bluuebunny/crossref_metadata_2025 huggingface dataset:
Pharmacokinetics and haemodynamic effects of prolonged methohexitone infusion.
Authors: Le Normand Y. , de Villepoix C. , Pinaud M. , Bernard JM , Fraboul JP , Athouel A. , Ribeyrol M. , Beneroso N. , Larousse C.
Published: July 2012

1. The use of continuous infusion anaesthesia has only been of interest since the development of short‐acting, less cumulative and less toxic drugs. 2. This study aimed to compare pharmacokinetics and haemodynamic effects during and after long time methohexitone constant rate infusion. Sixteen patients were given either 60 or 90 micrograms kg‐1 min‐1 methohexitone during 14 h. Blood samples were taken hourly during this time and 12 h following the end of infusion. 3. Infusion period was analysed by a single exponential model; post‐infusion time showed a three compartment model, the intermediate phase parameters corresponding to those of the infusion period. 4. Methohexitone was haemodynamically well tolerated; prolonged infusion decreases oxygen consumption, mainly by a decrease in oxygen demand. 5. Many patients remained unconscious for unacceptably long periods of time after post‐ operative sedation by methohexitone.
Evidence of prednisolone induced mood change ('steroid euphoria') in patients with chronic obstructive airways disease.
Authors: Swinburn CR , Wakefield JM , Newman SP , Jones PW
Published: July 2012

1. It is a clinical impression that some patients given oral corticosteroids develop a sense of wellbeing that is 'inappropriate' to improvements in physical health. This has been termed steroid 'euphoria', but unlike steroid‐induced psychosis it has not been documented. 2. To test for the size and frequency of this phenomenon, 20 patients with severe chronic obstructive airways disease (mean FEV1 0.86 l) were given 30 mg of prednisolone for 14 days, after a period of placebo administration in a single‐blind study. 3. Lung spirometry and arterial saturation during exercise were measured serially, together with established measures of mood state. 4. No changes in spirometry or arterial saturation during exercise were detected until 7 days of active therapy. 5. Mood state did not change during the placebo period, but small significant reductions in anxiety and depression were measured after 3 days of prednisolone and before any measurable improvement in lung function. Mood state did not then further improve, despite measurable improvements in lung spirometry. 6. This is evidence that prednisolone may produce a mild 'inappropriate' sense of wellbeing within a population receiving the drug, rather than as an occasional idiosyncratic response.
Assessment of erectogenic properties of apomorphine and yohimbine in man.
Authors: Danjou P. , Alexandre L. , Warot D. , Lacomblez L. , Puech AJ
Published: July 2012

1. In a four period, double‐blind, placebo‐controlled study, apomorphine (0.009 mg kg‐1 subcutaneous route) and yohimbine (0.30 mg kg‐1 i.v. route) were administered to 10 male healthy volunteers. Penile circumference was monitored using plethysmography and subjective sexual arousal was self‐assessed. Data were collected before, during and after a stimulation session during which 50 erotic slides were projected to the subjects. 2. Apomorphine induced an erection starting from the fourth minute post‐injection, and potentiated the visually‐ induced response. Self assessment showed increased tumescence and rigidity without modifications of sexual arousal. 3. Yohimbine did not modify penile diameter without stimulation and did not affect the physiological response to erotic stimuli. 'Sexual excitement' was decreased by yohimbine during the post‐stimulation phase. One subject experienced severe anxiety while he was infused with yohimbine. 4. These results are discussed with reference to animal data and to recent studies carried out in impotent patients.
Pharmacokinetics of lisinopril, enalapril and enalaprilat in renal failure: effects of haemodialysis.
Authors: Kelly JG , Doyle GD , Carmody M. , Glover DR , Cooper WD
Published: July 2012

1. Lisinopril and enalapril were administered as 2.5 mg single doses and as eight single daily 2.5 mg doses to separate groups of six patients with chronic renal failure. Patients were receiving regular haemodialysis. 2. In the absence of haemodialysis, the decline in plasma concentrations of lisinopril and enalaprilat was extremely slow and plasma concentrations were generally high. 3. Haemodialysis had large effects on plasma concentrations of lisinopril and enalaprilat. A 4 h period reduced plasma concentrations of both drugs by around one‐ half and often by significantly more than this. Even 1 or 2 h of haemodialysis had significant effects. 4. Haemodialysis plasma clearance was similar for both drugs with mean values of the order of 40 ml min‐1. Clearance did not markedly differ when measured after 1, 2 or 4 h of haemodialysis or after single or multiple doses of lisinopril or enalapril. 5. The design of dosage regimens of both lisinopril and enalapril for patients with severe renal impairment or chronic renal failure should take into consideration the use and effects of haemodialysis.
Chronic dose urinary and serum pharmacokinetics of norfloxacin in the elderly.
Authors: Kelly JG , Deaney NB , Lavan J. , Noel J.
Published: July 2012

1. Norfloxacin was administered as two daily 400 mg oral doses to eight elderly patients requiring treatment for urinary tract infections. Blood specimens were obtained for pharmacokinetic profiles following the first and fifteenth doses. Further specimens were obtained before each morning's dose of norfloxacin. Specimens of urine were obtained to ascertain if adequate antimicrobial concentrations were reached in these patients with diminished renal function. 2. Norfloxacin half‐life was consistent with that expected in mild renal impairment and was not different between the first and fifteenth doses. Based on ratios of AUC values, accumulation is probably related to renal function, being greatest for creatinine clearance values below 30 ml min‐1. 3. On the great majority of occasions, the urinary concentrations of norfloxacin exceeded 20 micrograms ml‐1. On days 2‐7, the mean percentage 12 h renal elimination of norfloxacin was 18.6 +/‐ 1.47 (mean of 82 separate observations). Norfloxacin 400 mg twice daily was well tolerated in this group of elderly patients and produced adequate antimicrobial concentrations in urine.
Venous responsiveness to atrial natriuretic factor in man.
Authors: Ford GA , Eichler HG , Hoffman BB , Blaschke TF
Published: July 2012

The venorelaxant effect of atrial natriuretic factor in man was studied using the dorsal hand vein technique. Infusion of met‐ANF to preconstricted veins at doses up to 240 ng min‐1 in 11 healthy male subjects caused only minimal venorelaxation. Atrial natriuretic factor is unlikely to have a significant venorelaxant effect at physiological doses in man.
Equivalence of conventional and sustained release oral dosage formulations of acetazolamide in primary open angle glaucoma.
Authors: Joyce PW , Mills KB , Richardson T , Mawer GE
Published: July 2012

1. Outpatients with primary open angle glaucoma uncontrolled on single topical therapy with either pilocarpine or timolol were recruited for a stratified double dummy cross over trial. Once or twice daily sustained release acetazolamide (SRA) was compared with an identical regimen of conventional tablets (CA). 2. During the run in period the patients received 500 mg SRA once or twice daily as needed to control intraocular pressure (IOP). The dose was thereafter kept constant and patients were allocated randomly to 4 weeks treatment with CA followed by 4 weeks SRA or vice versa. IOP and venous plasma concentrations of acetazolamide were measured at weekly intervals. At the end of each 4 week course, patients were admitted for a 24 h profile of IOP and drug concentration measurements. 3. Thirty‐five patients were recruited, but eleven were withdrawn during the run in period largely because of adverse effects; these became less troublesome when it was decided to give the once daily dose at 22.00 h. Four were withdrawn during the cross over, two because of inadequate IOP control. Twenty completed the trial. 4. The morning plasma concentration of acetazolamide measured each week showed no tendency to accumulation during the study. The mean swing (maximum minus minimum) in plasma acetazolamide concentration during the 24 h profile was less (P less than 0.005) with the SR formulation (11.6 +/‐ 4.9; mg l‐1) +/‐ s.d.) than with the conventional (15.5 +/‐ 4.7) but the mean concentrations over the 24 h profile were indistinguishable (P greater than 0.05; 9.7 +/‐ 3.8 and 8.6 +/‐ 2.8 respectively). 5. Satisfactory control of IOP (no more than one reading above 22 mmHg) was maintained despite the changes in formulation in all but two of the patients who entered the cross over study. No close relationship between IOP and plasma concentration of acetazolamide was found. The 24 h IOP profiles whilst receiving each of the formulations were indistinguishable; thus the smoothing of the plasma drug concentration profile achieved by the SR formulation did not reduce the amplitude of swings in IOP. Similarly, no difference was observed between the formulations with respect to adverse effects. 6. It is concluded that the SR and conventional formulations were equivalent with respect to mean plasma acetazolamide concentration, IOP control and adverse effects. The SR formulation did not show practical advantages over the conventional formulation which was equally effective even with dosage intervals of 12 or 24 h.
Self‐medication in urban and rural Zimbabwean communities.
Authors: Stein CM , Gora NP , Macheka BM
Published: July 2012

1. A questionnaire examining the use of, and knowledge about over‐the‐ counter (OTC) drugs was administered verbally to representatives from 200 urban and 200 rural households. Self‐medication was common in both groups but there were more drugs present in rural (336 items) than urban homes (231 items) with the differences largely due to the more frequent presence of traditional medicines in rural homes. 2. Analgesics were the commonest items in the homes of both groups. A positive urine screening test for aspirin, chloroquine, or antibiotics was found in 25% of urban and 27% of rural samples tested. Respondents who elected to use an OTC drug for a particular symptom usually chose an appropriate drug. 3. Rural respondents were more likely to use traditional medicines particularly for the treatment of cough, abdominal pain, and diarrhoea. 4. Knowledge about dosages, the possibility of adverse reactions, and the seriousness of potential poisoning with OTC drugs was inadequate and needs to be corrected for more efficient self‐medication.
A study of the transport of lithium across the erythrocyte membrane in vivo and of the effects of the ion transport inhibitors digoxin and dipyridamole.
Authors: Wood AJ , Aronson JK , Bunch C , Grahame‐Smith DG
Published: July 2012

1. We have given an oral load of lithium carbonate to healthy volunteers in order to investigate the transport of lithium across the erythrocyte membrane in vivo and the effects of known inhibitors of that transport. 2. Using this technique we have shown that pretreatment with either digoxin, an inhibitor of the sodium/potassium pump, or dipyridamole, an inhibitor of the anion transporter, does not alter the plasma or erythrocyte lithium concentration profiles, nor any of the pharmacokinetic variables derived from these data, and we conclude that these two transport pathways do not contribute significantly to the in vivo handling of lithium by erythrocytes. 3. We have also shown that erythrocyte lithium concentrations measured directly differ significantly from the predicted concentrations calculated using the two‐compartment pharmacokinetic model which has been used in some earlier comparisons of in vitro and in vivo lithium handling. 4. We suggest that the in vivo administration of lithium carbonate may permit a specific measure of the in vivo activity of the sodium/sodium countertransport pathway.
The potassium channel opening drug cromakalim produces arterioselective vasodilation in the upper limbs of healthy volunteers.
Authors: Webb DJ , Benjamin N , Vallance P
Published: July 2012

1. The effect of the K+ channel opening drug cromakalim on forearm blood flow during direct infusion into the brachial artery, and on the size of noradrenaline preconstricted hand veins during infusion directly into the vein, was studied in eight healthy volunteers. 2. Cromakalim (0.01‐10.0 micrograms min‐1) produced a dose‐dependent increase in blood flow in the infused forearm, from 5.4 +/‐ 2.5 to 15.1 +/‐ 7.3 ml 100 ml‐1 forearm min‐1 at 10 micrograms min‐1 (P less than 0.001). The half‐time of offset of its action was 30 min. There was no change in blood flow in the non‐infused forearm. 3. There was no increase in the size of noradrenaline pre‐constricted dorsal veins during local infusion of cromakalim (0.001‐1.0 microgram min‐1). Glyceryl trinitrate (0.4 microgram min‐1) however, completely reversed the constriction to noradrenaline (P less than 0.001). 4. The clear arterioselectivity of cromakalim, as with other members of this new class of drug, accords with the dependency of venoconstriction on receptor‐operated, rather than potential‐operated mechanisms which are of importance in resistance vessels. With this haemodynamic profile cromakalim may prove of value in the treatment of arterial hypertension.
Bioavailability of hydroxychloroquine tablets in healthy volunteers.
Authors: Tett SE , Cutler DJ , Day RO , Brown KF
Published: July 2012

1. Five healthy volunteers received, in a randomised crossover design study, a 155 mg oral tablet and an intravenous infusion of 155 mg racemic hydroxychloroquine (200 mg hydroxychloroquine sulphate) to assess the bioavailability of the commercially available tablet (Plaquenil, Winthrop Laboratories, Australia). 2. The terminal elimination half‐life of hydroxychloroquine is more than 40 days, thus blood and urine samples were collected for 5 months following each dose to characterise adequately the terminal elimination phase and obtain accurate estimates of the areas under the concentration‐time curves. 3. The mean (+/‐ s.d.) fraction of the oral dose absorbed, estimated from the blood and urine data, was 0.74 (+/‐ 0.13). A wide range of estimates of the fraction of the oral dose absorbed was calculated from the plasma data (0.41 ‐ 1.53), reflecting the difficulties of accurate measurement of hydroxychloroquine in plasma. 4. A period of 6 months is required to achieve 96% of steady‐state levels of hydroxychloroquine with the usual once daily, oral dosage regimen. Pharmacokinetic factors may thus be partly responsible for the delayed action of the drug in rheumatic conditions. 5. Haemodialysis will not aid in the case of oral overdose with hydroxychloroquine. Although the proportionate increase in clearance may be large, the increase in the fraction of the dose excreted will be negligible. The extensive sequestration of the drug by tissues limits effectiveness of haemodialysis.
Inter‐subject variability in the metabolism of proguanil to the active metabolite cycloguanil in man.
Authors: Ward SA , Watkins WM , Mberu E , Saunders JE , Koech DK , Gilles HM , Howells RE , Breckenridge AM
Published: July 2012

1. The metabolism of proguanil to the active metabolite cycloguanil has been evaluated in 135 British Troops and 26 Kenyan schoolchildren. 2. Large inter‐subject variability was observed in both plasma and urinary concentrations of proguanil and cycloguanil after standard doses of drug. 3. Based on the ratio of proguanil to cycloguanil (P/C) in urine the British troops formed a non‐normal distribution. 90% of the population formed a discrete distribution with P/C ranging from 0.5 to 9.0 while the remaining 10% were scattered throughout the distribution to an extreme value of 39. A similar pattern of variability was observed using P/C from a 6 h plasma sample. 4. This variability was due to differences in the ability of individuals to metabolise proguanil to cycloguanil. 5. Thirteen schoolchildren who had experienced malaria during prophylaxis with proguanil and thirteen matched controls each received proguanil (100 mg). We could not discriminate between the two groups based on P/C ratio in either a 6 h plasma or 0‐6 h urine sample.
Differential effects of flurbiprofen and aspirin on acetazolamide disposition in humans.
Authors: Sweeney KR , Chapron DJ , Antal EJ , Kramer PA
Published: July 2012

The plasma concentration‐time profile of acetazolamide (AZ) following an intravenous bolus dose (5 mg kg‐1) was determined during control, aspirin and flurbiprofen (FLU) treatment periods. The unbound fraction of AZ in plasma increased three‐fold in the presence of salicylate (SA) while, in contrast, FLU produced consistent, but statistically insignificant, increases in binding. SA caused a two‐fold decrease in both unbound AZ renal clearance and apparent volume of distribution at steady‐state, while FLU produced a small, but significant, increase only in the latter. The area under the concentration‐time curve for AZ in erythrocytes was increased by about 40% during SA treatment while FLU had no effect. Our results suggest that on a pharmacokinetic basis FLU may be a safer nonsteroidal anti‐inflammatory drug (NSAID) to co‐ administer with AZ.
Interaction between vigabatrin and phenytoin.
Authors: Rimmer EM , Richens A
Published: July 2012

1. The study was designed to determine the mechanism by which vigabatrin causes a fall in plasma phenytoin concentrations when added to the drug therapy of eight epileptic patients. 2. Total plasma phenytoin concentration was measured before and at intervals during 5 weeks' treatment with vigabatrin. 3. Plasma protein binding of phenytoin, the urinary ratio of phenytoin to 5‐(p‐hydroxyphenyl)‐5‐ phenylhydantoin, and antipyrine clearance were measured before and at the end of treatment period. 4. Mean plasma phenytoin concentration fell significantly by 23% during the fifth week. 5. No change was found in any of the other measures. 6. Although an interaction between phenytoin and vigabatrin has been confirmed, the mechanism has not been elucidated.
Effects of vigabatrin on evoked potentials in dogs.
Authors: Arezzo JC , Schroeder CE , Litwak MS , Steward DL
Published: July 2012

1. The purpose of this study was to evaluate possible changes in brain morphology and evoked potentials associated with daily administration of 300 mg kg‐1 vigabatrin in dogs. 2. Somatosensory evoked potentials (SEP) and auditory evoked potentials (AEP) were recorded at baseline and weekly for 12 weeks of treatment and every 2 weeks for 17 weeks of recovery. Morphology was assessed immediately after treatment for two treated dogs and after recovery for the remaining five treated and two control dogs. 3. Vigabatrin produced a significant slowing of the central transmission measure of the SEP with no alteration in the AEP. Vigabatrin was associated with microvacuolation in select regions of the brain including the fornix, septum, optic tract, hypothalamus, thalamus and cortex. In addition, some microglial proliferation was noted. 4. Changes in SEP and the microvacuolation fully recovered after 17 weeks of treatment. 5. The study confirms vigabatrin‐induced microvacuolation in the dog and suggests these changes are associated with functional slowing of conduction in the somatosensory pathways.
Effects of long term vigabatrin on somatosensory evoked potentials in epileptic patients.
Authors: Liegeois‐Chauvel C , Marquis P , Gisselbrecht D , Pantieri R , Beaumont D , Chauvel P
Published: July 2012

1. Vigabatrin has proved to be a very effective antiepileptic in clinical trials, with excellent long term tolerability. 2. The purpose of this study was to test the central nervous system (CNS) safety of the drug during long term clinical use, due to the existence of species‐ dependent intramyelinic oedema in animal toxicology studies. 3. Somatosensory evoked potentials were recorded repeatedly over a mean period of 11 months, in 54 adult patients with refractory epilepsy who received vigabatrin as add‐on therapy to their current antiepileptic regime. 4. There was no suggestion throughout the study that vigabatrin could lead to a prolongation of neuronal conduction times within the CNS pathways. 5. The results are consistent with previous studies of somatosensory, visual and brainstem auditory evoked potentials in patients. In view of the results observed in the dog, where increases in central latencies of somatosensory evoked potentials were clearly apparent, these data provide strong reassurance about the neurological safety of vigabatrin in the treatment of epileptic patients.
The effect of different vigabatrin treatment regimens on CSF biochemistry and seizure control in epileptic patients.
Authors: Ben‐Menachem E , Persson LI , Schechter PJ , Haegele KD , Huebert N , Hardenberg J , Dahlgren L , Mumford JP
Published: July 2012

1. Vigabatrin, 50 mg kg‐1, was administered orally as add‐on therapy to 11 patients with drug‐resistant complex partial epilepsy as a single dose, then once every third day for 2 months, every other day for 2 months and daily for 1 month. 2. Lumbar punctures were carried out prior to treatment and at the end of each dosage regimen and cerebrospinal fluid (CSF) evaluated for concentrations of free and total GABA, homocarnosine (GABA‐histidine dipeptide), homovanillic acid (HVA), 5‐hydroxyindole acetic acid (5‐HIAA) and vigabatrin. 3. Each regimen resulted in significant increases in CSF concentrations of free and total GABA and homocarnosine compared with the immediately preceding regimen. 4. CSF concentrations of HVA significantly increased after a single vigabatrin dose but returned to pre‐treatment levels with subsequent dosing schedules. In contrast, 5‐HIAA concentrations also increased with the single dose but were significantly decreased, compared with pre‐treatment values, following alternate day and daily vigabatrin administration. 5. Seizure frequency progressively decreased with decreasing dosing interval. Daily vigabatrin administration was associated with greater than 50% decrease in seizures in 8 of the 10 patients treated.
Response to vigabatrin in relation to seizure type.
Authors: Michelucci R , Tassinari CA
Published: July 2012

1. The purpose of this study was to evaluate the efficacy of vigabatrin in relation to the seizure type. 2. A review of the literature concerning the efficacy of vigabatrin in clinical trials was performed. 3. To date, vigabatrin has been used in a small number of patients with generalized seizures: in this group no significant effect was noted. 4. Vigabatrin was also given to a large number of patients with complex partial seizures: in this group vigabatrin produced a greater than 50% decrease in seizure frequency in almost 50% of patients included. 5. This review provides evidence that vigabatrin is effective in the treatment of complex partial seizures: patients with only one seizure type, low seizure frequency and unifocal EEG abnormalities are particularly expected to respond. 6. This implies that patients with complex partial seizures do not constitute an homogeneous group and that various parameters should be considered in the evaluation of the response to treatment.
Cardiovascular responses to metipranolol and timolol eyedrops in healthy volunteers.
Authors: Bacon PJ , Brazier DJ , Smith R. , Smith SE
Published: July 2012

1. Intraocular pressure and cardiovascular responses to metipranolol 0.1% and 0.3% and timolol 0.25% eyedrops were measured in a balanced single dose placebo‐controlled crossover study in eight healthy volunteers aged 34‐58 years. 2. Timolol 0.25% and metipranolol 0.3% reduced intraocular pressure throughout the 6 h period of observation to a similar extent. Metipranolol 0.1% was marginally less effective, significantly reducing pressure up to 4 h only. 3. No drug treatment significantly altered resting heart rate or blood pressure. Timolol 0.25% significantly reduced exercise tachycardia (P less than 0.05), an effect which was not shown by metipranolol 0.1 or 0.3%. Exertional pain in the legs occurred more frequently after timolol 0.25% and metipranolol 0.3% than after metipranolol 0.1% or placebo eyedrops. 4. Octan‐1‐ol/pH 7.4 buffer distribution coefficients at 37 degrees C were found to be: metipranolol 5.19, timolol 0.84, indicating that metipranolol has an approximately 6‐fold greater lipid solubility. 5. It is concluded that, by comparison with timolol, metipranolol in eyedrop concentrations up to 0.3%, despite its greater lipid solubility, reaches concentrations in the systemic circulation which are less likely to affect the heart.
Alfuzosin and the venous reflex response: studies in normal subjects.
Authors: Sinclair AJ , Davies IB , Warrington SJ
Published: July 2012

1. Alfuzosin is a post‐synaptic alpha‐adrenoceptor antagonist with antihypertensive and peripheral vasodilator properties. 2. We measured the effect of alfuzosin, 5 mg, on sympathetically‐mediated venoconstriction by changes in the venous reflex response (VRR) in a randomised, double‐blind, placebo‐controlled, crossover study in a group of 10 healthy volunteers. 3. There was a significant inhibition of the VRR after alfuzosin compared with placebo (P less than 0.001) which was present 1 h after the dose and still evident at 6 h. 4. Supine blood pressure was significantly lower (P less than 0.01) and supine heart rate was significantly higher (P less than 0.001) after alfuzosin compared with placebo. 5. Inhibition of the VRR by alfuzosin was observed to precede the development of reflex tachycardia.
Lisinopril population pharmacokinetics in elderly and renal disease patients with hypertension.
Authors: Thomson AH , Kelly JG , Whiting B.
Published: July 2012

1. The population pharmacokinetics of lisinopril were investigated using data collected from two multicentre trials of lisinopril in the treatment of hypertension in elderly patients (n = 40) and patients with renal disease (n = 20). 2. Lisinopril was started at doses of 2.5‐ 5 mg daily and increased at 2‐4 weekly intervals as required for control of blood pressure. Steady‐state concentration‐time profiles were measured after at least 2 weeks at a constant dose. 3. All concentration‐time data were analysed simultaneously using the program NONMEM and the influence of clinical factors on clearance/F and volume of distribution/F was tested. 4. Clearance was significantly influenced by creatinine concentration, age, weight and cardiac failure. No clinical features tested were found to influence volume of distribution. 5. The influence of renal function and cardiac failure on lisinopril clearance has been confirmed using a population pharmacokinetic analysis technique.
Pharmacokinetics of felodipine in patients with impaired renal function.
Authors: Edgar B. , Regardh CG , Attman PO , Aurell M. , Herlitz H. , Johnsson G.
Published: July 2012

1. The pharmacokinetics of felodipine and its effects on blood pressure and heart rate were studied in eight male patients aged between 28 and 57 years with a glomerular filtration rate, GFR, between 8 and 68 ml min‐1, following single i.v. and oral administration. 2. Clearance, Cmax, AUC, Vss and V, of felodipine were unaffected by the renal disease. The metabolite excretion (14C‐labelled) was slower than in healthy subjects. Initial renal clearance of these metabolites correlated with individual GFR values. The total amount of the dose excreted in the urine was also decreased.
Rate‐controlled rectal absorption enhancement of cefoxitin by co‐ administration of sodium salicylate or sodium octanoate in healthy volunteers.
Authors: Van Hoogdalem EJ , Wackwitz AT , De Boer AG , Cohen AF , Breimer DD
Published: July 2012

1. The effects of sodium octanoate and sodium salicylate on the rectal absorption of cefoxitin were investigated in healthy volunteers. Drug solutions were given either as a bolus or as a zero‐order infusion. 2. On rectal infusion sodium octanoate and sodium salicylate both enhanced mean cefoxitin bioavailability (+/‐ s.d.) from 5.0 +/‐ 1.2% to 9.1 +/‐ 1.3% and 9.2 +/‐ 1.5%, respectively. After rectal bolus delivery octanoate increased the mean cefoxitin bioavailability from 7 +/‐ 3% to 17 +/‐ 3%, whereas bolus salicylate did not produce a statistically significant effect. All formulations were well tolerated by the volunteers. 3. It is concluded that both octanoate and salicylate are capable of enhancing rectal cefoxitin absorption in man; rate of delivery seems to be an important factor.
A comparison of the influence of famotidine and cimetidine on phenytoin elimination and hepatic blood flow.
Authors: Sambol NC , Upton RA , Chremos AN , Lin ET , Williams RL
Published: July 2012

The H2‐receptor antagonist cimetidine has been reported to decrease the hepatic clearance of numerous drugs by inhibiting cytochrome P‐450 metabolism, decreasing liver blood flow or both. In this open‐label, randomized crossover study we determined whether therapeutic doses of famotidine, a newer H2‐receptor antagonist, has similar effects. Ten healthy subjects received single doses of both phenytoin 100 mg orally and indocyanine green intravenously without other treatment, and then again during treatment with famotidine or cimetidine. After a drug‐free period, this sequence was repeated with the alternate H2‐receptor antagonist. Cimetidine decreased the plasma clearance of phenytoin by 16% +/‐ 14% (mean +/‐ s.d.), but was not found to have a significant influence on phenytoin volume of distribution or terminal elimination rate constant nor on blood clearance of indocyanine green. Famotidine was not found to alter either phenytoin or indocyanine green kinetics.
The effect of disodium cromoglycate and ketotifen on the excretion of histamine and N tau‐methylimidazole acetic acid in urine of patients with mastocytosis.
Authors: Mallet AI , Norris P. , Rendell NB , Wong E. , Greaves MW
Published: July 2012

Treatment of four mastocytosis patients with the mast cell stabilising drugs, disodium cromoglycate and ketotifen failed to alter significantly the urinary excretion levels of histamine or N tau‐ methylimidazole acetic acid. No clinical improvement was noted in any subject after treatment by either drug.
Pharmacological characterization of histamine receptors in the human temporal artery.
Authors: Ottosson A. , Jansen I. , Edvinsson L.
Published: July 2012

1. The subtypes of histamine‐receptors which mediate dilatation of small human temporal arteries have been characterized in vitro using 'selective' agonists and antagonists. 2. Dilatory responses were studied after preconstriction with prostaglandin F2 alpha since contraction was not seen at histamine concentrations up to 10(‐4) M. Histamine caused a concentration‐related relaxation of cerebral vessels with an IC50 value of 2.8 +/‐ 0.6 X 10(‐7) M. 3. Cimetidine caused a parallel shift to the right of the histamine concentration‐response curve whereas mepyramine was without observable effect. This suggests the presence of histamine H2‐receptors only. However, combined treatment with mepyramine and cimetidine caused a more marked displacement of the concentration‐response curve to the right. Schild analysis indicated that in situations of near complete blockade of the histamine H1‐receptor subtypes, simple competitive antagonism at H2‐ receptors can be revealed with a pA2 value of 6.58 for cimetidine. The apparent pA2 value for mepyramine was 8.58. 4. The 'selective' H1‐ receptor agonists pyridylethylamine, 2‐methylhistamine and thiazolylethylamine, and the H2‐receptor agonists dimaprit, impromidine and 4‐methylhistamine all mimicked the histamine response, but all except impromidine were less potent than histamine. The order of potency was impromidine greater than thiazolylamine greater than 4‐Me‐ histamine greater than 2‐Me‐histamine greater than dimaprit greater than pyridylethylamine greater than tele‐Me‐histamine. 5. These results indicate that the histamine‐induced dilatation in small human temporal arteries is mediated by both H1‐ and H2‐receptors and that the latter subtype of histamine receptors predominates.
The effects of lisuride, terguride and bromocriptine on intraocular pressure (IOP).
Authors: Al‐Sereiti MR , Turner P.
Published: July 2012

1. The effects of a single oral dose of the dopaminergic agonists lisuride (0.1 mg), terguride (0.25 mg) and bromocriptine (1.25 mg) on IOP were studied in eight normal volunteers using the non‐contact tonometer. 2. Considering all post‐dose measurements, compared with placebo, bromocriptine and lisuride but not terguride reduced IOP significantly in both eyes. 3. There was no significant difference between the ocular hypotensive effect of bromocriptine and lisuride. 4. Terguride reduced IOP significantly in the left eye at the 3 h time point after drug administration. 5. The result of this study confirms the reported ocular hypotensive effect of bromocriptine and showed that lisuride is as effective as bromocriptine in reducing IOP. 6. To evaluate the clinical importance of these drugs as ocular hypotensive agents other studies are needed using eye drops.
Oral absorption profile of nitrendipine in healthy subjects: a kinetic and dynamic study.
Authors: Soons PA , de Boer AG , van Brummelen P. , Breimer DD
Published: July 2012

1. In nine healthy male subjects the kinetics of nitrendipine were assessed after i.v. administration and its absorption profile was studied when given by a tablet formulation and by an osmotic pumping device (Osmet) with a zero‐order in vitro release of 2.62 +/‐ 0.19 mg h‐ 1 for 13 h. 2. Plasma concentrations of nitrendipine and its pyridine metabolite, heart rate and blood pressure were determined at regular intervals after drug administration. 3. After i.v. nitrendipine, the plasma concentration declined triexponentially with a mean terminal elimination half‐life of 11.7 +/‐ 5.4 h. The mean systemic plasma clearance was 1.47 +/‐ 0.22 l min‐1. 4. Administration of the Osmet resulted in a relatively smooth plasma concentration‐time profile in comparison with the tablet. The mean plateau concentration was 2.63 +/‐ 1.31 ng ml‐1 and the duration of this plateau was 10.7 +/‐ 3.2 h. The intake of food gave rise to a transient increase of the plasma concentration of both nitrendipine and its pyridine metabolite. 5. The mean bioavailability of nitrendipine from the Osmet (8.2 +/‐ 1.6%) was lower than from the tablet (11.1 +/‐ 4.5%), which is probably due to release of nitrendipine in lower parts of the G.I. tract where absorption is not or less possible. 6. Intravenous administration caused a transient decrease in DBP of 26 +/‐ 4%, accompanied by a maximal reflex tachycardia of 46 +/‐ 17%. No clear haemodynamic effects were observed after oral administration. The Osmet produced less side‐ effects (headache) than the tablet.
Dextromethorphan: polymorphic serum pattern of the O‐demethylated and didemethylated metabolites in man.
Authors: Mortimer O. , Lindstrom B. , Laurell H. , Bergman U. , Rane A.
Published: July 2012

1. The interindividual differences in serum concentrations of dextromethorphan (DM) and its metabolites were studied in 29 healthy subjects given 120 mg orally. They were also phenotyped according to the urinary ratio of debrisoquine and 4‐hydroxy‐debrisoquine. 2. Four (14%) subjects were found to be poor metabolizers (PM) with a dextromethorphan/dextrorphan metabolite ratio in plasma of 3.6 or more compared with extensive metabolizers (EM) with a ratio of 0.11 or less. Significant levels of 3‐hydroxymorphinan were measurable in all individuals except two, both of whom were PMs. This subdivision corresponded to the phenotype determined by the metabolic ratio of debrisoquine (r = 0.92). 3. Twelve of the 29 subjects reported adverse drug reactions after dextromethorphan administration compared with none after placebo.
Inhibition of monoamine oxidase by moclobemide: effects on monoamine metabolism and secretion of anterior pituitary hormones and cortisol in healthy volunteers.
Authors: Koulu M. , Scheinin M. , Kaarttinen A. , Kallio J. , Pyykko K. , Vuorinen J. , Zimmer RH
Published: July 2012

1. Single oral doses (100, 200 and 300 mg) of moclobemide, a reversible inhibitor of monoamine oxidase (MAO) with predominant effects on the A‐ type of the enzyme, were administered to eight young, healthy male volunteers in a double‐blind, random‐order, placebo‐controlled study. The investigation was thereafter continued in an open fashion by administering a single 10 mg dose of the MAO‐B inhibitor deprenyl to the same subjects. 2. Deamination of catecholamines was powerfully and dose‐dependently inhibited by moclobemide, as evidenced by up to 40% decreases in the urinary excretion of deaminated catecholamine metabolites, corresponding increases in the excretion of non‐ deaminated, methylated metabolites, and up to 79% average decreases in the plasma concentration of 3,4‐dihydroxyphenylglycol (DHPG), a deaminated metabolite of noradrenaline (NA), and up to 75% average decreases in the plasma concentrations of 3,4‐dihydroxyphenylacetic acid (DOPAC), a deaminated metabolite of dopamine. The urinary excretion of 5‐hydroxyindoleacetic acid (5‐HIAA) was only slightly reduced. In contrast, deprenyl, in a dose which almost totally inhibited MAO‐B activity in blood platelets, did not appreciably affect the plasma concentrations of DHPG or DOPAC. 3. Due to the rapid, reversible, dose‐dependent and MAO‐A specific effect of moclobemide on plasma concentrations of DHPG, it is suggested that DHPG in plasma may be a useful indicator of the magnitude and duration of MAO‐A inhibition in man. 4. Sympatho‐adrenal function at rest was not significantly altered by moclobemide, as judged by unchanged plasma catecholamine concentrations and stable blood pressure and heart rate recordings. 5. Monoamine oxidase type B activity in blood platelets was slightly (less than 30%) and transiently inhibited after moclobemide. 6. The secretion of prolactin was dose‐dependently stimulated by moclobemide, whereas the plasma concentrations of growth hormone (hGH) and cortisol remained unchanged.
Lack of effect of paracetamol on the pharmacokinetics of chloramphenicol.
Authors: Stein CM , Thornhill DP , Neill P. , Nyazema NZ
Published: July 2012

The effect of oral paracetamol (1 g) on the pharmacokinetics of oral chloramphenicol (500 mg) was examined in five adult male Zimbabwean patients with normal hepatic and renal function. No significant alteration of half‐life, area under the concentration‐time curve or peak concentration of chloramphenicol was observed. The previously reported, potentially serious interaction between chloramphenicol and paracetamol administered intravenously was not observed with the more commonly used oral preparations.
Effects of atenolol vs diltiazem on the haemodynamic effects of an inhaled beta 2‐adrenoceptor agonist.
Authors: Chapman KR , Galko BM , Smith DL , Leenen FH
Published: July 2012

To determine the effects of concurrent beta 1‐adrenoceptor blocker or calcium channel antagonist administration on the haemodynamic sequelae of an inhaled beta 2‐selective adrenoceptor agonist bronchodilator, we examined echocardiographically the effects of fenoterol (400 micrograms) by metered dose inhaler following oral pre‐treatment with (a) placebo, (b) atenolol or (c) diltiazem. Following placebo, fenoterol produced significant decreases in diastolic blood pressure (14% +/‐ 6%), total peripheral vascular resistance (TPR) (31% +/‐ 9%) and end‐systolic stress (ESS) (15% +/‐ 21%). Cardiac output rose significantly (42% +/‐ 23%) as did heart rate (25% +/‐ 13%). After atenolol, responses to fenoterol were significantly blunted. Post‐ fenoterol heart rate, systolic blood pressure, % fractional shortening, stroke volume, ejection fraction, cardiac output and pressure/volume ratio increased significantly less after atenolol pre‐treatment as compared to placebo pretreatment. TPR decreased significantly less. After diltiazem pre‐treatment, the response to inhaled fenoterol was not different from that following placebo pre‐treatment. We conclude that atenolol blunts the haemodynamic changes induced by fenoterol inhalation whereas diltiazem has little effect.
Substantial rise in sparteine metabolic ratio during haloperidol treatment.
Authors: Gram LF , Debruyne D. , Caillard V. , Boulenger JP , Lacotte J. , Moulin M. , Zarifian E.
Published: July 2012

A sparteine test was carried out in 14 patients suffering from acute schizophrenic psychoses before and 1‐2 times during oral haloperidol treatment in doses of 10‐40 mg day‐1. In patients classified as extensive metabolisers (sparteine MR less than 20 before treatment), haloperidol treatment resulted in a rise in sparteine MR that correlated with the serum‐haloperidol concentration both within and between patients. At the highest serum haloperidol concentrations (60‐ 80 nM) an increase in sparteine MR by a factor 15‐50 was seen, but no patients were transformed into phenotypically poor metabolisers. The steady state concentration of haloperidol on the initial standard dose of 10 mg day‐1 was the same in one patient classified as a sparteine poor metaboliser (MR = 112) as in eleven patients classified as extensive metabolisers (MR:0.22‐1.47).
Seasonal variation in responsiveness of human eccrine sweat glands to phenylephrine.
Authors: Banjar WM , Bradshaw CM , Szabadi E.
Published: July 2012

The responses of eccrine sweat glands to intradermally injected phenylephrine were studied in six healthy male volunteers in two experiments carried out in February and June. Phenylephrine (10(‐7)‐10(‐ 2) M, 50 microliters) had no consistent effect on sweat gland activity during February, but evoked dose‐related increases in sweat gland activity during June. Responsiveness to phenylephrine could be antagonized by prazosin (10(‐5) and 10(‐4) M) added to the injection solution.
A controlled evaluation of a homoeopathic preparation in the treatment of influenza‐like syndromes.
Authors: Ferley JP , Zmirou D. , D'Adhemar D. , Balducci F.
Published: July 2012

1. A controlled clinical trial was conducted to assess the effectiveness of a homoeopathic preparation in the treatment of influenza‐like syndromes. 2. 237 cases received the test drug and 241 were assigned to placebo. Patients recorded their rectal temperature twice a day, and the presence or absence of five cardinal symptoms (headache, stiffness, lumbar and articular pain, shivers) along with cough, coryza and fatigue. 3. Recovery was defined as a rectal temperature less than 37.5 degrees C and complete resolution of the five cardinal symptoms. 4. The proportion of cases who recovered within 48 h of treatment was greater among the active drug group than among the placebo group (17.1% against 10.3%, P = 0.03). 5. The result cannot be explained given our present state of knowledge, but it calls for further rigorously designed clinical studies.
The effects of intradermal bradykinin are potentiated by angiotensin converting enzyme inhibitors in hypertensive patients.
Authors: Ferner RE , Wilson D. , Paterson J.R. , Wilkinson R. , Rawlins MD
Published: July 2012

1. To test the hypothesis that angiotensin converting enzyme (ACE) inhibitors potentiate the tissue effects of bradykinin, the thickness of weals produced by intradermal injections of bradykinin was measured in 17 hypertensive subjects whose antihypertensive regimen included an ACE inhibitor, and in 12 whose treatment did not. 2. Weal thickness increased linearly with the logarithm of the bradykinin dose in both groups (P less than 0.0001). 3. The patients receiving ACE inhibitors showed a mean response of 1.18 +/‐ 0.08 mm (mean +/‐ s.e. mean), compared with a mean response of 0.75 +/‐ 0.08 mm for patients not receiving an ACE inhibitor (P = 0.002). Mean weal response (1.08 +/‐ 0.9 mm) was not significantly different in patients taking captopril (n = 11) compared with that (1.29 +/‐ 0.12 mm) in patients taking enalapril (n = 9). 4. Facial flushing during the experiment occurred in six patients taking ACE inhibitors but none who were not. 5. Dermal responses to bradykinin are enhanced in patients taking ACE inhibitors as routine antihypertensive therapy. This study supports the hypothesis that bradykinin may be responsible for some of the adverse effects of these drugs.
Pharmacokinetics of cyclosporin: influence of rate‐duration profile of an intravenous infusion in renal transplant patients.
Authors: Gupta SK , Bakran A. , Johnson RW , Rowland M.
Published: July 2012

1. The pharmacokinetics of cyclosporin were studied in six renal transplant patients, following intravenous administration of 5 mg kg‐1 infused over 3, 6 and 24 h. 2. Plasma, separated at 37 degrees C, was analysed for cyclosporin by h.p.l.c. 3. The data were described by a biexponential disposition model. 4. None of the disposition parameters (clearance, initial volume of distribution, half‐lives) changed with the duration of infusion.
24 h blood pressure control with the once daily calcium antagonist, amlodipine.
Authors: Heber ME , Brigden G. , Al‐Khawaja I. , Raftery EB
Published: July 2012

1. Amlodipine is a novel calcium antagonist which, although pharmacologically similar to other dihydropyridine calcium antagonists, has a long plasma half‐life, permitting steady state blood levels to be achieved with a once‐daily dose regimen. 2. We have performed a study to examine the effects of this drug on the blood pressure of hypertensive patients over a 24 h period. After a placebo run‐in, the drug was administered to 11 patients at a starting dose of 5 mg, and increased to 10 mg after 2 weeks of treatment if the cuff diastolic blood pressure response was unsatisfactory. Cuff measurements were made at entry, after 2 weeks treatment with placebo, after 2 weeks on amlodipine 5 mg once daily, and after a further 4 weeks on amlodipine 5 mg or 10 mg once daily. Intraarterial blood pressure recordings were made at the end of the placebo phase and at completion of the study. 3. Mean supine blood pressure measured sphygmomanometrically was 168/103 (n = 11) mm Hg at entry, 169/104 (n = 11) mm Hg at the end of the placebo phase, 153/95 (n = 11) mm Hg after 2 weeks of treatment and 146/92 (n = 11) mm Hg at the end of the study. Blood pressure curves plotted for each phase of the study revealed an effective 24 h duration of action. Mean daytime blood pressure was reduced from 165/103 to 147/89 mm Hg (P less than 0.05, n = 10), and mean night‐time blood pressure was reduced from 137/79 to 121/69 mm Hg (P less than 0.05, n = 10).(ABSTRACT TRUNCATED AT 250 WORDS)
An investigation of premedication with morphine given by the buccal or intramuscular route.
Authors: Simpson KH , Tring IC , Ellis FR
Published: July 2012

1. Premedication with 30 mg buccal morphine or 10 mg intramuscular morphine was evaluated in 40 healthy women undergoing major gynaecological surgery. 2. Buccal administration of morphine produced lower plasma morphine concentrations than intramuscular injection of morphine (P less than 0.01). 3. The mean systemic availability of the buccal tablet, during the first 5 h after administration, was approximately 3% relative to that of the intramuscular preparation. 4. Poor absorption of buccal morphine resulted in inadequate sedation prior to surgery and poor post‐operative analgesia. 5. Patients experienced difficulty with the buccal formulation of morphine; tablet bitterness and failure to dissolve were particular problems.
Captopril: a free radical scavenger.
Authors: Chopra M. , Scott N. , McMurray J. , McLay J. , Bridges A. , Smith WE , Belch JJ
Published: July 2012

The use of captopril in heart failure and hypertension is becoming increasingly accepted. Captopril has a sulphydryl group in its molecular structure. We wondered if this might confer free radical scavenging activity on the drug and have investigated this in an in vitro system. Results show that captopril is a free radical scavenger and we suggest that this action might be relevant in its use in heart failure and other vascular diseases.