , Letteron P , Berson A , Labbe G , Pessayre D
Published: July 2012

Genetically‐controlled drug oxidation capacity was studied using dextromethorphan, an anti‐tussive drug, as the test compound in 103 healthy white French subjects (61 males and 42 females). Phenotyping was performed using the metabolic ratio (MR) calculated as MR = 0‐10 h urinary output of dextromethorphan/0‐10 h urinary output of dextrorphan, after oral administration of 40 mg (113.6 mumol) of dextromethorphan hydrobromide. The log MR was bimodally distributed: 99 subjects (96.1%) were phenotyped as extensive metabolizers; they had a log MR between −3.1 and −1.1, a urinary output of dextromethorphan below 5 mumol 10 h‐1 and a urinary output of dextrorphan above 20 mumol 10 h‐1. Four subjects (3.9%) were phenotyped as poor metabolizers; they had a log MR between −0.5 and +0.7, a urinary output of dextromethorphan above 5 mumol 10 h‐1 and a urinary out of dextrorphan below 20 mumol 10 h‐1.
Serum morphine concentrations after buccal and intramuscular morphine administration.
Authors: Fisher AP , Fung C , Hanna M
Published: July 2012

1. This study compared serum concentrations of morphine after administration of a buccal tablet (25mg) with those after intramuscular injection (10mg). 2. Buccal morphine was administered to eleven healthy volunteers and intramuscular morphine was given to five preoperative surgical patients. Serum morphine concentrations were assayed by high performance liquid chromatography (h.p.l.c.) in samples taken up to 8 h after drug administration. 3. Mean maximum morphine concentrations were eight times lower after buccal administration than after intramuscular injection and occurred at a mean of 4 h later. Individual morphine concentration‐time profiles showed marked interindividual variability after administration of the buccal tablet, consistent with considerable variation in tablet persistence time on the buccal mucosa.
Ketanserin in essential hypertension: use as monotherapy and in combination with a diuretic or beta‐adrenoceptor antagonist.
Authors: Cameron HA , Waller PC , Ramsay LE
Published: July 2012

1. The antihypertensive efficacy and tolerability of twice‐daily treatment with the 5‐hydroxytryptamine antagonist ketanserin were examined in a double‐blind, placebo‐controlled trial of 7 weeks duration in 56 hypertensive patients. Twenty were untreated, 20 were already taking bendrofluazide 5 mg daily, and 16 were already taking atenolol 100 mg daily. Randomisation was stratified to compare ketanserin with placebo as monotherapy (n = 20), when added to bendrofluazide (n = 20), and when added to atenolol (n = 16). 2. The antihypertensive effect of ketanserin in all patients completing the study (mean daily dose 71 mg) was 10/6 mm Hg supine (P less than 0.01/P less than 0.01) and 6/6 mm Hg standing (NS/P less than 0.01) when blood pressure was measured 2 h after the morning dose. Responses were similar in patients taking ketanserin as monotherapy, in addition to bendrofluazide, and in addition to atenolol, with reductions in mean arterial pressure of 4.6, 7.4 and 8.9 mm Hg respectively. 3. Ketanserin had no antihypertensive effect when measured 14 h after the last dose. The rise in blood pressure between 2 and 14 h after dosing was 11/4 mm Hg supine (P less than 0.01/NS) and 8/5 mm Hg standing (P less than 0.05/P less than 0.05). 4. The antihypertensive response to ketanserin was positively related to initial blood pressure and, independent of this, to age. It was not related to plasma concentrations of ketanserin or ketanserinol. 5. Five of 28 patients taking ketanserin discontinued treatment because of side‐effects, compared with one of 28 patients taking placebo.(ABSTRACT TRUNCATED AT 250 WORDS)
Effects of fenoldopam, a specific dopamine receptor agonist, on blood pressure and left ventricular function in systemic hypertension.
Authors: Caruana MP , Heber M , Brigden G , Raftery EB
Published: July 2012

1. The effects of fenoldopam, an orally active, specific dopamine‐1 receptor agonist, were studied in eleven patients with essential hypertension, using intra‐arterial blood pressure recording and equilibrium gated radionuclide angiography. 2. A single dose of fenoldopam 100 mg produced a fall in blood pressure (BP) starting after 20 min. The maximum BP reduction (23/25 mm Hg) occurred after 50 min and was accompanied by a heart rate (HR) increase of 10 beats min‐1. The acute effects on BP lasted for 130 min. 3. After 8 weeks of fenoldopam 100 mg, twice daily, only a small, statistically insignificant, hypotensive effect was still apparent after each dose of drug. The duration of the effect was too short to be clinically useful. Tilt‐testing produced a BP fall of 24/14 mm Hg and a HR increase of 17 beats min‐1. Three patients experienced symptoms of postural hypotension during the study. 4. The drug attenuated the blood pressure rise produced by dynamic cycle exercise and isometric hand grip. 5. Acute administration of fenoldopam increased the left ventricular ejection fraction from 61% to 71% (P less than 0.005) and increased the peak filling rate from 2.52 to 3.86 end diastolic vol s‐1 (P less than 0.002). After chronic fenoldopam administration, the left ventricular ejection fraction was 65% (P = NS) pre‐dose, rising to 69% (P less than 0.02) post‐dose and the peak filling rate was increased from 2.7 to 3.38 end diastolic vol s‐1 (P less than 0.01) 60 min post‐ dose.(ABSTRACT TRUNCATED AT 250 WORDS)
The comparative effects of ICI 118551 and propranolol on essential tremor.
Authors: Jefferson D , Wharrad HJ , Birmingham AT , Patrick JM
Published: July 2012

1. The effects of the selective beta 2‐adrenoceptor antagonist ICI 118551 on essential tremor, heart rate and blood pressure were compared with those of propranolol. 2. ICI 118551 (150 mg daily for 7 days) and propranolol (120 mg daily for 7 days) were about equally effective in reducing essential tremor (by about 40%) and were more effective than placebo. 3. When compared with the effect of placebo, propranolol reduced blood pressure and exercise heart rate whereas ICI 118551 had no significant effect on blood pressure and produced a small but significant reduction in exercise‐induced tachycardia. 4. ICI 118551 may be useful in the management of essential tremor while having fewer cardiovascular side‐effects than non‐selective beta‐adrenoceptor antagonists.
The effect of dosing time on the pharmacokinetics and pharmacodynamics of a ‘once‐a‐day’ sustained release theophylline preparation.
Authors: Lamont H , Pauwels R , Van der Straeten M
Published: July 2012

1. The pharmacokinetics and the bronchodilating effect of theophylline were studied during 1 week of morning dosing and 1 week of evening dosing in a randomized cross‐over design in thirteen patients with reversible airways obstruction, treated with a new ‘once‐a‐day’ theophylline capsule formulation. 2. There were no differences between the mean pre‐dose trough plasma concentration, maximal plasma concentration, trough‐to‐peak variation, tmax, area under the plasma drug concentration time‐curve after morning or evening dosage. There was only a slightly but significantly higher plasma theophylline concentration between 16 and 20 h after evening dosing. 3. The mean plasma drug concentration time‐curves were relatively flat with a mean trough to peak variation of 73.9% after morning dosing and 66.7% after evening dosing. Both sets of mean data were within the 10‐20 mg l‐1 therapeutic range. 4. The variations in FEV1 and PEFR throughout the 24 h after either morning or evening dosing were similar and followed the normal pattern of diurnal variation. 5. Adverse effects were mild and occurred in three patients without causing discontinuation of the study. 6. The theophylline preparation used appears suitable for once a day administration either in the morning or in the evening.
Inflammatory responses to intradermal injection of platelet activating factor, histamine and prostaglandin E2 in healthy volunteers: a double blind investigation.
Authors: Sciberras DG , Goldenberg MM , Bolognese JA , James I , Baber NS
Published: July 2012

1. The local responses to intradermal injection of PAF, histamine and PGE2 were investigated in eight healthy male volunteers. Acute effects were monitored by weal and flare measurement; delayed effects were investigated by pain threshold testing and skinfold thickness measurements. 2. PAF and PGE2 were found to induce weal and flare responses which were clearly distinguishable from vehicle and dose related. 3. PAF was approximately 50 times as potent as PGE2 at inducing weal on a molar basis. 4. A dose related hyperalgesia was recorded in response to PGE2. No hyperalgesia could be demonstrated following PAF injection compared with vehicle. 5. PAF and histamine elicited an increase in skinfold thickness up to 2 h after injection which was distinguishable from vehicle.
Single dose pharmacokinetics of proguanil and its metabolites in healthy subjects.
Authors: Wattanagoon Y , Taylor RB , Moody RR , Ochekpe NA , Looareesuwan S , White NJ
Published: July 2012

1. Plasma and whole blood concentrations of proguanil and its two major metabolites cycloguanil (CG) and 4‐chlorophenylbiguanide (CPB) were measured by a sensitive h.p.l.c. technique in nine healthy adult male volunteers after a single oral dose of proguanil 200 mg. 2. Proguanil was absorbed with a median time to peak plasma concentration of 3 h (range 2‐4 h). 3. Peak plasma concentrations of proguanil ranged between 150 and 220 (median 170) ng ml‐1 compared with 12 to 69 (median 41) ng ml‐1 for the active antimalarial metabolite CG, and 3 to 16 (median 11) ng ml‐1 for CPB. Peak (mean +/‐ s.d.) plasma CG concentrations occurred 5.3 +/‐ 0.9 h and peak CPB concentrations occurred 6.3 +/‐ 1.4 h after oral administration of proguanil. 4. Whole blood concentrations of proguanil were approximately five times higher, and whole blood CPB concentrations were four times higher than corresponding plasma values, whereas plasma and whole blood concentrations of CG were similar. 5. A triexponential function was fitted to these data; mean (+/‐ s.d.) values for the AUC were 3046 +/‐ 313 ng ml‐1 h for proguanil, 679 +/‐ 372 ng ml‐1 h for CG and 257 +/‐ 155 ng ml‐1 h for CPB. 6. Plasma and whole blood concentrations of proguanil and its metabolites declined in parallel with terminal elimination half‐lives estimated as 16.1 +/‐ 2.9 h and 15.7 +/‐ 2.4 h, respectively. Mean residence times in plasma and whole blood were estimated as 21.2 +/‐ 4.9 and 19.3 +/‐ 2.4 h.
Pharmacokinetics of N‐desmethylclobazam in healthy volunteers and patients with epilepsy.
Authors: Pullar T , Haigh JR , Peaker S , Feely MP
Published: July 2012

1. The single dose pharmacokinetics of N‐desmethylclobazam (NDMC) and clobazam were studied in eight healthy male volunteers. 2. Steady‐state pharmacokinetic data are described from four healthy male volunteers and eight epileptic patients taking NDMC. 3. A single 30 mg dose of NDMC produced a greater Cmax (P less than 0.001) and AUC0‐infinity (P less than 0.005) and a shorter tmax (P less than 0.05) and t1/2 (P less than 0.01) for NDMC than did 30 mg clobazam. 4. Mean steady‐state NDMC concentrations were greater in male patients than in female patients and also in male patients compared with male volunteers. The differences between patients and volunteers might be explained by concomitant antiepileptic medication.
Disposition of antipyrine in African patients with Hodgkin's lymphoma.
Authors: Juma FD
Published: July 2012

The pharmacokinetics of antipyrine were studied in 12 healthy volunteers and 10 patients of Kenya African origin with Hodgkin's lymphoma. The half‐life of antipyrine was 12.2 +/‐ 1.3 h (mean + s.d.), while the apparent volume of distribution (V) was 0.67 +/‐ 0.11 l kg‐1 (mean +/‐ s.d.) and the total body clearance was 40.7 +/‐ 3.2 ml kg‐1 h‐ 1 (mean +/‐ s.d.) in the healthy volunteers. The antipyrine half‐life in the patients with advanced Hodgkin's lymphoma was 17.1 +/‐ 2.7 h (mean +/‐ s.d.). The apparent volume of distribution was 0.72 +/‐ 0.14 l kg‐1 (mean +/‐ s.d.) which was larger than in healthy volunteers (P less than 0.05). The total body clearance was 30.3 +/‐ 9.4 ml kg‐1 h‐1 (mean + s.d.) and this was reduced compared with that in healthy volunteers (P less than 0.02). After cytotoxic therapy the half‐life in the patients with advanced Hodgkin's lymphoma was significantly decreased to 8.3 +/‐ 1.3 h (mean +/‐ s.d.) (P less than 0.07), and the apparent volume of distribution was reduced to 0.65 +/‐ 0.07 l kg‐1 (mean +/‐ s.d.) (P less than 0.05) while the total body clearance increased to 52.8 +/‐ 5.5 ml kg‐1 h‐1 (mean +/‐ s.d.) (P less than 0.01).
Respiratory stimulant effects of adenosine in man after caffeine and enprofylline.
Authors: Smits P , Schouten J , Thien T
Published: July 2012

In a double‐blind and randomized study the respiratory stimulant effect of continuous intravenous adenosine infusion was studied after previous administration of caffeine, placebo and enprofylline in 10 healthy young volunteers. After placebo, adenosine induced an increase of minute ventilation (from 6.3 to 12.5 l min‐1), tidal volume (from 0.60 to 0.96 l), and breathing rate (from 11.0 to 14.8 min‐1). Venous pCO2 fell and pH rose after adenosine. Caffeine significantly reduced the adenosine‐induced changes of minute ventilation, tidal volume, venous pCO2 and pH, whereas no changes occurred after enprofylline. Our results suggest that adenosine stimulates respiration in man by binding with specific P1‐purinoceptors, which can be blocked by caffeine, but not by enprofylline.
Flecainide distribution in human tissues.
Authors: Latini R , Cavalli A , Maggioni AP , Volpi A
Published: July 2012

The distribution of antiarrhythmic drugs in human tissues may yield a better understanding of their therapeutic action and side effects. We report tissue distribution of flecainide in a patient who died suddenly while being treated chronically with the drug. Lungs showed the highest concentration of flecainide (143 micrograms g‐1 wet tissue); liver, kidney and heart, in decreasing order, have good affinity for the drug. Flecainide was present also in the central nervous system in lower concentrations. The lowest concentration was found in the adipose tissue.
Inhibition by erythromycin of the conversion of carbamazepine to its active 10,11‐epoxide metabolite.
Authors: Barzaghi N , Gatti G , Crema F , Monteleone M , Amione C , Leone L , Perucca E
Published: July 2012

The serum levels of carbamazepine (CBZ) and its 10,11‐epoxide metabolite (CBZ‐E) were determined in seven subjects after a single dose of CBZ (400 mg) in the control state and during co‐administration of erythromycin (500 mg three times daily for 10 days). Erythromycin treatment was associated with a decrease in CBZ clearance and a prolongation of CBZ half‐life, while CBZ‐E levels were markedly reduced. These data provide evidence that erythromycin inhibits the conversion of CBZ to its epoxide metabolite.
Enalapril in essential hypertension: the comparative effects of additional placebo, nicardipine and chlorthalidone.
Authors: Donnelly R , Elliott HL , Meredith PA , Reid JL
Published: July 2012

The effect of adding placebo, a calcium antagonist, nicardipine and a thiazide diuretic, chlorthalidone, each for 2 weeks, to ongoing treatment with the ACE inhibitor, enalapril was evaluated in seven patients with essential hypertension. Compared with placebo, nicardipine and chlorthalidone both significantly enhanced the antihypertensive effect of enalapril: average blood pressure reductions over 8 h were respectively 26/16 and 33/17 mm Hg (supine) but the time‐ course of these augmented effects was significantly different. In particular, blood pressure control with the addition of nicardipine, despite apparently being at steady state, was significantly attenuated during the latter part of the dosage interval and therefore was less well sustained at 24 h. In contrast, an effect throughout 24 h appeared possible with the chlorthalidone‐enalapril combination.
Hypertension in pregnancy: whom and how to treat.
Authors: Lubbe WF
Published: July 2012

1. Elucidation of some of the mechanisms responsible for blood pressure elevation in pregnancy has permitted therapy to be based on more rational principles. The decreased arterial reactivity encountered in normotensive pregnancy is most likely mediated by prostaglandins; preventive therapy using low dose aspirin is an option to prevent development of proteinuria in pre‐existing hypertension and provide prophylaxis against pregnancy‐induced hypertension. 2. Antihypertensive therapy utilizing sympathetic inhibition with either methyldopa or alpha‐ and beta‐adrenoceptor blockade yields the most promising results. Vasodilation with hydralazine, calcium entry blockers (nifedipine), intravenous labetalol or diazoxide is primarily used in severely hypertensive patients. The use of orally administered nifedipine in severely hypertensive women is associated with encouraging results. 3. It is clear that women with blood pressure levels greater than 170/110 mm Hg need antihypertensive therapy for maternal safety; it remains to be proven to what extent foetal growth and welfare can be improved in women with diastolic pressure levels 85‐ 110 mm Hg when adrenoceptor blocking agents are used for blood pressure control. Initial studies are suggestive of improved foetal growth, prevention of proteinuria and the respiratory distress syndrome but more long‐term controlled studies are required. 4. In a recent study, at our institution, of foetal growth during long term antihypertensive therapy, treatment with pindolol yielded better foetal growth than therapy with atenolol. It is as yet unclear whether the ISA or beta 2‐ mediated vasodilation associated with pindolol was responsible for the improved foetal growth. Further controlled studies are indicated in hypertension in pregnancy to confirm the suggested benefits of beta‐ adrenoceptor blocker therapy.
Cardiac effects of beta‐adrenoceptor blockade with intrinsic sympathomimetic activity during submaximal exercise.
Authors: Ades PA
Published: July 2012

1. beta‐adrenoceptor blocking agents with intrinsic sympathomimetic activity (ISA) are characterized by lesser depression of cardiac performance during low levels of sympathetic stimulation than beta‐ adrenoceptor blocking agents lacking ISA. Studies of the effects of ISA on cardiac output and on the determinants of myocardial oxygen demand during submaximal exercise are described and distinct differences between beta‐adrenoceptor antagonists with and without ISA emerge. 2. At doses which produce similar effects on maximal exercise heart rate, and resting and exercise systolic blood pressure, pindolol, a beta‐ adrenoceptor blocking agent with substantial ISA, allows a higher submaximal exercise cardiac output and submaximal heart rate X systolic blood pressure product than does propranolol, a beta‐adrenoceptor antagonist without ISA. 3. These findings may have clinical relevance in specific groups of patients such as those with arterial hypertension, where the preservation of cardiac function may allow for a more physiologic exercise response. Implications in patients with coronary artery disease and chronic heart failure await further study.
ISA‐vasodilatation: improvement of organ perfusion.
Authors: Hansson L
Published: July 2012

1. In almost all forms of established hypertension the increase in blood pressure can be attributed to increased total peripheral vascular resistance. 2. beta‐adrenoceptor blocking compounds, which are frequently used as first‐line therapy in hypertension, may compromise blood flow to vital organs in view of the fact that they reduce cardiac output both acutely and during long‐term treatment. 3. beta‐ adrenoceptor blocking agents with a marked intrinsic sympathomimetic activity (ISA) such as pindolol differ in this respect by lowering arterial pressure without lowering cardiac output while causing a reduction in total peripheral resistance. 4. Direct vascular effects of beta‐adrenoceptor blockers with marked ISA could contribute to the normalisation of hypertension‐induced structural arteriolar changes. The effect appears to be dissociated from the effect caused by the lowering of blood pressure per se.
Comparison of the onset of the antihypertensive action of pindolol and propranolol. A 24 h haemodynamic study.
Authors: Van den Meiracker AH , Man in't Veld AJ , Schalekamp MA
Published: July 2012

1. Haemodynamic changes during the onset of the antihypertensive action of pindolol, 10 mg twice daily, and propranolol, 80 mg three times daily, were studied for 24 h in two groups of 10 patients with uncomplicated essential hypertension. 2. Baseline haemodynamics were not different between the two groups. 3. Pindolol, with considerable intrinsic sympathomimetic activity (ISA) exerted its maximal antihypertensive efficacy within 3‐4 after dosing (−15 +/− 3%, mean +/− s.e. mean, P less than 0.001). This effect was maintained for 24 h. 4. After propranolol, which is devoid of ISA, arterial pressure fell more gradually, but after 24 h the two drugs shared an equal antihypertensive effect. 5. Cardiac output rose after pindolol by 16 +/− 5% (P less than 0.01). It decreased transiently by 16 +/− 6% (P less than 0.01) 1‐4 h after propranolol. At that time vascular resistance had risen by 18 +/− 5% (P less than 0.001). 6. The onset of the antihypertensive action of the two drugs was associated with reductions in vascular resistance. Since reflex vasoconstriction did not occur after pindolol, vascular resistance was always lower on this drug than on propranolol (‐29 +/− 4%, P less than 0.001 vs −15 +/− 5%, P less than 0.01). 7. Cardiac filling pressures, pulmonary artery pressure and pulmonary vascular resistance did not change after pindolol but they rose after propranolol. 8. During the onset of the vasodilator and antihypertensive effects of the two beta‐adrenoceptor blockers heart rate, stroke volume and cardiac output rose, despite cardiac beta‐ adrenoceptor blockade, suggesting a reduction of parasympathetic tone and an increase in venous return.(ABSTRACT TRUNCATED AT 250 WORDS)
Reversibility of structural changes in the resistance vessels in hypertension: a review of studies with pindolol.
Authors: Duner H
Published: July 2012

1. In recent years evidence has accumulated which indicates that although various beta‐adrenoceptor antagonists are equally effective in lowering blood pressure in patients with essential hypertension the mechanisms of action of the different drugs are heterogeneous. 2. Pindolol, a beta‐adrenoceptor antagonist with pronounced intrinsic sympathomimetic activity (ISA) appears, to some extent, to act via peripheral vascular mechanisms. 3. Following prolonged treatment with pindolol in essential hypertension peripheral vascular resistance at maximal vasodilatation has been found to be decreased compared with the pretreatment values suggesting that the structural vascular changes characteristic of established hypertension may be reversible.
A long‐term study on the effect of pindolol on serum lipoproteins: a preliminary report.
Authors: Carlson LA , Ribacke M , Terent A
Published: July 2012

1. Preliminary results are reported from a long‐term study aimed at recording the concentrations of serum lipids and lipoproteins at 6, 12 and 24 months of treatment with pindolol in young/middle‐aged males with moderate hypertension. 2. Seventy‐three patients have been recruited, of whom 47 have completed 6 months treatment. After 6 months treatment 35/47 patients had attained the target blood pressure of less than or equal to 95 mm Hg and analysis of plasma lipid and lipoprotein concentrations revealed a tendency for an increase of serum triglycerides and a lowering of low density lipoprotein cholesterol.
The relationship between inhibition of vitamin K1 2,3‐epoxide reductase and reduction of clotting factor activity with warfarin.
Authors: Choonara IA , Malia RG , Haynes BP , Hay CR , Cholerton S , Breckenridge AM , Preston FE , Park BK
Published: July 2012

1 The effect of low dose steady state warfarin (0.2 mg and 1 mg daily) on clotting factor activity and vitamin K1 metabolism was studied in seven healthy volunteers. 2 Steady state plasma warfarin concentrations were 41‐99 ng ml‐1 for the 0.2 mg dose and 157‐292 ng ml‐1 for the 1 mg dose. 3 There was a significant prolongation of the mean prothrombin time (0.9 s) after 1 mg warfarin daily, but no significant change in prothrombin time after 0.2 mg warfarin daily. There was no significant change in individual clotting factor activity (II, VII, IX or X) with either dose of warfarin. 4 Following the administration of a pharmacological dose of vitamin K1 (10 mg), all seven volunteers had detectable levels of vitamin K1 2,3‐epoxide with both doses of warfarin (Cpmax 31‐409 ng ml‐1). 5 Both the Cpmax and the AUC for vitamin K1 2,3‐ epoxide were significantly greater on 1 mg of warfarin daily than 0.2 mg daily (P less than 0.01). 6 The apparent dissociation between inhibition of vitamin K1 2,3‐epoxide reductase and reduction of clotting factor activity, produced by warfarin, may reflect the insensitivity of functional clotting factor assays to a small reduction in clotting factor concentration.
Pharmacokinetic and pharmacodynamic properties of intravenous fenoldopam, a dopamine1‐receptor agonist, in hypertensive patients.
Authors: Weber RR , McCoy CE , Ziemniak JA , Frederickson ED , Goldberg LI , Murphy MB
Published: July 2012

1 The pharmacokinetic properties of intravenous fenoldopam, a selective dopamine1‐receptor agonist, were studied in 10 patients with essential hypertension. 2 Reduction in blood pressure was linearly related to the log fenoldopam plasma concentration (r = 0.69) and the log fenoldopam infusion rate (r = 0.71). 3 The mean elimination half‐life (+/‐ s. e. mean) was 9.8 +/‐ 1.0 min. The total body clearance was 30.3 +/‐ 2.3 ml kg‐1 min‐1 and the volume of distribution was 582 +/‐ 62 ml kg‐1. 4 The rapid onset of action, short elimination half‐life, linear dose‐ response relationship, and ease of administration suggest that fenoldopam may have a role where parenteral treatment of hypertension is required.
The in vitro 5‐lipoxygenase and cyclo‐oxygenase inhibitor L‐652,343 does not inhibit 5‐lipoxygenase in vivo in human skin.
Authors: Barr RM , Black AK , Dowd PM , Koro O , Mistry K , Isaacs JL , Greaves MW
Published: July 2012

1 3‐hydroxy‐5‐trifluoromethyl‐N‐[2‐(2‐thienyl)‐2‐phenyl‐ethenyl]‐ benzo(B) thiophene‐2‐carboxamide (L‐652,343) is a 5‐lipoxygenase and cyclo‐oxygenase inhibitor in vitro. 2 In psoriasis increased concentrations of arachidonic acid transformation products are found in the lesional skin which may be important in the pathogenesis of the disease. We have measured the effect of orally administered L‐652,343 on the concentration of LTB4 and prostaglandins in the lesional skin. 3 Eight patients with stable chronic plaque psoriasis received 500 and 250 mg of L‐652,343, 12 h apart. A chamber technique was used to collect skin exudate samples from abraded plaques before and at 4, 24 and 48 h after the first dose. Exudates were analysed for LTB4 by a neutrophil chemokinesis assay and for PGE2 and PGD2 by RIA. 4 PGE2 and PGD2 levels were significantly reduced at 4 and 24 h after the first dose of L‐652,343 but LTB4 levels were not affected indicating inhibition of the cyclo‐oxygenase pathway but not of the 5‐lipoxygenase pathway. This shows the importance of confirming that the action of 5‐ lipoxygenase inhibiting drugs in vitro occurs in vivo.
The effect of probenecid on the renal tubular excretion of benzylpenicillin.
Authors: Overbosch D , Van Gulpen C , Hermans J , Mattie H
Published: July 2012

1 The aim of this study was to establish whether the renal tubular excretion of benzylpenicillin is saturable and whether the effect of probenecid on the tubular excretion of benzylpenicillin is dose‐ dependent. 2 Each of four volunteers underwent three experiments. In each experiment benzylpenicillin was administered by continuous infusion, such that three different consecutive concentration levels were reached. In the first experiment no probenecid was given; in the second and third experiments, probenecid was administered by continuous infusion at a low and higher rate, respectively. 3 Plasma and urinary concentrations of benzylpenicillin were determined at 30 min intervals by high performance liquid chromatography. 4 By fitting the equation Rtub = Rtub, max. Cp/(EC50 + Cp) to the values of the tubular excretion rate found for benzylpenicillin (Rtub) vs the free plasma concentration (Cp), the values of Rtub, max and EC50 could be calculated: 3350 (+/‐ 606) mg h‐1 for Rtub, max and 48.0 (+/‐ 17.8) mg l‐1 for EC50 (in the absence of probenecid). 5 The EC50 for benzylpenicillin increased significantly with increasing doses of probenecid. 6 The dose of probenecid at which 50% of the excretory system is occupied by probenecid in the absence of benzylpenicillin (ED50) ranged from 13.2 to 108.5 mg h‐1. 7 The EC50 of probenecid in one subject could actually be measured: 52.3 mg l‐1. 8 Extrapolating these results to the clinical situation, the commonly used daily dose of 2 g of probenecid is likely to be close to the maximal effective dose for inhibition of the tubular excretion of benzylpenicillin.
Mephenytoin hydroxylation in the Cuna Amerindians of Panama.
Authors: Inaba T , Jorge LF , Arias TD
Published: July 2012

1 Mephenytoin p(4′)‐hydroxylation, which is deficient in 3‐5% of Caucasians, was examined in 96 Cuna Amerindians of Panama. 2 Attempts were made to exclude poor compliance with urine collection and ingestion of the drug dose since the assignment of phenotype was based upon urinary recovery of the metabolite. These involved the measurement of the urinary recovery of sparteine, added to the ingested capsule, and of the renal excretion of creatinine. 3 Of the 90 Cunas deemed to be reasonably complaint, none of them appeared to be deficient in p(4′)‐ hydroxylation of mephenytoin.
The contribution of histamine release to bronchoconstriction provoked by inhaled benzalkonium chloride in asthma.
Authors: Miszkiel KA , Beasley R , Rafferty P , Holgate ST
Published: July 2012

1. To investigate the possibility that benzalkonium chloride‐induced bronchoconstriction results from the endogenous release of histamine, we examined the effect of the selective histamine antagonists terfenadine and astemizole, on the airways response to inhaled benzalkonium chloride and histamine in 12 asthmatic subjects. 2. Double‐ blind concentration‐ and time‐course studies were undertaken, 3 h after treatment with terfenadine or matched placebo. 3. Benzalkonium chloride and histamine caused concentration‐related falls in FEV1 in all subjects with benzalkonium chloride being 7.4 times less potent as a bronchoconstrictor agonist than histamine. Terfenadine displaced to the right the benzalkonium chloride and histamine concentration‐response curves by 3.7 and 111 fold respectively. Terfenadine attenuated the initial (5 min) bronchoconstrictor response to benzalkonium chloride by 40%. However, over the whole 45 min period, the response was reduced by only 13% compared with 86% inhibition of the response to histamine. 4. In an open study, eight of the 12 subjects undertook a time course study with inhaled benzalkonium chloride after pretreatment with the chemically unrelated histamine antagonist astemizole. Astemizole inhibited benzalkonium chloride‐induced bronchoconstriction to an almost identical degree as that achieved with terfenadine. 5. We conclude that the initial bronchoconstrictor effect of benzalkonium chloride is due, in part, to histamine release. However, the majority of the adverse effect relates to other, as yet unrecognised effects of this bacteriocidal substance.
The effect of age and cardiac failure on xamoterol pharmacokinetics.
Authors: Scott AK , Webster J , Petrie JC , Bastain W
Published: July 2012

1. Xamoterol is a cardioselective beta‐adrenoceptor partial agonist which may have a role in the management of cardiac failure. Excretion is mainly by the renal route. 2. The kinetics of a single 200 mg oral dose of xamoterol were studied in eight elderly (age 67‐82 years) volunteers, eight young (age 21‐43 years) volunteers; eight patients with mild to moderate cardiac failure and eight age and sex matched controls. 3. Elderly volunteers had a significantly longer time to reach peak concentration (mean +/‐ s.e. mean 2.1 +/‐ 0.2 vs 1.1 +/‐ 0.1 h) and elimination half‐life time (27.0 +/‐ 2.8 vs 16.4 +/‐ 3.1 h) compared with young volunteers. The renal clearance of xamoterol was lower in the elderly (115 +/‐ 12 vs 185 +/‐ 19 ml min‐1) and showed a significant correlation with creatinine clearance (r = 0.85, P less than 0.001). 4. There was no significant difference in any of the pharmacokinetic parameters measured in patients with cardiac failure compared with healthy age and sex matched controls. 5. These results suggest that the maintenance dose of xamoterol could be reduced in elderly patients in relation to impairment of renal function.
The pharmacokinetics of oral and intravenous nalbuphine in healthy volunteers.
Authors: Aitkenhead AR , Lin ES , Achola KJ
Published: July 2012

The pharmacokinetics of nalbuphine were studied in 10 healthy volunteers on two separate occasions following administration by either the intravenous (20 mg) or oral (60 mg) route. After administration, serum concentrations of nalbuphine were measured for 12 h using a high pressure liquid chromatography assay, and pharmacokinetic parameters were derived using a three compartment model. After i.v. administration, elimination half‐life was 222 (111‐460) min (mean and range) and total body clearance was 1.5 (0.8‐2.3) 1 min‐1. Cmax after oral administration was 21.4 (6.0‐36.2) ng ml‐1 and tmax was 46.6 (15.3‐ 89.0) min. Bioavailability of the oral preparation was 11.8 (6.1‐20.1)%.
Comparison of neurokinin A and substance P on cardiovascular and airway function in man.
Authors: Evans TW , Dixon CM , Clarke B , Conradson TB , Barnes PJ
Published: July 2012

The airway and cardiovascular effects of intravenous neurokinin A (NKA) and substance P (SP) were compared in six normal subjects. Both SP and NKA increased skin temperature (SkT) and heart rate (HR), but SP was more potent than NKA by factors of 6 and 20 respectively. No change in systolic blood pressure (BP) occurred with either peptide, but diastolic BP fell significantly with SP infusion. SP caused bronchodilation and NKA bronchoconstriction. NKA and SP have differing physiological roles and may activate different receptor populations.
The effect of combined therapy on the pharmacokinetics and pharmacodynamics of verapamil and propranolol in patients with angina pectoris.
Authors: McCourty JC , Silas JH , Tucker GT , Lennard MS
Published: July 2012

1. The pharmacokinetics and pharmacodynamics of oral verapamil and propranolol were studied in patients with stable angina pectoris during chronic mono‐ and dual therapy. 2. The peak plasma concentrations (Cmax) and areas under the plasma concentration‐time curves (AUC) of verapamil were similar during combined treatment with propranolol (mean +/‐ s.d.: Cmax = 491 +/‐ 397 ng ml‐1; AUC = 2075 +/‐ 1524 ng ml‐1 h) or atenolol (mean +/‐ s.d.: Cmax = 372 +/‐ 320 ng ml‐1; AUC = 1985 +/‐ 1660 ng ml‐1 h). 3. No differences in Cmax and AUC were observed during verapamil monotherapy (mean +/‐ s.d.: Cmax = 287 +/‐ 105 ng ml‐1; AUC = 1375 +/‐ 455 ng ml‐1 h) vs combined treatment with propranolol (mean +/‐ s.d.: Cmax = 312 +/‐ 55 ng ml‐1; AUC = 1566 +/‐ 486 ng ml‐1 h). 4. Treatment with verapamil increased the Cmax (mean +/‐ s.d.: 227 +/‐ 117 vs 116 +/‐ 62 ng ml‐1, P less than 0.05) and AUC (1389 +/‐ 617 vs 837 +/‐ 316 ng ml‐1 h, P = 0.0625) of propranolol in all subjects. 5. Transient atrioventricular dissociation occurred in two patients 2 h after dosing with verapamil and propranolol or atenolol. 6. Close observation of patients is essential when beta‐adrenoceptor antagonists and verapamil are used together.