bluuebunny/crossref_metadata_2025 huggingface dataset:
Bronchodilator activity of a new inhaled beta 2‐adrenoceptor agonist, tulobuterol and its protective effect in exercise‐induced asthma.
Authors: Patel KR
Published: July 2012

In fifteen patients with asthma tulobuterol, a new beta 2‐adrenoceptor agonist, given by inhalation in 100 micrograms increments up to a cumulative dose of 600 micrograms produced dose related increases in both the FEV1 and FVC. The bronchodilation was observed within 5 min of the first dose. In a further nine patients tulobuterol 200 micrograms and 400 micrograms aerosol inhibited exercise‐induced asthma following 6‐8 min treadmill exercise and the effect was comparable to 200 micrograms salbutamol aerosol. Minor muscle tremors were observed in two patients with 400 micrograms of tulobuterol but no significant changes in pulse rate or blood pressure were noted.
Does 2‐mercaptoethane sulphonate (mesna) prevent cyclophosphamide and azathioprine induced immunosuppression? In vitro studies.
Authors: Al‐Safi SA , Maddocks JL
Published: July 2012

The effect of 2‐mercaptoethane sulphonate (mesna) on the inhibition of the human MLR by 4‐hydroxycyclophosphamide or azathioprine was studied. 4‐Hydroxycyclophosphamide (34 microM) completely inhibited the MLR and this inhibition was unaffected by 122 microM of 2‐mercaptoethane sulphonate or its disulphide. At high concentrations (mM) 2‐ mercaptoethane sulphonate inhibited the MLR reaching 85% at 24 mM. 2‐ Mercaptoethane sulphonate (15‐122 microM) had no effect on azathioprine (36 microM) inhibition. The results of these in vitro studies suggest that 2‐mercaptoethane sulphonate does not interfere with cyclophosphamide or azathioprine induced suppression of cellular immunity.
The bioavailability and pharmacokinetics of slow release nifedipine during chronic dosing in volunteers.
Authors: Debbas NM , Jackson SH , Shah K. , Abrams SM , Johnston A. , Turner P.
Published: July 2012

Eight healthy volunteers received slow release nifedipine 20 mg 12 hourly, for six doses. A nifedipine pharmacokinetic profile was performed after the fifth dosing interval using 12 sampling times over 12 h. A specific high pressure liquid chromatography (h.p.l.c.) nifedipine assay was used. Six of the volunteers subsequently received an i.v. infusion of 3.5 mg of nifedipine after an identical period (five dosing intervals) of chronic oral dosing with slow release nifedipine 20 mg 12 hourly. An identical pharmacokinetic profile was performed after the infusion. Bioavailability, clearance (CL), apparent volume of distribution (V), apparent half life (t1/2) and area under the curve (AUC) were calculated. The geometric mean apparent t1/2 for the slow release preparation was 6.3 +/‐ 2.0 h. In the six volunteers, the mean bioavailability was 46% (range 29‐86%), the mean CL was 588.0 +/‐ 67.1 ml min‐1, the mean apparent V was 160.1 +/‐ 61.7 l. The pharmacokinetics of slow release nifedipine during chronic dosing appear similar to those derived from single dose studies.
The effects of sulindac and indomethacin on the anti‐hypertensive and diuretic action of hydrochlorothiazide in patients with mild to moderate essential hypertension.
Authors: Koopmans PP , Thien T. , Thomas CM , Van den Berg RJ , Gribnau FW
Published: July 2012

In this double‐blind two period crossover study, we investigated the effect of indomethacin and sulindac on blood pressure in 25 hypertensive patients being treated with hydrochlorothiazide. The study consisted of seven 4 week periods. In the first and the last period the patients took placebos, in period two, four and six they were treated with hydrochlorothiazide 50 mg once daily alone, and in the third and fifth period hydrochlorothiazide 50 mg once daily was given in combination with either indomethacin 50 mg twice daily or sulindac 200 mg twice daily in double‐blind random order. Blood pressure, measured by sphygmomanometer and arteriosonde, and body weight were determined every 2 weeks. Compared with placebo hydrochlorothiazide decreased the mean arterial pressure by 8%. Addition of both indomethacin and sulindac resulted in only slight and generally similar changes of this blood pressure lowering effect. This was found both for the whole group and when both treatment sequence groups were analysed separately. In contrast to sulindac, indomethacin attenuated the hydrochlorothiazide‐ induced decreases of body weight, plasma potassium and the increase of plasma renin activity. Both non‐steroidal anti‐inflammatory drugs (NSAID) reduced the 24 h urinary excretion of prostaglandins (PGs), i.e. PGF2 alpha, 6 ketoPGF1 alpha and thromboxane B2 except PGE2. From this study it can be concluded that, in contrast to sulindac, indomethacin attenuated the diuretic action of hydrochlorothiazide, however apparently without consequences for its long‐term blood pressure lowering effect. This study does not support the hypothesis that the difference between the two NSAIDs can be explained by different effects on renal PG synthesis.
Trends in the development of new medicines by UK‐owned pharmaceutical companies (1964‐1980).
Authors: Prentis RA , Walker SR
Published: July 2012

One hundred and ninety‐seven new chemical entities (NCEs) were investigated in man for the first time between 1964 and 1980 by the seven UK‐owned pharmaceutical companies. Thirty‐five of these NCEs have been marketed and 137 withdrawn from further research and development. There was an increase in the number of NCEs investigated each year, but this was counter‐balanced by an increase in the number rejected. Development times increased from about 4.5 years in the 1960s to 9 years in the 1970s with an accompanying reduction in the effective patent life.
Plasma catecholamines following exercise in hypertensives treated with pindolol: comparison with placebo and metoprolol.
Authors: Vandongen R. , Margetts B. , Deklerk N. , Beilin LJ , Rogers P.
Published: July 2012

This study re‐examines the proposal that beta‐adrenoceptor blockers with intrinsic sympathomimetic activity decrease plasma noradrenaline levels. Thirteen patients (aged 29‐65 years) with uncomplicated essential hypertension were randomly allocated to a three period, double‐blind cross‐over trial. The treatment periods, each of 3 weeks duration, were composed of placebo, pindolol (5 mg twice daily) and metoprolol (100 mg twice daily), dispensed in identical capsules. At the end of each treatment period, patients were exercised on a bicycle ergometer to a predetermined workload. Blood pressure and heart rate were measured before, immediately on completion of exercise and after 10 min post‐exercise rest. Blood samples for plasma noradrenaline and adrenaline determination were also collected at these times. Blood pressures were similar during treatment with pindolol and metoprolol. As expected, heart rate was consistently lower during metoprolol treatment. Basal, pre‐exercise plasma noradrenaline and adrenaline were similar at the end of each treatment period. However, the increase following exercise was significantly greater during metoprolol treatment. The post‐exercise increase during pindolol treatment was indistinguishable from that in the placebo period. These findings, in a randomised placebo‐controlled study, therefore demonstrate that pindolol does not influence basal or exercise‐stimulated plasma noradrenaline and adrenaline concentrations. This is best explained by a lack of effect of pindolol on the plasma clearance of catecholamines, which is impaired by beta‐adrenoceptor blockers devoid of intrinsic sympathomimetic activity.
The effect of 8 weeks treatment with the calcium antagonist felodipine on blood pressure, heart rate, working capacity, plasma renin activity, plasma angiotensin II, urinary catecholamines and aldosterone in patients with essential hypertension.
Authors: Katzman PL , Hulthen UL , Hokfelt B.
Published: July 2012

The effect of 8 weeks treatment with the calcium antagonist felodipine‐ a new long‐acting dihydropyridine derivative‐in a dose of 10 mg twice daily was studied in 10 male patients with essential hypertension, WHO grade I‐II, aged 25‐62 years. Diastolic blood pressure was reduced in supine and upright position. Systolic blood pressure was reduced only in the upright position. Heart rate was unchanged in the supine and decreased in the upright position. During dynamic exercise blood pressure was reduced. The maximal working capacity decreased, whereas the maximal heart rate attained was unchanged. Twenty‐four hour urinary noradrenaline excretion, plasma renin activity and 24 h urinary aldosterone excretion were increased. Plasma angiotensin II and 24 h urinary adrenaline excretion were unchanged. In conclusion, felodipine is an effective long‐acting blood pressure lowering drug with minor side effects. After 8 weeks on felodipine treatment heart rate was not increased, although the activity of the sympathetic nervous system and the renin‐aldosterone system seemed enhanced.
Differential effects of atenolol and enalapril on memory during treatment for essential hypertension.
Authors: Lichter I. , Richardson PJ , Wyke MA
Published: July 2012

A randomized single‐blind study was designed to compare the performance on memory tests requiring recall of information relevant to everyday life of two groups of hypertensive patients. One group of 13 patients were taking a beta‐adrenoceptor blocker (atenolol) and the other group of 12 patients received the angiotensin‐converting enzyme inhibitor (enalapril). The results suggested that when compared with placebo the group of patients treated with enalapril showed no changes in memory function, whilst there was a mild, but consistent deficit in the group taking atenolol.
Knowledge of and attitudes to medicines in the Southampton community.
Authors: Ridout S. , Waters WE , George CF
Published: July 2012

A 1 in 200 sample of the Southampton electorate was sent a postal questionnaire in January, 1984. Of the 740 adults surveyed, 443 (59.9%) returned completed questionnaires. One hundred and eighty‐eight (42.4%) of those replying had been prescribed a medicine within the previous month. Two hundred and seventy‐five respondents (62%) felt that not enough was explained about medicines by doctors or pharmacists. Consistent with this, was the fact that 37% were unaware of safe methods of disposal of leftover medicines. In addition, 112 of 154 (72.7%) people currently taking a prescribed medicine knew of no side‐ effects which could result from this. Eighty‐three per cent of respondents thought an information leaflet would be helpful. Of nine items which previous authors had suggested should be included, seven were thought to be important by more than 75% of those replying. Although 54% of people wanted detailed information, 43% stated a preference for short, summarized points. We conclude that most patients need to have more information about prescribed medicines and they would welcome written leaflets. However, further work is necessary to determine the best format for such leaflets.
Quantitative assessment of caffeine partial clearances in man.
Authors: Lelo A. , Miners JO , Robson RA , Birkett DJ
Published: July 2012

Five subjects who participated in an earlier study (Lelo et al., 1986b) of the comparative pharmacokinetics of caffeine (CA) and its primary monodemethylated metabolites paraxanthine (PX), theobromine (TB) and theophylline (TP) were administered CA to steady‐state. Using areas under the plasma concentration‐time curves for each of the dimethylxanthines derived from CA in the steady‐state study and individual plasma clearances of PX, TB and TP determined in the previous study, the fractional conversion of CA to PX, TB and TP and the individual partial clearances of CA have been defined. The mean (+/‐ s.d.) fractional conversion of CA to PX, TB and TP was 79.6 +/‐ 21.0%, 10.8 +/‐ 2.4% and 3.7 +/‐ 1.3%, respectively. When only demethylation pathways are considered PX, TB and TP accounted for 83.9 +/‐ 5.4%, 12.1 +/‐ 4.1% and 4.0 +/‐ 1.4%, respectively of the CA demethylations. The mean partial clearance of CA to PX was approximately 8‐fold and 23‐fold greater than those to TB and TP respectively. These data confirm earlier reports that PX is the major metabolite of CA in humans but suggest that PX formation is quantitatively more important than previously believed.
Quantitative and qualitative binding characteristics of disopyramide in serum from patients with decreased renal and hepatic function.
Authors: Pedersen LE , Bonde J , Graudal NA , Backer NV , Hansen JE , Kampmann JP
Published: July 2012

Protein binding of disopyramide, binding capacities, affinity constants and serum concentrations of alpha 1‐acid glycoprotein (AAG) were studied in five groups of patients. A: young healthy volunteers (n = 8); B: elderly patients with minor symptoms of ischaemic heart disease (n = 9); C: patients with cirrhosis of the liver and normal values of coagulation factors (II, VII and X), albumin and immunoglobulin G (n = 8); D: patients with cirrhosis and at least two abnormal of the previously mentioned values (n = 9) and E: eleven patients with severely impaired renal function. Subfractions of AAG (Fr1, Fr2 and Fr3) were determined by affinoimmunoelectrophoresis. AAG concentration was significantly (P less than 0.005) elevated in group E patients and decreased (P less than 0.025) in group D patients. Fr2 is probably associated with the high affinity, first binding site of disopyramide to AAG. Earlier observations of a reduced qualitative binding of disopyramide in patients with cirrhosis can be explained by a significant decrease in Fr2 (P less than 0.001) in group D patients. The protein binding of disopyramide in patients with uraemia was significantly increased due to a significant (P less than 0.005) increase in AAG concentration in spite of a smaller (P less than 0.025) affinity constant. Suggestions for therapeutic drug monitoring based on total serum concentrations are given.
Extracts of feverfew inhibit mitogen‐induced human peripheral blood mononuclear cell proliferation and cytokine mediated responses: a cytotoxic effect.
Authors: O'Neill LA , Barrett ML , Lewis GP
Published: July 2012

Feverfew has been used since antiquity to treat inflammatory conditions. Extracts of the herb were found to inhibit mitogen‐induced tritiated thymidine ([3H]‐TdR) uptake by human peripheral blood mononuclear cells (PBMC), interleukin 2 (IL‐2)‐induced [3H]‐TdR uptake by lymphoblasts and PGE2 release by interleukin 1 (IL‐1)‐stimulated synovial cells. Parthenolide, a major secondary metabolite from the herb also blocked [3H]‐TdR uptake by mitogen‐induced PBMC. However, both crude extracts and parthenolide proved cytotoxic to mitogen‐ induced PBMC and IL‐1 stimulated synovial cells, the cytotoxic effect being functionally indistinguishable from the inhibitory effects. The pharmacological properties of feverfew may thus be due to cytotoxicity, although the time course of the events described in this paper is different from those where feverfew appears to have more specific inhibitory effects.
Pharmacokinetics of intravenous amodiaquine.
Authors: White NJ , Looareesuwan S , Edwards G , Phillips RE , Karbwang J , Nicholl DD , Bunch C , Warrell DA
Published: July 2012

Amodiaquine hydrochloride (3 mg base kg‐1) was given by constant rate intravenous injection over 10 min to seven healthy adult male volunteers, and by constant rate infusion (10 mg base kg‐1) over 4 h to 10 adult patients admitted to hospital with falciparum malaria. After intravenous injection in volunteers there was considerable variation in plasma concentration profiles between subjects; peak plasma concentrations ranged between 65 and 1921 ng ml‐1. A biexponential equation was fitted to the plasma concentration time data and the following estimated pharmacokinetic parameters (geometric mean; range) were derived; lambda 1 = 24.4 (7.6‐95.0) h‐1, lambda 2 = 0.33 (0.12‐ 0.79) h‐1, V1:1.1 (0.3‐3.6) 1 kg‐1, Vss: 17.4 (2.3‐95.9) 1 kg‐1 and systemic clearance 13.0 (4.7‐56.6) 1 kg‐1 h‐1. After intravenous infusion there was also considerable variability between patients with post‐infusion plasma concentrations ranging between 82 and 836 ng ml‐1. The plasma concentration‐time profiles were biphasic with the following estimated pharmacokinetic parameters (geometric mean; range) alpha = 1.87 (0.60‐8.52) h‐1, beta = 0.069 (0.021‐0.265) h‐1, V1: 4.6 (0.5‐ 29.3) 1 kg‐1, Vss: 38.3 (3.7‐127.9) 1 kg‐1 and systemic clearance CL (1.6‐17.3) 1 kg‐1 h‐1. There was no measurable long terminal elimination phase, and the principal metabolite desethyl amodiaquine was not detected in the plasma samples. There was no serious toxicity in either group. During intravenous injection there was a significant fall in systolic blood pressure in four subjects (mean fall 16 mm Hg) but there was no significant change in heart rate.(ABSTRACT TRUNCATED AT 250 WORDS)
Preliminary studies of the pharmacokinetics and pharmacodynamics of prochlorperazine in healthy volunteers.
Authors: Taylor WB , Bateman DN
Published: July 2012

The pharmacokinetics and pharmacodynamics of prochlorperazine were studied in healthy volunteers using a recently developed h.p.l.c. assay. Eight subjects received 12.5 mg and 6.25 mg i.v. doses of prochlorperazine, a 25 mg oral dose and placebo in random order. Plasma half‐life (t1/2) of prochlorperazine was 6.8 +/‐ 0.7 h and 6.9 +/‐ 0.8 h for the 12.5 mg and 6.25 mg i.v. doses respectively. Apparent volume of distribution and plasma clearance were high and the kinetics did not appear to be dose‐related. Absorption of oral prochlorperazine appeared to be slow and bioavailability was very low. A metabolite, possibly prochlorperazine sulphoxide, was noted after oral dosing. Mild sedation was common after i.v. prochlorperazine, but cardiovascular effects were minimal. The main adverse effect was akathisia which was reported by five out of eight subjects after the higher i.v. dose. These results provide preliminary information on the pharmacokinetics of i.v. prochlorperazine which were previously unknown.
Differences between acute and long‐term metabolic and endocrine effects of oral beta‐adrenoceptor agonist therapy with pirbuterol for cardiac failure.
Authors: Canepa‐Anson R , Dawson JR , Kuan P , Poole‐Wilson PA , Sutton GC , Cockrill B , Reuben SR
Published: July 2012

The metabolic, hormonal and haemodynamic effects of oral pirbuterol, a new beta 2‐adrenoceptor agonist, were studied acutely (n = 19) and after 3 months treatment (n = 11) in patients with severe heart failure receiving chronic frusemide therapy. In the acute study fasted patients (n = 10) showed reductions in plasma K+ (P less than 0.005) and cortisol (P less than 0.01) and increases in plasma glucose (P less than 0.005), insulin (P less than 0.01), lactate (P less than 0.005) and pyruvate (P less than 0.0025). These acute changes were less in unfasted subjects (n = 9). Maximal increase in stroke volume occurred at approximately half the plasma pirbuterol concentration required for maximal effect on plasma insulin. Treatment with pirbuterol for 3 months was associated with sustained increases in stroke volume and fasting plasma glucose and insulin, but there was loss of all other acute metabolic effects. Despite concurrent frusemide and digoxin therapy acute hypokalaemia caused no adverse effects. Hypokalaemia did not occur with chronic pirbuterol administration.
The analysis of dose‐response curves‐a practical approach.
Authors: Jackson SH , Jamieson MJ , Johnston A , Shepherd AM
Published: July 2012

The rationale for the objective assessment of dose‐response curves (DRCs) is presented. Using data derived from isoprenaline/heart rate responses studies, two new statistical methods of objectively defining the terminal linear segment of an incomplete DRC are presented. Using data derived from phenylephrine/diastolic blood pressure response studies, the parallel shift quadratic model of Sumner et al. (1982) has been extended to include a measure of the suitability of the quadratic model for each individual data set using the Akaike information criterion. A parallel shift Emax model is proposed for complete DRCs.
Intravenous midazolam for upper gastrointestinal endoscopy: a study of 800 consecutive cases relating dose to age and sex of patient.
Authors: Bell GD , Spickett GP , Reeve PA , Morden A , Logan RF
Published: July 2012

In many endoscopy units midazolam is replacing diazepam as the intravenous sedative of first choice. Midazolam is approximately twice as potent as diazepam. Although generally considered a safe drug, there have been a number of recent reports, particularly in the elderly, of the drug causing hypotension, respiratory depression and even death. There have been at least ten studies comparing diazepam with midazolam for upper gastrointestinal endoscopy but many have involved relatively small numbers and none have adequately addressed the question of dosage in the elderly. We have carefully recorded the dose of intravenous midazolam used to produce adequate sedation prior to upper gastrointestinal endoscopy in 800 consecutive patients. The dose of midazolam decreased markedly with age in both male and female patients. There was a highly significant correlation in both sexes between age and the dose of midazolam (rho −0.787, P less than 0.001 for males and rho −0.768, P less than 0.001 for females). There was only a small difference in dose in men and women, an average of 1 mg; and no difference in dose over the age of 70 years. In patients over 70 years of age the dose of midazolam necessary for endoscopy is often so small that overdosage is all too easy.
The metabolism of 17 alpha‐ethinyloestradiol by human liver microsomes: formation of catechol and chemically reactive metabolites.
Authors: Purba HS , Maggs JL , Orme ML , Back DJ , Park BK
Published: July 2012

The metabolism of 17 alpha‐ethinyloestradiol (EE2) to catechol and reactive metabolites by human liver microsomes was investigated. 2‐ Hydroxyethinyloestradiol (2‐OHEE2) was either the sole or principal metabolite. Small amounts of 6‐hydroxyethinyloestradiol and 16‐ hydroxyethinyloestradiol were produced by some of the livers. EE2 (10 microM) underwent substantial (5‐20% of incubated drug), though highly variable, NADPH‐dependent metabolism to material irreversibly bound to microsomal protein. 2‐OHEE2 appeared to be the pro‐reactive metabolite. The maximum EE2 2‐hydroxylase activity was 0.67 nmol min‐1 mg‐1 microsomal protein, with a Km value of 8.6 microM. Oestradiol, which is mainly hydroxylated to 2‐hydroxyoestradiol, was the most potent inhibitor of hydroxylase activity and exhibited competitive inhibition. Progesterone, which undergoes 2‐hydroxylation to a minor extent was also a competitive inhibitor, whereas cholesterol and cortisol did not have any appreciable inhibitory effect. Primaquine was the most potent non‐steroidal inhibitor but was non‐competitive. Other non‐steroidal compounds investigated, e.g. antipyrine, did not show any significant effect on EE2 2‐hydroxylation. The results of this study suggest that EE2 2‐hydroxylation is metabolised by a form(s) of cytochrome P‐450 which has affinity for endogenous steroids.
A quinine a day keeps the leg cramps away?
Authors: Warburton A , Royston JP , O'Neill CJ , Nicholson PW , Jee RD , Denham MJ , Dobbs SM , Dobbs RJ
Published: July 2012

A double‐blind, placebo‐controlled, cross‐over trial of quinine in leg cramps occurring at rest was conducted in 22 elderly cramp sufferers. Despite demonstration of impaired quinine elimination in the elderly, prescription of the traditional dose of 300 mg quinine bisulphate at night failed to produce a significant (P = 0.1) reduction in the number or severity of cramps. There was a significant relationship between serum quinine concentration and attenuation of cramps. However, the simple expedient of increasing the nightly dose of quinine may carry the concomitant risk of cinchonism.
Excretion of chloroquine and desethylchloroquine in human milk.
Authors: Ogunbona FA , Onyeji CO , Bolaji OO , Torimiro SE
Published: July 2012

The excretion of chloroquine and the major metabolite, desethylchloroquine, in breast milk was investigated in eleven lactating mothers following a single oral dose of chloroquine (600 mg base). The average milk to plasma concentration ratio at the 24th hour was 6.6 +/‐ 2.4 for chloroquine and 1.5 +/‐ 0.6 for desethylchloroquine in five of the volunteers. In five other volunteers the elimination half‐life of chloroquine in milk was 8.8 +/‐ 4.7 days which was longer than that in saliva (3.9 +/‐ 1.0 days) from the same volunteers. The maximum daily dose of the drug that the infant can receive from breastfeeding was about 0.7% of the maternal start dose of the drug in malaria chemotherapy. It is, therefore, suggested that it is safe for mothers to breastfeed their infants when undergoing treatment for malaria with chloroquine.
Captopril: 4 years of post marketing surveillance of all patients in New Zealand.
Authors: Edwards IR , Coulter DM , Beasley DM , MacIntosh D
Published: July 2012

The Intensive Medicines Monitoring Programme (IMP), a specialised part of the New Zealand Post Marketing Surveillance system, has been used to monitor captopril since it was first approved for marketing for the treatment of hypertension and heart failure. Monitoring has consisted of (1) spontaneous reporting for which doctors have been encouraged to report all clinical events, (2) a specific event recording survey at the end of the first year and (3) a controlled patient survey of taste disturbance. The IMP gathers prescription information on about 85% of all patients. There were 4,124 patients at the end of the first 4 years. Reported events involved 4% of patients, the majority being cutaneous (1%) and gastrointestinal (0.7%). The event recording survey gave an overall rate of adverse events of 2.2 per patient year. The taste survey showed a remarkably high incidence of taste disturbance in the control population and only taste loss was significantly higher (P less than 0.01) for captopril. This ongoing study has so far demonstrated a low incidence of adverse effects due to captopril, which is reassuring in view of its increasing use for mild hypertension and early cardiac failure.
Clinical pharmacology of a new antidepressant, Y‐8894 in healthy young and elderly volunteers.
Authors: Ogura C , Kishimoto A , Kunimoto N , Omura F , Matsubayashi M , Tsutsui T , Shimizu M
Published: July 2012

In the first experiment the influences of a single oral administration of a new antidepressant, Y‐8894 50 mg, nortriptyline 50 mg, and placebo on physiological and psychological parameters were evaluated by a double‐blind, crossover method in 10 healthy male volunteers. As the second experiment eight elderly healthy men were also recruited to examine the clinical pharmacology of Y‐8894. Y‐8894 50 mg showed no significant anticholinergic, sedative, or cardiovascular effect on any of the measures used in young subjects. In the elderly Y‐8894 50 mg increased pulse rate (P less than 0.05‐0.01), lowered systolic blood pressure (P less than 0.05‐0.005), and decreased salivary flow (P less than 0.05) compared with those of pre‐drug baseline. C.f.f. was improved after Y‐8894 50 mg, but not significantly. Neither psychomotor performance nor immediate memory was influenced after either treatment in young subjects. Furthermore, in the elderly Y‐8894 50 mg did not affect these parameters. In the elderly both k21 and ke were smaller, t1/2,z was longer, and AUC was larger compared with young subjects (P less than 0.01). In conclusion, Y‐8894 50 mg seemed to lack the anticholinergic, sedative and cardiovascular effects which were observed after nortriptyline 50 mg in young subjects. In the elderly some affects were recognized, in part, due to pharmacokinetic alteration.
Reduction of metformin renal tubular secretion by cimetidine in man.
Authors: Somogyi A , Stockley C , Keal J , Rolan P , Bochner F
Published: July 2012

To determine whether cimetidine altered the renal handling of metformin, seven subjects took 0.25 g metformin daily with and without cimetidine 0.4 g twice daily. Blood and urine samples were collected and assayed for metformin, cimetidine and creatinine by h.p.l.c. Cimetidine significantly increased the area under the plasma metformin concentration‐time curve by an average of 50% and reduced its renal clearance over 24 h by 27% (P less than 0.008). There was no alteration in the total urinary recovery of metformin when cimetidine was co‐ administered. The effect of cimetidine on the renal clearance of metformin was time dependent, being significantly reduced up to 6 h following cimetidine. These results appeared to be consistent with competitive inhibition of renal tubular secretion. Cimetidine had no effect on the renal clearance of creatinine, but time‐dependent variations in both metformin and creatinine renal clearance were observed. Metformin had no effect on cimetidine disposition. It is concluded that cimetidine inhibits the renal tubular secretion of metformin in man, resulting in higher circulating plasma concentrations. Because of its propensity for causing dose and concentration‐dependent adverse effects, the dose of metformin should be reduced when cimetidine is co‐prescribed.
The oral retention and antiplaque efficacy of triclosan in human volunteers.
Authors: Gilbert RJ , Williams PE
Published: July 2012

An antiplaque toothpaste containing 0.2% (w/w) triclosan significantly inhibited overnight plaque growth in 12 human volunteers. After use of a 1 g quantity of the toothpaste containing 0.2% (w/w) [3H]‐triclosan, 36.3 +/‐ 1.4% of the triclosan was retained. The mean concentration (+/‐ s.d.) achieved in saliva 5 min after toothpaste use was 8.16 +/‐ 2.50 micrograms g‐1. The saliva decay curve for triclosan was consistent with a two phase model with t1/2 values of 0.45 h and 2.42 h, respectively. Triclosan was present in bacterial plaque for at least 8 h after dosage and in the oral mucosa for at least 3 h.
ORG 10172: a low molecular weight heparinoid anticoagulant with a long half‐life in man.
Authors: Bradbrook ID , Magnani HN , Moelker HC , Morrison PJ , Robinson J , Rogers HJ , Spector RG , Van Dinther T , Wijnand H
Published: July 2012

ORG 10172 is a heparinoid with mean molecular weight 6500 daltons. Intravenous bolus injections of ORG 10172 were compared with placebo and heparin injections in 91 separate studies in 83 healthy male subjects. 6400 units ORG 10172 produced a mean maximum change of 14.7 s in kaolin cephalin time (c.f. greater than 120 s for 5000 units heparin). Changes in prothrombin time were minimal (1.6 s for 6400 units ORG 10172 and 4.5 s after 5000 units heparin). A dose‐related increase in bleeding time occurred after ORG 10172 and at high doses (greater than 3200 units) some secondary bleeding, which was never serious, occurred at between 1 and 4 h after incision. A dose‐dependent reduction in ex vivo platelet adhesiveness was found at 10 min after ORG 10172 injection. ORG 10172 promoted a much smaller release of lipoprotein lipase as compared with heparin. The effect of ORG 10172 on plasma factor Xa activity (one measure of its action) was described by a biexponential decay with a mean distribution half‐life of 2.34 (s.e. mean 0.16) h and mean disposition half‐life of 17.6 (s.e. mean 1.1) h. It thus has a much longer duration of effect than heparin. There was a linear relationship of plasma anti‐Xa response to increasing dose although there was some variability only partly explained by differences in body weight or surface area. ORG 10172 administration by bolus intravenous injection was well tolerated and there was no evidence of adverse effects on clinical chemistry or haematology tests.
Intravenous midazolam: a study of the degree of oxygen desaturation occurring during upper gastrointestinal endoscopy.
Authors: Bell GD , Reeve PA , Moshiri M , Morden A , Coady T , Stapleton PJ , Logan RF
Published: July 2012

Intravenous midazolam (mean dose of 6.3 mg) was given to 100 consecutive patients coming to endoscopy. All patients had an ear oximeter attached throughout the procedure to record continuously their levels of oxygen saturation. Eighty‐five of the 100 patients had pre‐ endoscopy respiratory function tests measured, and 82 wore an induction plethysmograph vest to get a continuous qualitative estimate of respiratory rate and excursion throughout the procedure. Following intravenous midazolam a reduction in respiratory excursion was observed in 80% of patients. The initial baseline oxygen saturation of 95.4% fell 3.3% (P less than 0.0005) following intravenous midazolam to 92.1%. During the endoscopic procedure there was a further 3.1% decrease in oxygen saturation to 89.0% (P less than 0.0005) and in 7% the level fell to below 80%. Age, sex, dose of midazolam given and pre‐ endoscopy respiratory function tests failed to identify those patients at risk of hypoxia during the endoscopy.
Plasma antipyrine half‐life can be determined from urine data.
Authors: Atiba JO , Taylor G , Pershe RA , Blaschke TF
Published: July 2012

Antipyrine half‐life has been determined from measurements of antipyrine concentrations in spontaneously voided urine specimens in eleven subjects, studied on a total of forty‐seven different occasions while receiving no drugs, interferon or ketoconazole. Plasma and saliva half‐lives show good intrasubject correlation. Plasma and urine half‐ lives show good intrasubject correlation provided total urine output is at least 1.1 l day‐1. The range of intrasubject correlation coefficients for plasma and urinary half‐lives was 0.76 to 0.98, with a median value of 0.85. Saliva and urine half‐lives show good intrasubject correlation, with the range of intrasubject correlation coefficients from 0.74 to 0.98, and with a median value of 0.75. There is a small but consistent bias towards shorter urinary half‐life estimates; this averaged 0.75 h for the plasma‐urine studies and 0.192 h for the saliva‐urine studies. There were parallel changes in antipyrine half‐life estimated from plasma and urine for one of our subjects who received multiple doses of recombinant beta‐interferon and had a 150% increase in antipyrine half‐life over the study period.
Paracetamol interaction with oral contraceptive steroids: increased plasma concentrations of ethinyloestradiol.
Authors: Rogers SM , Back DJ , Stevenson PJ , Grimmer SF , Orme ML
Published: July 2012

The effect of a single dose of paracetamol (1 g) on plasma concentrations of the oral contraceptive steroids ethinyloestradiol (EE2) and levonorgestrel (LNG) has been studied in six healthy female volunteers. The area under the plasma concentration‐time curve (AUC0‐ 24) of EE2 was significantly increased following paracetamol administration by 22% (control 2221 +/‐ 291; following paracetamol, 2702 +/‐ 452 pg ml‐1 h; mean +/‐ s.d.; P less than or equal to 0.05). The greatest effect was evident in the time period 0‐3 h. There was a significant decrease in the AUC of EE2‐sulphate after paracetamol (7736 +/‐ 3791 pg ml‐1 h) compared with control (13161 +/‐ 4535 pg ml‐1 h; P less than or equal to 0.05). Plasma concentrations of LNG were unaltered by concurrent paracetamol administration. We conclude that the administration of a single 1 g dose of paracetamol causes an increase in plasma concentrations of EE2 as a result of a reduction in the sulphation of the steroid. This interaction may be of clinical significance in women on oral contraceptive steroids who regularly take paracetamol.
Captopril and hydrochlorothiazide: rationale for their combination.
Authors: Ambrosioni E , Borghi C , Costa FV
Published: July 2012

The results of controlled clinical studies have shown that about 80% of hypertensive patients have a satisfactory blood pressure reduction when treated with a combination of captopril and thiazide diuretics. The high response rate to this treatment can be explained on the basis of the mechanism of action of these drugs. In the long term, diuretics act by reducing peripheral vascular resistance. The mechanism by which they reduce peripheral vascular resistance is the subject of debate, but could be explained on the basis of cellular ionic changes. From our studies, it was observed that thiazides cause a reduction in intracellular Na+ (Nai) and in intra‐ and extracellular K+ (Ki, Ke). Since in many patients Ke losses are greater than Ki losses, the Ki/Ke ratio (which is directly related to membrane potential and thus to vascular tone) increases. Captopril also reduces Nai, but its effects on Ke and Ki are quite different from those of thiazides. Captopril in fact causes an increase in Ki inducing a net increase in Ki/Ke. This increase can also be observed when captopril is given in combination with thiazides. Therefore the combination of captopril and thiazides has an additive effect on Nai, and increases Ki/Ke in the vast majority of patients. The decrease in Nai probably acts by reducing membrane sensitivity to catecholamines and angiotensin, whereas the increase in Ki/Ke acts by hyperpolarizing vascular smooth muscle membrane. The combination of captopril an thiazides also has favourable metabolic effects.(ABSTRACT TRUNCATED AT 250 WORDS)
Determination of the optimal dosage regimen of captopril + hydrochlorothiazide in the treatment of moderate arterial hypertension.
Authors: Steru D , Childs M , Lancrenon S , Languillat JM , Mattei A , Millet B , Schwebig A , Stephan A
Published: July 2012

A multicentre controlled trial was carried out to determine the optimal dosage of a 2/1 combination of captopril plus hydrochlorothiazide (HCTZ) in mild hypertension at three doses against placebo in a 6 week double‐blind trial. The number of patients was 111:27 received placebo; 26 were treated with captopril 25 mg plus HCTZ 12.5 mg (25/12.5); 25 with captopril 50 mg plus HCTZ 25 mg (50/25); and 33 with captopril 100 mg plus HCTZ 50 mg (100/50). A significant fall in blood pressure was seen in all four groups, but was greater with the active treatments. The percentage of patients who were normalized [diastolic blood pressure (DBP) less than or equal to 90 mm Hg] or good responders (10% fall in DBP) increased as a function of the dose. At Day 21, the antihypertensive effect of 50/25 was similar to that of 100/50, but greater than that of captopril 25‐HCTZ 12.5. At Day 42, the antihypertensive effects of the three doses were similar. Tolerance data showed a higher incidence of side‐effects with 100/50 than with the other dosages. Thus, 50/25 appeared to be the optimal dosage for the control of mild hypertension.
The disposition of antipyrine and its metabolites in young and elderly healthy volunteers.
Authors: Posner J , Danhof M , Teunissen MW , Breimer DD , Whiteman PD
Published: July 2012

1 Oxidative metabolism of antipyrine (AP) was compared in 11 elderly (greater than 65 years) and 12 young (less than 40 years) volunteers. All subjects were non‐smokers, consumed little if any alcohol and were in good health. 2 After a single dose of AP 500 mg, its clearance from saliva and profiles of the parent drug and its major metabolites in urine were determined using high‐performance liquid chromatography. 3 Mean total AP clearance from saliva was lower in the elderly (P less than 0.05). Mean weight‐normalised volume of distribution was also smaller (P less than 0.01) so that elimination half‐life in the elderly was not significantly different from that in the young. 4 The percentage dose excreted in 48 h urine as norantipyrine (NORA) and its clearance for production were lower in the elderly (P less than 0.001 and P less than 0.01 respectively). Urinary 3‐hydroxymethylantipyrine (HMA) and free antipyrine were present in greater quantities in 48 h urine in the elderly (P less than 0.001 and P less than 0.05) while the amounts of 4‐hydroxyantipyrine (OHA) were almost identical in the two age groups. 5 The findings suggest that there is a selective impairment of N‐demethylation in the elderly which may have important implications for dosage of elderly patients with drugs metabolised by this route.
Passage of paracetamol into breast milk and its subsequent metabolism by the neonate.
Authors: Notarianni LJ , Oldham HG , Bennett PN
Published: July 2012

1 Paracetamol was administered to nursing mothers. The drug passed rapidly into milk and the milk:plasma concentration ratio was approximately unity. 2 The estimated maximum dose to the neonate was 1.85% of the weight‐adjusted maternal oral dose of paracetamol 1.0 g. Recovery of paracetamol was greater from the breast from which samples were taken frequently than from the breast which was sampled only once. 3 Paracetamol, its glucuronide, sulphate, cysteine and mercapturate conjugates were found in the urine of the neonates although only the parent drug was detected in breast milk. 4 The neonates excreted significantly greater proportions of unchanged paracetamol (P less than 0.01) and significantly lesser proportions of paracetamol sulphate (P less than 0.001) than did healthy volunteers aged 11‐80 years who received a therapeutic dose of paracetamol. 5 The findings are compatible with a deficiency of sulphate conjugation by the neonate.
Low‐dose phenobarbitone as an indicator of compliance with drug therapy.
Authors: Feely M , Cooke J , Price D , Singleton S , Mehta A , Bradford L , Calvert R
Published: July 2012

1 To assess the potential value of low‐dose phenobarbitone (PB) as a marker of compliance we studied the relationship between plasma level of PB and dose (2‐16 mg daily) following 3 or 4 weeks treatment in healthy volunteers (n = 26) and in‐patient volunteers (n = 7). 2 Also, to simulate poor compliance, PB levels were measured in some volunteers following alternate‐day (n = 6) or short‐term (n = 5) treatment with similar doses. These levels, expressed as the level: dose ratios (LDRs), did not overlap with those obtained following 3 or 4 weeks of daily PB intake. 3 To evaluate the efficacy of this marker in patients taking other drugs we gave a group of out‐patients (n = 24) compound tablets containing B vitamins and a small dose (16 mg) of PB; their compliance over 2‐5 weeks was assessed both by measuring plasma levels of PB and residual tablet counting. 4 In the latter study, as well as providing absolute evidence of good compliance by many patients, the plasma levels of PB proved particularly valuable when non‐compliant individuals ‘forgot’ to bring their residual tablets. 5 We suggest that phenobarbitone, in doses low enough to be non‐sedative and non‐enzyme inducing, is potentially useful as a pharmacological indicator of compliance with drug therapy.
Assessment of a new hypnotic imidazo‐pyridine (zolpidem) as oral premedication.
Authors: Cashman JN , Power SJ , Jones RM
Published: July 2012

1 A new imidazo‐pyridine hypnotic (zolpidem 10 mg and 20 mg) was compared with placebo as premedication before general anaesthesia in female patients undergoing minor gynaecological surgery. Efficacy and tolerance before and after anaesthesia were assessed. Psychomotor testing was used to study recovery from anaesthesia. 2 Both doses of zolpidem produced good sedation pre‐operatively but only the higher dose was associated with anterograde amnesia. 3 Premorbid anxiety scores were low in the group of patients studied and were unaffected by either dose of zolpidem. 4 There were no significant effects on the course of anaesthesia. However, postoperatively there was a tendency for wake‐up to be delayed in those patients who received either dose of zolpidem. 5 Postoperative recovery, as indicated by tests of psychomotor performance, was noticeably delayed with a dose of 20 mg compared with placebo whilst psychomotor performance had returned towards baseline levels 3 h after wake‐up in those patients who had received placebo. The zolpidem 10 mg group was intermediate. 6 Zolpidem may be a suitable premedicant when hypnosis and amnesia only are required.
Does regular treatment with ketotifen inhibit bronchoconstriction induced by isocapnic hyperventilation?
Authors: Rafferty P , Tweeddale PM , Ferguson RJ , Biggs BA , Grant IW
Published: July 2012

Eight asthmatic patients completed a 12‐week, double‐blind, placebo controlled study to assess the efficacy of ketotifen, 1 mg twice daily, in the inhibition of bronchoconstriction induced by isocapnic hyperventilation (IH). There was no significant difference in the degree of bronchoconstriction produced by IH after treatment with ketotifen or placebo.
Calcitonin suppresses gastric emptying of a radiolabelled solid meal in humans.
Authors: Jonderko G , Golab T , Jonderko K
Published: July 2012

The effects on gastric emptying of calcitonin/i.v. 1.5 i.u. kg‐1 body mass bolus or 10 i.u. followed by infusion to overall 1.5 i.u. kg‐1 body mass dose vs placebo were studied in four healthy volunteers and in four patients with an active peptic ulcer. Gastric emptying of a radiolabelled solid meal was surveyed. Pronounced delay in gastric emptying was observed in all studied subjects, mean transit time MTT90 calcitonin 39.2 +/‐ 0.85 min vs placebo 32.8 +/‐ 1.31 min, P less than 0.001.
Lack of inhibitory effect of metronidazole on theophylline disposition in healthy subjects.
Authors: Adebayo GI , Mabadeje AF
Published: July 2012

The effect of metronidazole, at a dose of 1.2 g daily, on theophylline disposition was studied in 10 healthy adult volunteers. Neither theophylline half‐life, volume of distribution nor total body clearance was altered by the anti‐microbial. It is concluded that metronidazole does not impair theophylline metabolism despite the fact that it is a substituted imidazole.
The actions of calcitonin gene related peptide and vasoactive intestinal peptide as vasodilators in man in vivo and in vitro.
Authors: Thom SM , Hughes AD , Goldberg P , Martin G , Schachter M , Sever PS
Published: July 2012

1 The two peptides calcitonin gene related peptide (CGRP) and vasoactive intestinal peptide (VIP) produced marked dilatation of the forearm vascular bed when infused via the brachial artery. 2 CGRP relaxed preconstricted segments of human radial, coronary, gastric and cerebral arteries in an endothelium dependent manner. 3 VIP relaxed human gastric and transverse cervical arteries in an endothelium dependent manner, but relaxation of the human pulmonary artery was not dependent on endothelium. 4 The characteristics of the endothelium dependent relaxation of these medium‐sized muscular arteries indicated involvement of the endothelium derived relaxing factor in vitro. 5 Caution is expressed in drawing comparisons between the mechanisms involved in the in vivo and in vitro vascular responses.
Post‐exercise hypotension: the effects of epanolol or atenolol on some hormonal and cardiovascular variables in hypertensive men.
Authors: Wilcox RG , Bennett T , Macdonald IA , Pipkin Broughton F , Baylis PH
Published: July 2012

1 Eight men with primary hypertension were treated for 3 weeks with placebo, epanolol (200 mg or 400 mg), or atenolol 100 mg in a randomised cross‐over study. Each active treatment period was preceded by a 3 week placebo treatment period and both investigators and subjects were blind to the active drug sequence. 2 At the end of each period, measurements were made of resting cardiovascular (heart rate, blood pressure, forearm blood flow) and biochemical variables (plasma renin, angiotensin II, aldosterone, adrenaline, noradrenaline, vasopressin, sodium and potassium concentrations and osmolality). Responses to exercise (including gas exchange, sweat rate, and ratings of perceived exertion) and the reflex cardiovascular adjustments to distal body subatmospheric pressure were also assessed. 3 The reduction of exercise‐induced tachycardia by epanolol 400 mg was comparable to that of atenolol. There was very little difference in the effects of atenolol or epanolol 400 mg on resting blood pressure, but in both cases blood pressures were usually significantly lower than with epanolol 200 mg. 4 Although each active treatment influenced the renin‐ angiotensin system and circulating levels of catecholamines, the exercise‐induced reduction in blood pressure was unaffected. Thus, the hypotensive effects of pharmacological and non‐pharmacological interventions were additive.