bluuebunny/crossref_metadata_2025 huggingface dataset:
Indoramin‐prolongation of repolarization time, a mechanism of bradycardia in man?
Authors: Harron DW , Nicholls DP , Shanks RG
Published: July 2012

The effect of indoramin, a selective alpha 1‐adrenoceptor antagonist, on ECG time intervals in normal man was studied. Significant prolongation of QTc was observed after indoramin 100 mg, with no change in QRS duration. In addition, the slope of the RR/QT relationship was changed by indoramin 100 mg. These results suggest that indoramin may have Class III antiarrhythmic activity. If such activity were to affect the SA node, it may explain at least in part the observed lack of reflex tachycardia after indoramin administration.
Cimetidine's effect on dermal H1‐receptor antagonist tolerance.
Authors: Fairris GM , Fairris N
Published: July 2012

The effect of the H2‐receptor antagonist cimetidine upon H1‐receptor antagonist tolerant histamine induced weal and flare responses was studied in nine healthy male subjects taking clemastine 1 mg orally twice a day. After 21 days clemastine therapy, the weal response became tolerant to clemastine but the flare response did not. Cimetidine, 400 mg, did not produce a significantly greater decrease in the area of the H1‐receptor antagonist tolerant weal response than in the non‐tolerant weal response. The results suggest that histamine mediated skin reactions may develop a tolerance to H1‐receptor antagonist therapy that cannot be overcome by the addition of the H2‐receptor antagonist cimetidine.
Red wine contains a potent inhibitor of phenolsulphotransferase.
Authors: Littlewood JT , Glover V , Sandler M
Published: July 2012

Many ethanolic drinks, especially red wine, contain potent inhibitors of phenolsulphotransferase. At a dilution of 1/75 from the original beverage, extracts from six types of red wine inhibited human platelet phenolsulphotransferase P by a mean of 99% and human platelet phenolsulphotransferase M by 12%. Such extracts had no significant effect on rat liver monoamine oxidase A or human platelet monoamine oxidase B. The inhibitors, which have not yet been identified, can be extracted into ethyl acetate at acid or neutral pH. Thus, they are not monoamines. Flavonoid phenols are plausible candidates. As phenolsulphotransferase M and P are involved in the metabolism of many phenols, including drugs, the inhibition of these enzymes could result in the enhancement of pharmacological potency and have important clinical consequences.
Comparative clinical efficacy of bepridil, propranolol and placebo in patients with chronic stable angina.
Authors: Rae AP , Beattie JM , Lawrie TD , Hutton I
Published: July 2012

A randomised double‐blind parallel group study was performed to compare the clinical efficacy of bepridil, a new calcium slow channel blocker, with that of propranolol and placebo in patients with chronic stable angina of effort. Efficacy was assessed objectively by dynamic exercise testing using an upright bicycle ergometer and subjectively by patient documentation of anginal frequency and nitrate consumption. The administration of bepridil resulted in a significant improvement in physical work capacity expressed as calculated maximal oxygen uptake (Vo2 max) and exercise time. This was associated with subjective improvement in terms of reduced anginal frequency. Despite baseline differences in exercise performance and anginal frequency between the three treatment groups, the beneficial effects of bepridil were statistically significant when compared to propranolol. Although minor electrocardiographic changes were noted, no adverse effects were evident when bepridil was prescribed in doses of up to 400 mg/day over a 10 week period.
Influence of advanced age on the disposition of acetazolamide.
Authors: Chapron DJ , Sweeney KR , Feig PU , Kramer PA
Published: July 2012

The disposition kinetics of acetazolamide (AZ) has been studied in four young and four elderly healthy volunteers, each of whom received an intravenous bolus dose of 5 mg/kg. The concentration time profile of AZ was determined in plasma, plasma ultrafiltrate, erythrocytes and urine. While the mean area under unbound plasma concentration‐time curves was 81% higher in elderly subjects, areas based on total drug concentrations were similar in both groups. The mean renal plasma clearance was similar in both groups. The mean renal plasma clearance was similar between young and old for total AZ, but was significantly lower in the elderly for unbound drug (8.88 ml min‐1 kg‐1 vs 15.7 ml min‐1 kg‐1). Renal clearance of unbound AZ correlated well with creatinine clearance (r = 0.846, P less than 0.01). Peak erythrocyte levels were 45% higher in the elderly group (37.2 micrograms/ml vs 25.3 micrograms/ml) and were paralleled by a 46% increase in the mean area under the erythrocyte concentration‐time curve for this age group. The unbound fraction of AZ in plasma was significantly greater in elderly than younger subjects (6.9 vs 4.1%, P less than 0.05). Integrated AZ erythrocyte concentrations correlated positively with AZ free fraction in plasma and inversely with its unbound renal clearance. These observed differences in AZ disposition between elderly and young have served to clarify host factors which may importantly influence susceptibility to adverse effects.
Comparative effects of adimolol, labetalol and propranolol on heart rate and blood pressure in man.
Authors: Riddell JG , Harron DW , Shanks RG
Published: July 2012

The cardiovascular effects of adimolol, a new, potent, long acting beta‐ adrenoceptor blocking drug were investigated in three studies. In the first study blood pressure and heart rate were measured in five male volunteers before and at 2, 4, 6, 8, 24, 32, 48, 72 and 96 h after single oral doses of adimolol. All doses of adimolol reduced supine, standing and exercise heart rates in a dose dependent manner. The maximum effect ranged from 18% following 25 mg to 29% following 600 mg and all doses showed an effect at 96 h (range 3.5‐17.2%). In the second study the effects of adimolol, 25 and 400 mg, labetalol, 200 and 800 mg, propranolol 40 mg and placebo were compared on supine and standing heart rate and blood pressure and on exercise heart rate before and at 2, 4, 6 and 8 h after single oral doses. The exercise heart rate was significantly reduced at all times following adimolol 25 and 400 mg, labetalol 800 mg and propranolol 40 mg. At 2 h all the drugs significantly reduced standing systolic blood pressure. In the third study, 4 h after single oral doses of adimolol 400 mg, labetalol 400 mg and propranolol 40 mg six subjects received serial 4 min infusions of phenylephrine. The blood pressure was measured after each infusion. Labetalol 400 mg significantly shifted the blood pressure dose‐response curve to the right. There was no difference between propranolol 40 mg and adimolol 400 mg. These studies show that adimolol is a potent, long acting beta‐adrenoceptor blocking drug without evidence of alpha‐ adrenoceptor blockade in man.
Dynamics of beta‐adrenoceptor blockade with cetamolol.
Authors: Coelho J , Schnelle K , Joubert L , Ventura D , Mullane J
Published: July 2012

Cetamolol is a new beta‐adrenoceptor blocking agent shown in animals to have moderate beta 1‐adrenoceptor selectivity and partial agonist activity. In healthy normal volunteers, beta 1‐adrenoceptor blockade was measured as the reduction of exercise‐induced tachycardia, systolic blood pressure, and double product at 2, 8, and 24 h after a single oral dose of 10, 25, and 50 mg cetamolol. beta 1‐adrenoceptor blockade was significantly linearly related to log serum cetamolol level, was maximal at 2 h, and was still clinically significant at 24 h. A crossover study of single 0, 10, and 25 mg doses confirmed these findings.
The natriuresis following oral administration of the calcium antagonists‐nifedipine and nitrendipine.
Authors: Ene MD , Williamson PJ , Roberts CJ , Waddell G
Published: July 2012

Ten healthy individuals received in random order placebo, nifedipine 10 mg, nifedipine 20 mg, nitrendipine 10 mg and nitrendipine 20 mg as single oral administrations at weekly intervals. On the day before each treatment placebo was administered. Urine was collected for 6 h and then for 18 h after each administration. There was a significant increase in urine volume and sodium excretion after the drugs, but no change in potassium excretion. The effect was most evident in the 6 h after drug administration. The effect was no greater at the higher doses of either drug. A natriuretic‐diuretic action of nifedipine and nitrendipine has been confirmed in man. The mechanism of the effect remains unclear.
The effect of domperidone on oesophageal emptying in diabetic autonomic neuropathy.
Authors: Maddern GJ , Horowitz M , Jamieson GG
Published: July 2012

Oesophageal emptying of solids was studied with a scintigraphic technique in 12 patients with insulin dependent diabetes complicated by autonomic neuropathy and in 22 control subjects. In the diabetics the acute and chronic effects of oral domperidone on oesophageal emptying and symptoms of heartburn and dysphagia were assessed. The number of swallows required to clear the oesophagus in the diabetics (median 9.5, range 2‐30) was significantly greater (P less than 0.001) than in normal controls (median 2, range 1‐14). Domperidone did not increase solid oesophageal emptying in diabetic patients either after acute or after chronic administration.
Lung function and plasma levels of thromboxane B2, 6‐ketoprostaglandin F1 alpha and beta‐thromboglobulin in antigen‐induced asthma before and after indomethacin pretreatment.
Authors: Shephard EG , Malan L , Macfarlane CM , Mouton W , Joubert JR
Published: July 2012

The effect of specific antigen challenge on the lung function of eight allergic asthmatic patients after placebo and indomethacin pretreatment has been investigated. Plasma levels of thromboxane B2(TxB2), metabolite of thromboxane A2, 6‐keto‐PGF1 alpha, metabolite of epoprostenol, (prostacyclin, PGI2) and beta‐thromboglobulin (beta TBG) following antigen challenge in these eight patients have also been measured after placebo and indomethacin pretreatment. Each patient underwent two antigen inhalations 1 week apart. One challenge took place after 4 days pretreatment with indomethacin capsules 25 mg four times daily, and the other took place following 4 days placebo pretreatment, one matched capsule four times daily. The order of administration was random but balanced and blind with respect to the patient. Following placebo pretreatment two patients presented with an early antigen response only, four presented with a biphasic antigen response and two presented with a delayed antigen response only. The asthmatic response for each patient was consistent on re‐exposure. Indomethacin pretreatment suppressed the delayed antigen induced asthmatic response. This suppression was reproducible. There was a rise in plasma TxB2 levels on antigen challenge following placebo pretreatment but not following indomethacin pretreatment, whereas there was a rise in 6‐keto‐PGF1 alpha after antigen challenge following indomethacin but not placebo pretreatment. No significant change in plasma beta TBG or platelet counts from control values was observed following antigen challenge with either placebo or indomethacin pretreatment. It is suggested that the production of PGI2 and suppression of TxA2 by indomethacin pretreatment contribute to the suppression of the delayed antigen induced asthmatic response and that platelets play a minimal role in this process.
An investigation of the cause of accumulation of verapamil during regular dosing in patients.
Authors: Schwartz JB , Abernethy DR , Taylor AA , Mitchell JR
Published: July 2012

The accumulation of verapamil during regular dosing conditions was studied. Plasma concentrations of verapamil (V) and norverapamil (NV) were measured as were urinary concentrations of verapamil, norverapamil, and four other N‐ and O‐dealkylated metabolites in nine patients after an initial single dose and after chronic oral verapamil administration to steady‐state plasma concentrations. Indocyanine green (ICG) clearance was determined immediately prior to the initial verapamil dose and prior to the verapamil washout from regular dosing. An approximately two‐fold accumulation of V had occurred during regular dosing. The area under the plasma concentration‐time curve (AUC1) after the first dose was 417.4 +/‐ 276.7 ng ml‐1 h (mean +/‐ s.d.) and increased to 786.5 +/‐ 54 ng ml‐1 h (P less than 0.01) during one dosage interval at steady‐state (AUCss). NV also tended to accumulate from an AUC1 of 552.6 +/‐ 411 to an AUCss 668.7 +/‐ 332 ng ml‐1 h (P less than 0.09). The ratio of AUC‐V to AUC‐NV was unchanged. The verapamil elimination half‐life (t 1/2) increased from 8.4 +/‐ 4.2 to 12.0 +/‐ 3.6 h (P less than 0.01) whereas the norverapamil t 1/2 was unchanged. ICG clearance was unchanged. Urinary excretion of NV increased slightly but the ratio of urinary V/NV concentrations was not significantly altered nor was the ratio of four other metabolites to verapamil or the ratio of the combined o‐demethylated to the N‐ dealkylated metabolites.(ABSTRACT TRUNCATED AT 250 WORDS)
Comparison of the effects of chronic administration of ciclazindol and desipramine on pupillary responses to tyramine, methoxamine and pilocarpine in healthy volunteers.
Authors: Kerr FA , Szabadi E
Published: July 2012

Twenty‐nine healthy volunteers participated in an experiment lasting for 8 weeks: Phase I (2 weeks)‐pre‐treatment control period; Phase II (4 weeks)‐medication with either ciclazindol hydrochloride (50 mg twice daily), or desipramine hydrochloride (50 mg twice daily) or lactose placebo (twice daily) administered in a single‐blind fashion; Phase II (2 weeks)‐recovery. Experimental sessions took place twice weekly for the photographic assessment of resting pupil diameter, and for the assessment of one of the following pupillary responses: mydriatic response to methoxamine, mydriatic response to tyramine, miotic response to pilocarpine. Resting pupil diameter increased during medication with either ciclazindol or desipramine. Methoxamine‐evoked mydriasis and tyramine‐evoked mydriasis were antagonized by both ciclazindol and desipramine. Pilocarpine‐evoked miosis was potentiated by both ciclazindol and desipramine. The steady‐state plasma levels (mean +/‐ s.e. mean) of the antidepressants were: ciclazindol: 5.90 +/‐ 0.74 microM; desipramine: 0.60 +/‐ 0.17 microM. The antagonism of methoxamine‐evoked mydriasis is likely to reflect the blockade of postsynaptic alpha 1‐adrenoceptors in the iris by the antidepressants, whereas the antagonism of tyramine‐evoked mydriasis may reflect both the blockade of uptake of tyramine into presynaptic adrenergic terminals and the blockade of postsynaptic alpha‐adrenoceptors. There is no immediate explanation for the potentiation of pilocarpine‐evoked miosis by the two antidepressants.
Pharmacokinetics and pharmacodynamics following single and repeated nightly administrations of loprazolam, a new benzodiazepine hypnotic.
Authors: McInnes GT , Bunting EA , Ings RM , Robinson J , Ankier SI
Published: July 2012

The pharmacokinetics of oral loprazolam and pharmacodynamic responses on the morning following nightly drug administration were examined after single and after seven consecutive 1 mg doses in six non‐fasting healthy subjects. The serum concentration‐time profiles for unchanged loprazolam measured by a specific high pressure liquid chromatography/gas chromatography (h.p.l.c./g.c.) method and for benzodiazepine material measured by radioimmunoassay (RIA) were qualitatively similar although RIA levels were consistently higher. Approximate elimination half‐life of unchanged loprazolam after single doses was 8.0 h. For RIA measured material, approximate half‐life was 11.7 h following acute administration and 12.8 h after seven consecutive doses. Compared to results after single doses, maximum serum concentration and AUC were greater following 1 week's treatment. Using RIA results, the increases were 27.2% (95% CL 6.9 to 47.4%) and 35.1% (95% CL 15.8 to 54.3%) respectively and using h.p.l.c./g.c. data, 11% (95% CL − 22.6% to 44.5%) and 41% (95% CL − 50.9 to 133.0%). After repeated doses of loprazolam, there were no significant changes with respect to results after single doses in psychomotor function assessed objectively by critical flicker fusion threshold or choice reaction time, or in sleep quality or behaviour on awakening assessed subjectively by 10 cm analogue scales. Mean time to maximum serum concentration was 4.95 h with considerable inter‐individual variability (range 1‐12 h) and there was a lag time of 1–1.5 h before drug was detectable in blood.(ABSTRACT TRUNCATED AT 250 WORDS)
Attempts to phenotype human liver samples in vitro for debrisoquine 4‐ hydroxylase activity.
Authors: Boobis AR , Hampden CE , Murray S , Beaune P , Davies DS
Published: July 2012

Twenty‐eight samples of human liver have been characterised for cytochrome P‐450 content, aldrin epoxidase, debrisoquine 4‐hydroxylase and bufuralol 1'‐hydroxylase activities. Evidence is presented here and elsewhere that bufuralol 1'‐hydroxylase and debrisoquine 4‐hydroxylase are activities catalysed by the same form of cytochrome P‐450 in man, and that this form is different from that catalysing the epoxidation of aldrin. Attempts to phenotype liver samples in vitro, in the absence of any metabolic data in vivo for debrisoquine 4‐hydroxylation status, met with limited success. A combination of enzyme assays will most probably be required in any such phenotyping of human liver samples.
Plasma concentrations of nortriptyline and its 10‐hydroxy metabolite in depressed patients‐relationship to the debrisoquine hydroxylation metabolic ratio.
Authors: Nordin C , Siwers B , Benitez J , Bertilsson L
Published: July 2012

In 20 depressed patients treated with nortriptyline (NT) there was a significant relationship between the plasma concentration of NT and the debrisoquine metabolic ratio (rs = 0.77; P less than 0.01). (The debrisoquine test was performed after stopping NT treatment). This is in agreement with the hypothesis that the hydroxylations of NT and debrisoquine are mediated by similar enzymatic mechanisms. In contrast there was no significant relationship between the debrisoquine metabolic ratio and the plasma concentrations of the active metabolite 10‐hydroxy‐nortriptyline. In 11 of the patients the debrisoquine metabolic ratio was significantly higher during than after NT treatment. This may be due to an inhibition of the debrisoquine hydroxylation by NT.
The cardiovascular effects of regular and decaffeinated coffee.
Authors: Smits P , Thien T , Van't Laar A
Published: July 2012

In a single‐blind study the effects of drinking two cups of regular or decaffeinated coffee on blood pressure, heart rate, forearm blood flow and plasma concentrations of caffeine, renin and catecholamines were studied in 12 normotensive subjects. Drinking regular coffee led to a rise of blood pressure, a fall of heart rate and an increase of plasma catecholamines. Decaffeinated coffee induced a smaller increase of diastolic blood pressure without changing other parameters. This study shows that the cardiovascular effects of drinking coffee are mainly the result of its caffeine content.
Rating scales for depression and anxiety: a current perspective.
Authors: Snaith RP , Taylor CM
Published: July 2012

Research now requires instruments capable of a better distinction between depressive and anxiety disorders. The study is concerned with two relatively recent clinician‐rated scales, the Montgomery‐Asberg Depression Rating Scale and the Clinical Anxiety Scale together with two recent self‐assessment scales, the Irritability‐Depression‐Anxiety Scale and the Hospital Anxiety and Depression Scale. The concurrent validity of these scales as measures of the separate concepts of anxiety and depression is examined.
Treatment of affective disorders.
Authors: Lader MH
Published: July 2012

The diagnosis of affective disorders is difficult, especially at mild to moderate levels of severity. Often symptomatic treatment is given in the absence of a clear diagnosis. Antidepressants are often efficacious in helping anxiety symptoms but antianxiety compounds are generally inefficacious in treating depression. Alprazolam is a possible exception and may have both antianxiety and antidepressant properties.
A double‐blind comparison of alprazolam, diazepam and placebo in the treatment of anxious out‐patients.
Authors: Davison K , Farquharson RG , Khan MC , Majid A
Published: July 2012

In a double‐blind 28‐day comparison of alprazolam, diazepam and placebo, alprazolam 1.5‐3 mg/day was of equivalent anxiolytic effect to 15‐30 mg diazepam/day and there was some evidence of antidepressant activity by alprazolam, but not diazepam, in neurotic depression. No serious side‐effects or laboratory abnormalities were encountered.
Investigation of drug absorption from the gastrointestinal tract of man. II. Metoprolol in the jejunum and ileum.
Authors: Vidon N , Evard D , Godbillon J , Rongier M , Duval M , Schoeller JP , Bernier JJ , Hirtz J
Published: July 2012

Absorption of metoprolol in jejunum and ileum was investigated in eight healthy subjects using an intestinal perfusion technique below an occlusive balloon. An isotonic saline solution, with or without metoprolol, was perfused at a flow rate of 10 ml/min, either at the angle of Treitz or in the middle part of the ileum. The absorption in a 30 cm intestinal segment was evaluated at metoprolol concentrations of 20, 40 and 60 mg/l. Metoprolol did not affect gut motility. Metoprolol was similarly absorbed in the jejunum and ileum. The absorption rates appeared to be linearly related to the perfusion rates and to the mean concentration in the segment, indicating a first‐order kinetic process. The absorption rate of metoprolol perfused in the jejunum in a saline solution appeared to be lower than that observed after gastric administration of the drug incorporated in a meal. The findings in this and other studies in this series indicate that metoprolol is similarly absorbed throughout the small intestine.
Investigation of drug absorption from the gastrointestinal tract of man. IV. Influence of food and digestive secretions on metoprolol jejunal absorption.
Authors: Evard D , Vidon N , Godbillon J , Bovet M , Duval M , Schoeller JP , Bernier JJ , Hirtz J
Published: July 2012

The influence of nutrients and digestive secretions on the intestinal absorption and bioavailability of the beta‐adrenoceptor antagonist, metoprolol, was investigated in an isolated segment of jejunum using an intestinal perfusion technique. Two solutions containing metoprolol, one with, and one without nutrients, were perfused into the jejunum with an occluding balloon inflated or deflated. Jejunal fluid, blood and urine samples were then collected for drug or metabolite estimation. In the segment studied, metoprolol absorption from the nutrient solution was four times that observed during perfusion of the saline solution. Bile salts did not enhance drug absorption. Both in the presence and absence of nutrients, a linear relationship was observed between the computed cumulative amount of drug absorbed from the gastrointestinal tract and the resulting plasma concentration at each sampling time, indicating that first‐pass loss was not saturated. This result was also reflected in the similarity of the AUC:dose ratios, and in the lack of effect of nutrients on the metabolism of the drug.
Investigation of drug absorption from the gastrointestinal tract of man. V. Effect of the beta‐adrenoceptor antagonist, metoprolol, on postprandial gastric function.
Authors: Jobin G , Cortot A , Danquechin‐Dorval E , Godbillon J , Schoeller JP , Bernier JJ , Hirtz J
Published: July 2012

The role of the adrenergic system in normal gastric function was assessed in five healthy volunteers by measuring gastric secretion and emptying after a mixed meal containing a non‐absorbable marker, [14C]‐ PEG 4000, with and without 100 mg of metoprolol, a beta 1‐adrenoceptor antagonist. Intraduodenal perfusion of PEG 4000, and gastric and jejunal sampling was achieved by means of a gastrointestinal intubation technique. Gastric function was assessed from the degree of dilution of the duodenal marker. Analysis of acid content by titration allowed the gastric acid secretory rate to be determined. Gastric emptying of a meal over 4 h was similar with and without metoprolol, the time to 50% emptying being 100 min. In the presence of metoprolol, gastric acid content was significantly increased during the late postprandial period producing a corresponding increase in acid load delivered to the duodenum. beta 1‐adrenoceptor blockade appears to prolong the gastric secretory response to food without altering gastric emptying.
A multiple dose comparative study of the pharmacodynamic and pharmacokinetic behaviour of polymer‐matrix and Oros dosage forms of oxprenolol in healthy volunteers.
Authors: Woods KL , Jack DB , Kendall MJ , Halsey A , O'Donnell ML , Warrington SJ , John VA
Published: July 2012

A new osmotic drug delivery system (Oros) has been evaluated in multiple‐dose studies in young healthy volunteers as a sustained‐ release vehicle for once‐daily administration of oxprenolol. Two Oros systems were examined in two separate studies, one containing 170 mg oxprenolol succinate with an initial zero‐order release rate of 10 mg/h, and the other containing 260 mg oxprenolol succinate with an initial release rate of 16 mg/h. These were compared respectively with conventional oxprenolol hydrochloride (Trasicor) 80 mg twice daily and polymer‐matrix oxprenolol hydrochloride (Slow Trasicor) 160 mg once daily. Variations in mean plasma levels and beta‐adrenoceptor blockade (measured by inhibition of exercise tachycardia) were considerably reduced on the 10/170 Oros once‐daily compared with the Trasicor 80 mg twice‐daily regimen. With both formulations there was no significant change in mean plasma concentrations or areas under the curve after 8 days' treatment, and similar pre‐dose plasma concentrations were obtained. There was significant inhibition of exercise tachycardia throughout 24 h after the 10/170 Oros on the eighth day. The 16/260 Oros system gave smoother pharmacokinetic and pharmacodynamic profiles, and on repeated dosing a higher mean pre‐dose plasma oxprenolol concentration than Slow Trasicor. Drug availability was similar for the two dose forms, suggesting an acceptable level of absorption of oxprenolol from most of the gastrointestinal tract. On the eighth day exercise heart rate was significantly reduced throughout 24 h with 16/260 oxprenolol Oros, but only between 1 and 15 h with Slow Trasicor.
Pre‐dosing plasma concentrations and beta‐adrenoceptor blocking effects during repeated once daily dosing with 160 mg sustained‐release propranolol (Inderal LA) and 16/260 oxprenolol Oros to healthy volunteers.
Authors: Moppert J , Degen PH , Racine‐Poon A
Published: July 2012

Plasma drug concentrations and attenuations in sub‐maximal exercise tachycardia were measured in six healthy subjects 24 h after the third and fourth doses of Inderal LA and 16/260 oxprenolol Oros administered once daily. Both drugs significantly reduced exercise heart rates relative to the placebo response, at both observation times. The mean percentage reductions on the third and fourth days were, respectively, 15.7 and 11.6% for Inderal LA compared with 18.1 and 12.2% for 16/260 oxprenolol Oros. The differences between formulations were not statistically significant. The mean plasma concentrations at 24 h on the third and fourth day were 119 and 101 ng/g for oxprenolol and 16.2 and 15.8 ng/g for propranolol.
Exercise and resting blood pressure and heart rate changes 24 h after dosing in patients with essential hypertension receiving 16/260 oxprenolol Oros once daily.
Authors: Muller FB , Allsopp LF , Cooper GL , Bolli P , Frei P , Glaus L , Ritz R , Buhler FR
Published: July 2012

Nineteen patients receiving oxprenolol slow‐release (SR) 160 mg (three patients) or 320 mg (16 patients) once daily for mild to moderate hypertension were treated with oxprenolol Oros 16/260 once daily for 3 weeks following a 2 week placebo wash‐out period. Repeated dosing with both Oros and SR oxprenolol preparations, in comparison with placebo, significantly reduced supine systolic and diastolic blood pressures, and pulse rate at 24 h after dosing. Single Oros doses also significantly reduced pulse rate and diastolic, but not systolic, blood pressure at 24 h. The reduction in supine systolic blood pressure was greater during repeated dosing with oxprenolol SR than after a single dose of the Oros preparation. Control of supine diastolic blood pressure (less than or equal to 90 mm Hg) at 24 h after dosing was achieved in 13 out of 18 patients with oxprenolol SR (two out of three patients given 160 mg, and 11 out of 15 given 320 mg). Similar control was achieved in 11 out of 18 patients after a single dose of oxprenolol Oros, and in 13 out of 17 patients treated for 3 weeks. The mean percentage reduction in exercise heart rate (EHR) compared to placebo, at 24 h after dosing, was 16% following Oros treatment for 3 weeks, and 12% following SR administration. After a single dose of oxprenolol Oros EHR, was reduced by 9% at 24 h compared to placebo. At 3 weeks the Oros formulation was significantly better than the SR tablet at reducing EHR. Oxprenolol Oros 16/260 was effective over 24 h and well tolerated.(ABSTRACT TRUNCATED AT 250 WORDS)
Comparison of single‐dose pharmacokinetic and pharmacodynamic properties of two metoprolol Oros systems with different initial zero‐ order release rates.
Authors: Warrington SJ , Barclay SP , John VA , Shotton PA , Good W
Published: July 2012

Plasma concentrations and haemodynamic effects at rest and during exercise have been measured in six healthy volunteers after single oral dosing with two Oros drug delivery systems containing 190 mg metoprolol fumarate but with initial release rates of 14 and 19 mg/h, respectively. Sub‐maximal exercise heart rates were attenuated by both Oros systems throughout most of the 30 h study period but no significant differences were detected between the 14/190 and 19/190 forms. Resting pulse rates and blood pressure were similarly affected by the Oros preparations. Approximately the same amount of drug reached the circulation from the Oros systems, but the 19/190 form produced higher peak concentrations at earlier times after dosing. At 24 h higher plasma concentrations were observed for the 14/190 preparation, reflecting its longer duration of drug release. There was no apparent advantage of one form over the other as regards haemodynamic response. The reduced peak plasma concentration with 14/190 Oros may, however, be an advantage in terms of tolerability.
Controlled trial of ketanserin in hypertension.
Authors: McGourty JC , Silas JH , Cowen KJ
Published: July 2012

We have completed a double‐blind parallel group comparison of the 5‐HT2 receptor antagonist ketanserin with placebo in 22 hypertensive patients. Ketanserin (20‐40 mg twice daily) lowered sitting blood pressure more than placebo by 6.9 mm Hg systolic (NS), 13.1 mm Hg diastolic (P less than 0.05) and by 11.4 mm Hg mean arterial pressure (P less than 0.02). The fall in standing blood pressure was similar and we observed no first dose hypotensive effect. Ketanserin lowered the sitting heart rate by 11.1 beats/min (P less than 0.01). The drug was well tolerated.
Inhibition of methoxamine‐induced bronchoconstriction by ipratropium bromide and disodium cromoglycate in asthmatic subjects.
Authors: Black J , Vincenc K , Salome C
Published: July 2012

We compared the effects of pretreatment with saline, ipratropium bromide, and disodium cromoglycate (DSCG) on bronchoconstriction induced by methoxamine‐an alpha‐adrenoceptor agonist, in asthmatic subjects. All 12 patients bronchoconstricted in response to methoxamine after saline. The PD20 (the dose of methoxamine causing a 20% fall in forced expiratory volume in 1 s [FEV1]) ranged from 0.3‐18 mumol. Ipratropium bromide (200 micrograms administered by aerosol) significantly inhibited (P less than 0.05) the response to methoxamine in all patients without producing significant changes in the mean baseline lung function. The mean PD20 for methoxamine after saline was 6.8 mumol and 95% confidence limits (CL) were 3.6, 12.7 mumol. The mean PD20 for methoxamine after ipratropium bromide was 35.4 (95% CL 28.8, 43.6) mumol. DSCG also produced significant (P less than 0.05) shifts to the right in the methoxamine dose response curves, but did not affect resting airway calibre as measured by the FEV1. The mean PD20 for methoxamine increased from 3.3 mumol (95% CL 1.1, 10.0 mumol) after saline to 25.1 mumol (95% CL 14.1, 44.6) after DSCG pretreatment. These findings suggest that alpha‐adrenoceptors in the airways of asthmatic subjects may be located at sites other than smooth muscle‐possibly on mast cells but more likely on nerve endings and/or parasympathetic ganglia.
The metabolism of 7‐ethoxycoumarin in human liver microsomes and the effect of primary biliary cirrhosis: implications for studies of drug metabolism in liver disease.
Authors: Woodhouse KW , Mitchison HC , Mutch E , Wright PD , Rawlins MD , James OF
Published: July 2012

Using 7‐ethoxycoumarin as a probe substrate, microsomal monoxygenase activity has been measured in liver tissue from patients with primary biliary cirrhosis (PBC) of varying histological severity, and in histologically normal control tissue. Interindividual variation in enzyme activity was considerable, and in no histological category was the activity significantly different to control. We conclude that: (a) in PBC, hepatic microsomal monoxygenase activity is determined primarily by factors other than the histological severity of the liver disease, and (b) studies of xenobiotic metabolism in patients with liver disease should specify the nature of the underlying disease process.
Nadolol in essential hypertension: effect on ambulatory blood pressure, renal haemodynamics and cardiac function.
Authors: Dupont AG , Vanderniepen P. , Bossuyt AM , Jonckheer MH , Six RO
Published: July 2012

Chronic administration of nadolol has been reported to reduce blood pressure either without or with a concomitant fall of renal blood flow. We therefore studied the effects of nadolol 80 mg once daily on ambulatory blood pressure, renal and systemic haemodynamics in patients with mild to moderate essential hypertension. Ten patients took part in this randomized, double‐blind, placebo‐controlled, crossover study, each phase of which lasted 4 weeks. Nadolol significantly reduced ambulatory blood pressure and heart rate, but had no effect on blood pressure variability. Cardiac output was significantly reduced by nadolol and total peripheral resistance increased but without reaching statistical significance. Despite the fall in blood pressure and cardiac output, renal blood flow and glomerular filtration rate remained unchanged. The fraction of cardiac output reaching the kidneys rose significantly and renal vascular resistance was significantly reduced. Body weight, urinary sodium excretion and urine flow rate remained unchanged. We conclude that nadolol 80 mg once daily lowers ambulatory blood pressure in patients with mild to moderate hypertension without impairment of renal blood flow, indicating a redistribution of cardiac output to the kidneys. The mechanism of the renal vasodilator effect of nadolol remains to be determined.
Responsiveness to oral diazepam in the elderly: relationship to total and free plasma concentrations.
Authors: Swift CG , Ewen JM , Clarke P. , Stevenson IH
Published: July 2012

The immediate and residual response to single doses of oral diazepam 10 mg was measured in 11 young and 12 elderly healthy volunteers using postural sway, digit symbol substitution scores and subjective ratings. The effect on postural sway was markedly accentuated in the older volunteers, but the difference between groups in the effect on the other measures used did not achieve significance. The corresponding plasma total diazepam concentrations were lower in the older subjects beyond 0.5 h post dose and the concentrations of plasma desmethyldiazepam did not differ between the groups. Diazepam plasma protein binding was significantly reduced in the elderly subjects, but the plasma free (unbound) diazepam concentrations did not exceed those in the young group. There was poor correlation between the responses measured and the concentrations of either total diazepam, desmethyldiazepam or free diazepam. The results suggest the occurrence of a non‐uniform effect of age on different aspects of benzodiazepine response, and that where an accentuated effect occurs the mechanisms are substantially pharmacodynamic.
Haemodialysis does not affect the pharmacokinetics of nifedipine.
Authors: Martre H. , Sari R. , Taburet AM , Jacobs C. , Singlas E.
Published: July 2012

To establish dosage recommendations in patients with end‐stage renal disease undergoing chronic haemodialysis, nifedipine kinetics were studied between and during haemodialysis sessions. In eight patients, during the interdialytic period, peak plasma concentrations of nifedipine (29‐332 ng/ml) were reached 0.5‐1.0 h after administration of a single 10 mg oral dose. Elimination half‐life and oral plasma clearance were respectively 2.6 +/‐ 0.5 h and 1 176 +/‐ 412 ml/min. Nifedipine plasma protein binding was decreased in uraemic patients (88.8 +/‐ 0.3% vs 94.4 +/‐ 0.1%) but not affected by haemodialysis. Removal by haemodialysis was low: the dialyser extraction ratio and the dialysis clearance were respectively 2.3 +/‐ 0.8% and 2.8 +/‐ 0.9 ml/min.
Lipoxygenase products of arachidonic acid in human inflamed skin.
Authors: Black AK , Barr RM , Wong E. , Brain S. , Greaves MW , Dickinson R. , Shroot B. , Hensby CN
Published: July 2012

Monohydroxy acids (HETEs) and leukotriene B4 (LTB4) metabolites of arachidonic acid were measured in skin of healthy volunteers after ultraviolet B irradiation, and in the uninvolved skin of psoriatics after topical dithranol application. Exudate was collected from suction bullae on control and inflamed abdominal skin, and analysed for 12‐HETE and PGE2 by GC‐MS and LTB4 by bioassay. 12‐HETE and PGE2 were raised at 24 h but not at 72 h after u.v.B irradiation: control and 24 h values were 13.7 and 41.5 ng ml‐1 (P less than 0.05, n = 6) for 12‐HETE respectively, and 4.5 and 30.2 ng ml‐1 (P less than 0.01, n = 6) for PGE2. Dithranol application raised PGE2 levels from 23.1 ng ml‐1 in control exudate to 62 ng ml‐1 (P less than 0.01, n = 6) at 24 h before declining to base levels at 72 h. However, 12‐HETE was raised at 72 h (200 ng ml‐1, P less than 0.01, n = 5) but not at 24 h (104 ng ml‐1) compared to control levels (50 ng ml‐1, n = 5). The levels of the LTB4 were low (less than 100 pg ml‐1), and no significant increases were observed. Arachidonic acid in inflamed skin can be metabolised by the cyclo‐oxygenase and lipoxygenase pathway. It is probable that the lipoxygenase product 12‐HETE is involved in these inflammatory reactions.
The effect of enalapril on baroreceptor mediated reflex function in normotensive subjects.
Authors: Giudicelli JF , Berdeaux A. , Edouard A. , Richer C. , Jacolot D.
Published: July 2012

The effects of enalapril, 20 mg orally, on the responses to baroreflex activation and deactivation by respectively phenylephrine and nitroglycerin were investigated in normotensive subjects on a normal sodium diet, with simultaneous measurement of plasma renin activity (PRA), converting enzyme activity (PCEA), aldosterone and catecholamines. Enalapril, 4 h after administration, lowered artificial blood pressure without modifying heart rate and plasma catecholamines. PCEA was abolished, PRA increased and plasma aldosterone decreased. Enalapril (a) displaced to the left the baroreflex set‐point, (b) did not affect baroreflex sensitivity since the slopes of the RR‐ interval/systolic blood pressure regression lines remained unchanged during both activation and deactivation and (c) did not modify baroreflex efficacy since the maximal RR‐interval responses as well as the overall RR‐interval‐time products to identical blood pressure variations were not modified. Thus, enalapril induced a resetting of the baroreflex, which probably accounts for the lack of reflex tachycardia observed during the drug‐induced fall in blood pressure.
The effect of nisoldipine on apparent liver blood flow and effective renal plasma flow.
Authors: Meredith PA , Pasanisi F. , Elliott HL , Reid JL
Published: July 2012

The effects of the acute and continued administration of the calcium antagonist nisoldipine on hepatic and renal blood flow and on renal function were studied in nine normotensive volunteers. There were no significant changes in supine blood pressure or heart rate but acute administration significantly increased both apparent liver blood flow and effective renal plasma flow. With continued administration these increases were attenuated and were not significantly different from placebo after 4 days treatment. Acute nisoldipine administration was also associated with significant increases in glomerular filtration rate and urinary sodium excretion.
Failure to detect amodiaquine in the blood after oral administration.
Authors: Salako LA , Idowu OR
Published: July 2012

Plasma and red blood cell concentrations of amodiaquine (AM) and its metabolite, desethylamodiaquine (DAM), were monitored at intervals up to 21 days after a single oral dose of 600 mg amodiaquine in five normal African subjects. Concentrations of AM and DAM were determined using a high performance liquid chromatography technique with a lower limit of sensitivity of 10 ng ml‐1 for both compounds. AM was not detectable in plasma and red blood cell samples withdrawn from any of the subjects. DAM was detectable in both media. It appeared in the blood 0.5‐1 h after administering AM, reached a peak in 1.5‐2 h and subsequently declined slowly. We conclude that AM is rapidly converted to DAM and its blood concentration, compared with that of DAM, is very low if not negligible.
The pharmacokinetics of antipyrine in patients with graded severity of schistosomiasis.
Authors: el‐Raghy I. , Back DJ , Osman F. , Nafeh MA , Orme ML
Published: July 2012

The pharmacokinetics of antipyrine have been studied in patients with schistosomiasis. In comparison to a control group of subjects (n = 6), patients with early (active) schistosomiasis (passing live ova in urine or stools without clinical and laboratory evidence of liver involvement; n = 6) exhibited similar pharmacokinetic parameters. Of seven patients with hepatosplenic schistosomiasis (exhibiting hepatic fibrosis, splenomegaly, at least one episode of haematemesis, ascites), five showed markedly enhanced antipyrine half‐life and reduced clearance. Compared to controls, the mean half‐life of this group was increased from 10.9 +/‐ 2.4 to 19.9 +/‐ 9.5 h (mean +/‐ s.d.; P less than or equal to 0.05) and clearance reduced from 3.81 +/‐ 0.74 to 2.18 +/‐ 0.80 l h‐1 (P less than or equal to 0.01). There was no change in the apparent volume of distribution. Liver biopsy was performed on all patients diagnosed as having hepatosplenic schistosomiasis in the 2 weeks prior to the antipyrine study. The results of this study indicate that hepatic microsomal metabolism is impaired in patients with advanced hepatosplenic schistosomiasis.
The pharmacokinetics of L‐tryptophan following its intravenous and oral administration.
Authors: Green AR , Aronson JK , Cowen PJ
Published: July 2012

The pharmacokinetics of L‐tryptophan (5 g and 7.5 g) have been studied after its intravenous administration to healthy subjects and the results compared with those obtained after oral administration (0.7 g‐ 3.5 g). In order to do this, we have re‐analysed previously published data relating to oral administration. The data obtained following the oral administration of L‐tryptophan suggest that the total body clearance and apparent volume of distribution are saturable. The pharmacokinetics of tryptophan after intravenous administration of 5 g and 7.5 g were similar to those after the oral administration of 25 and 50 mg kg‐1 (i.e. 1.75 g and 3.5 g). Similar pharmacokinetic values were obtained following intravenous tryptophan when the same subjects were retested after a period of 2‐4 weeks.
The influence of ranitidine, alone and in combination with clemastine, on histamine‐mediated cutaneous weal and flare reactions in human skin.
Authors: Thomas RH , Browne PD , Kirby JD
Published: July 2012

Significant, (P less than 0.05) inhibition of histamine induced cutaneous weal and flare reactions by ranitidine at 10(‐5) M concentration has been demonstrated in a double blind, in vivo study; the results support the evidence for cutaneous H2‐histamine receptors provided by previous studies using cimetidine and metiamide. The degree of inhibition of histamine mediated cutaneous reactions achieved by clemastine was increased by the administration of clemastine and ranitidine together, for ranitidine concentrations 10(‐5) M (P less than 0.001) and 10(‐6) M (P less than 0.05). The magnitude of the inhibitory effect of ranitidine, both administered alone and in combination with clemastine, suggests that in the production of histamine induced cutaneous weal and flare reactions, the contribution afforded by stimulation of cutaneous H2‐histamine receptors is only small.
Comparison of oxyfedrine and atenolol in angina pectoris‐a double‐ blind study.
Authors: Fananapazir L. , Bray C.
Published: July 2012

We have compared oxyfedrine 24 mg four times daily with atenolol 100 mg once daily in the relief of angina pectoris in a double‐blind cross‐ over study; assessments were by diary cards and treadmill testing. Both oxyfedrine and atenolol reduced the frequency of angina by similar amounts and both produced similar improvements in treadmill performance. Side effects were infrequent and minor with both drugs. The model of action of oxyfedrine appears to be different from atenolol. Oxyfedrine allows the double product of systolic blood pressure X heart rate at peak exercise to be maintained at levels similar to those with placebo; the double product at peak exercise is significantly less with atenolol.
Contrasts between pindolol and propranolol concentration‐response relationships.
Authors: Carruthers SG , Pacha WL , Aellig WH
Published: July 2012

The plasma concentration‐response relationships of oral and intravenous pindolol and propranolol have been studied in a group of eight healthy male subjects who received each dosage form in a randomized single‐ blind cross‐over manner. Despite similar elimination half‐lives, the duration of action of pindolol was longer than that of propranolol. This longer duration of action was associated with a flatter concentration‐response curve for pindolol and may be related to the partial agonist activity of pindolol. Propranolol concentration‐ response curves were dependent on the route of drug administration whereas pindolol curves were similar following oral and intravenous routes of administration.
The effect of ultrasound on the percutaneous absorption of lignocaine.
Authors: McElnay JC , Matthews MP , Harland R. , McCafferty DF
Published: July 2012

The influence of ultrasound on the percutaneous absorption of lignocaine from a cream base was investigated in a double‐blind cross‐ over trial in healthy volunteers. Mean data indicated that there was a slightly faster onset time for local anaesthesia when ultrasound was administered when compared with control values (no ultrasound). However, the differences were not statistically significant. Further controlled clinical studies are required into the effect of ultrasound on percutaneous absorption since the technique (phonophoresis) has been alleged to enhance percutaneous penetration of a number of drugs.