bluuebunny/crossref_metadata_2025 huggingface dataset:
Propranolol LA and ambulatory blood pressure.
Authors: Mann S , Craig MW , Balasubramanian V , Raftery EB
Published: July 2012

1 The technique of continuous recording of intra‐arterial blood pressure in ambulant hypertensives has been used to investigate the effects of a long‐acting formulation of propranolol (propranolol LA). 2 Seven subjects with untreated essential hypertension were studied before and 2 months after commencing treatment with propranolol LA once daily in the morning, results showing that smooth control of blood pressure and heart rate occurred throughout 24 h. 3 Bicycle ergometry tests performed by these subjects during both studies showed significant blood pressure reduction by propranolol LA during the mild and moderate grades of dynamic exercise. 4 In a parallel study where six treated hypertensives were monitored before and after substitution of standard propranolol by the ‘LA’ form, close correspondence of blood pressure throughout the 24 h occurred with each regimen.
Methyl conjugation in uraemia: catechol‐O‐methyltransferase.
Authors: Pazmino PA , Weinshilboum RM
Published: July 2012

1 Erythrocyte (RBC) catechol‐9‐methyltransferase (COMT) activity is significantly higher in erythrocytes from uraemic patients on maintenance haemodialysis, 18.7 +/‐ 1.4 units/ml RBC (mean +/‐ s.e. mean, n = 22) than in the blood of randomly selected subjects, 12.0 +/‐ 0.2 units/ml (mean +/‐ s.e. mean, n = 557, P < 0.001). 2 Uraemic plasma contains larger quantities of endogenous methyl acceptors than does normal plasma, and it reversibly inhibits RBC lysate COMT activity to a greater degree than does normal plasma. 3 There are large individual variations in the degree of inhibition of RBC COMT activity plasma from patients with renal failure. Inhibition varied from 10‐43% when 40 microliters plasma from each of 19 randomly selected uraemic patients was tested, and there as a direct correlation between the inhibition of COMT by plasma from an individual uraemic patient and its content of endogenous methyl acceptors (r = 0.64, n = 19, P < 0.01). 4 Kinetic studies with pooled uraemic plasma demonstrate that inhibition of COMT by uraemic plasma is uncompetitive with respect to both the catechol substrate and the methyl donor for the reaction, S‐adenosyl‐L‐ methionine. 5 Plasma from uraemic patients does not inhibit partially purified rat liver COMT, an observation which suggests that the inhibition is not due to a direct effect on COMT but requires the presence of other constituents of the RBC lysate, perhaps other methyltransferase enzymes.
Clinical and pathological aspects of analgesic nephropathy.
Authors: Nanra RS
Published: July 2012

1 Analgesic nephropathy is part of the analgesic syndrome which has gastrointestinal, haematological, cardiovascular, psychological and psychiatric, and pregnancy and gonadal manifestations; premature ageing may also be a feature. 2 Analgesic nephropathy is a form of renal disease characterized by renal papillary necrosis, secondary chronic interstitial nephritis and renal failure with features of predominant tubulointerstitial dysfunction. 3 The percentage of patients with analgesic nephropathy who present with terminal renal failure is 12%. With appropriate management, 17% of analgesic nephropathy patients improve, 50% remain stable and 23% deteriorate. The 6 year cumulative survival is 70%. The major factors influencing deterioration are malignant hypertension, persistent proteinuria and small initial renal size. 4 The risk of renal papillary carcinoma in patients who regularly take analgesics is 8 per 100,000 patients per year. 5 Renal papillary necrosis is a consequence of the chronic toxicity of all non‐steroidal anti‐inflammatory drugs and results from medullary ischaemia secondary to suppression of prostaglandin E2 synthesis and from direct cellular toxicity. 6 Analgesic nephropathy is a preventable form of renal disease and renal failure. It can be prevented by limiting the abuse potential of analgesics rather than by making minor modifications in the composition of analgesic mixtures.
Abuse and paradoxical effects of analgesic drug mixtures.
Authors: Worz R
Published: July 2012

1 In patients with chronic pain, two types of analgesic drug dependence occur, that is, dependence of the barbiturate‐type and of the morphine‐ type. Eighty cases of analgesic drug dependence of the barbiturate‐type were examined. All these patients were dependent on drug combinations, not a single patient being on one analgesic alone. 2 Psychotropic agents were found to be the common pharmacological denominator of all abused preparations. These findings confirm the hypothesis that the addition of psychotropic or dependence‐producing substances to analgesics is the crucial factor in the complex of mild analgesic drug abuse. 3 One group of patients with chronic pain, who were dependent on analgesic drug mixtures, had both lowered experimental pain thresholds and tolerances. After drug withdrawal, these parameters showed a tendency to increase in some patients.
Metabolism of salicylate during chronic aspirin therapy.
Authors: Rumble RH , Brooks PM , Roberts MS
Published: July 2012

1. The effects of chronic administration of aspirin in therapeutic doses (3.9 g/day) on plasma and salivary salicylate levels were studied in eight subjects. 2. The urinary excretion profile for free salicylic acid and metabolites of salicylate were examined. 3. Plasma and salivary salicylate levels declined significantly after peak levels were achieved between days 3 and 10. 4. The decline in plasma and salivary salicylate levels may be due to an induction of a metabolic pathway such as salicylurate formation (Furst, Gupta & Paulus, 1977). Only the mean fraction of salicylate excreted as salicylurate appears to increase with time during the present study, although the change was not significant statistically. 5. The decline in plasma and salivary salicylate levels during chronic therapy may lead to an apparent ‘tolerance’ of some rheumatoid patients to aspirin.
Observations on the muscle abnormality of the human sigmoid colon in diverticular disease.
Authors: Rees BI , Bond J , Spriggs TL , Hughes LE
Published: July 2012

1 Pharmacological experiments were performed on circular and longitudinal muscle strips of sigmoid colon from diverticular disease specimens, and their responses compared with those of similar muscle strips from sigmoid colon resected from carcinoma (control). 2 The longitudinal muscle strips from diverticular disease specimens were significantly less responsive to acetylcholine, histamine or noradrenaline than control longitudinal muscle strips. 3 The responses of the diverticular circular muscle strips showed a small decrease to acetylcholine, a small increase to noradrenaline and no change to histamine when compared to control strips.
Effect of sulphinpyrazone on human platelet aggregation, 5‐ hydroxytryptamine release and adhesion ex vivo: comparison with naproxen.
Authors: Nunn B , James FJ
Published: July 2012

1 The effects of single doses of naproxen and sulphinpyrazone and of 4 and 8 days treatment with sulphinpyrazone on human platelet responsiveness were compared. 2 A single dose of sulphinpyrazone had no effect whereas a single dose of naproxen caused a five‐fold depression in responsiveness to collagen. 3 Repeated administration of sulphinpyrazone led to a weak and equivocal inhibitory effect on collagen‐induced aggregation, second phase aggregation in response to ADP and adhesion to collagen. There was no effect on ADP‐induced first phase aggregation, adrenaline‐induced second phase aggregation or platelet retention in glass bead columns. 4 It is concluded that the anti‐aggregant activity of sulphinpyrazone is too weak to be a major factor in its reported effect on the incidence of cardiac death.
Antihypertensive effect of guanfacine: a double‐blind cross‐over trial compared with clonidine.
Authors: Distler A. , Kirch W. , Luth B.
Published: July 2012

1. Sixteen patients with essential hypertension were treated with guanfacine and with clonidine for 5 weeks each in a double‐blind, placebo‐controlled, cross‐over trial. Dosage ranged from 2 to 6 mg guanfacine and from 0.3 to 0.9 mg clonidine daily in two or three divided doses. 2. Both compounds caused a significant and comparable decrease in blood pressure. Patients whose blood pressure was not reduced to normal by 2 to 3 mg guanfacine daily did not respond better to an increase in the dose. 3. Dryness of the mouth and constipation occurred with about equal frequency with both agents, but sedation and orthostatic circulatory effects were considerably more frequent with clonidine. 4. A withdrawal syndrome was observed on discontinuation of clonidine in one patient as opposed to no rebound hypertension on stopping guanfacine treatment. 5. Guanfacine caused a significant decrease in plasma noradrenaline and adrenaline, suggesting a decrease in sympatho‐adrenal activity.
Evaluation of long‐term treatment of essential hypertension with guanfacine.
Authors: Higuchi M. , Overlack A. , Stumpe KO
Published: July 2012

1. Twenty‐two patients with moderately severe essential hypertension were treated for a period of 12 months with guanfacine (BS 100‐141), a new centrally‐acting antihypertensive agent. A twice daily schedule was followed and the dose range of guanfacine was 1‐8 mg daily. 2. In twenty patients satisfactory blood pressure responses (diastolic pressure below 95 mmHg) were achieved in both the supine and the standing position. Pulse rate decreased slightly, though not significantly. 3. Tolerance to the pressure‐lowering effect of the drug developed during the third or fourth month of therapy. This could be overcome by either increasing dosage or adding a diuretic. 4. All patients reported side‐effects, mainly dryness of the mouth and fatigue. These side‐effects became less or disappeared at the end of 3 months. Rebound hypertension on discontinuation of therapy occurred in two patients. 5. Plasma concentrations of noradrenaline and adrenaline as well as plasma renin activity were decreased after 1 week of treatment with the drug. 6. Guanfacine in conjunction with a diuretic is a useful drug in the long‐term treatment of hypertension. Reduced central sympathetic outflow may be the major mechanism underlying the antihypertensive effect of the drug.
Guanfacine in the treatment of hypertension due to pre‐eclamptic toxaemia in thirty women.
Authors: Philipp E.
Published: July 2012

1. Thirty pregnant women aged 22‐34 yr presenting with pre‐eclampsia were treated with guanfacine for periods of 16‐68 days. 2. Elevated blood pressure was lowered to a statistically and clinically significantly extent in the first week of treatment, falling almost to normal levels before parturition in 24 cases. Four days after delivery all the patients had normal blood pressures. 3. Oedema (localized or generalized) was not reduced to any extent by guanfacine and additional treatment was necessary in 17 cases. There was little effect on proteinuria. 4. Twenty‐five patients reported side‐effects attributable to the treatment (sedation in 25 cases, dryness of the mouth in 15, and feelings of dizziness in 6 cases). 5. No notable changes were observed in either foetal or maternal heart rate during the period of treatment. Of the 30 deliveries, 19 were spontaneous, 5 by vacuum extraction, and 6 were by Caesarean section because of suspected placental insufficiency. Six of the infants were 'small‐for‐date babies', but all developed normally later.
The pharmacokinetics of methimazole in pregnant patients after oral administration of carbimazole.
Authors: Skellern GG , Knight BI , Otter M. , Low CK , Alexander WD
Published: July 2012

1 A high performance liquid chromatographic (HPLC) method was used to study the pharmacokinetics of methimazole after oral administration of carbimazole to women in various stages of pregnancy. 2 In one patient it was possible to conduct the study in the first and third timesters: there was an appreciable increase in the apparent clearance of methimazole. 3 Based on the assumption of complete absorption and hydrolysis of carbimazole to methimazole the mean apparent clearance was found to be significantly higher in pregnant patients receiving 10 mg carbimazole than in non‐pregnant patients receiving the same dose.
Elevated blood histamine levels and mast cell degranulation in solar urticaria.
Authors: Hawk JL , Eady RA , Challoner AV , Kobza‐Black A. , Keahey TM , Greaves MW
Published: July 2012

1 Ultraviolet radiation (UVR)‐induced wealing was studied in four patients with solar urticaria, whose measured action spectra were within the range 300 to 700 nm. 2 Elevated histamine levels were found in blood draining wealed skin in all four patients. 3 Histological and electron microscopial studies of the irradiated skin showed evidence of mast cell degranulation. 4 These findings demonstrate an association between histamine release from mast cells and wealing in solar urticaria, and should encourage evaluation of drugs which suppress histamine release in this disorder.
Ideal sampling time for drug assays.
Authors: Nicholson PW , Dobbs SM , Rodgers EM
Published: July 2012

Estimation of the mean steady state serum concentration of a drug from an isolated sample apparently requires a knowledge of both the timing of the sample within the dose interval and of the pharmacokinetic constants of the drug in the individual. Data from 80 general medical outpatients receiving maintenance digoxin has been used to derive a relationship between the serum digoxin concentration at any given time (C) and the mean steady state concentration (C), but this did not allow for individual variation in drug handling. It can be demonstrated theoretically that, for a one compartment model with instantaneous drug distribution and first order elimination, the ratio, C/C, is dependent on the half time of the drug, the dose interval and the time of sampling. Moreover, for higher values of half time the ratio is virtually constant at 11 h after a daily dose. This, then, would be an ideal sampling time. The above approach can be extended to any drug provided that its half time is at least 15 h in healthy subjects and that the concentration/time curve approximates to a simple exponential decay during virtually the entire dose interval. Orally administered digoxin meets both of these provisions, the ratio at 11 h being 0.97, which is only slightly different from the 1.02 of the theoretical model. Ideal sampling times and the conditions under which they apply may be derived for other dose intervals.
Metabolic and cardiovascular side effects of the beta 2‐adrenoceptor agonists salbutamol and rimiterol.
Authors: Phillips PJ , Vedig AE , Jones PL , Chapman MG , Collins M. , Edwards JB , Smeaton TC , Duncan BM
Published: July 2012

The metabolic and cardiovascular side‐effects of intravenous infusions of therapeutic doses of beta 2‐adrenoceptor agonists salbutamol and rimiterol have been determined in four healthy male subjects. There were dose‐related increases in plasma glucose, renin activity, serum insulin and heart rate, and significant hyperlactataemia and ketonaemia. There were dose‐related decreases in plasma potassium, phosphate and corticosteroids and significant hypocalcaemia and hypomagnesaemia. The effects of equivalent molar amounts of salbutamol and rimiterol were similar. Whichever drug is used, special care is required with patients who may have abnormal glucose tolerance, potassium depletion, or be predisposed to lactic acidosis. Rimiterol may be preferable for infusion because of its short plasma half‐life.
Measurement of drug dosage intensity in MVPP therapy in Hodgkin's disease.
Authors: Green JA , Dawson AA , Fell LF , Murray S.
Published: July 2012

The dose of combination chemotherapy in Hodgkin's disease is commonly calculated from a formula based on the body surface area. A method is described for measuring the intensity of combination chemotherapy actually received compared to the calculated planned dose. The technique is applied to 56 patients receiving mustine, vinblastine, procarbazine and prednisolone, but would also be suitable for other cytotoxic regimens. The planned dosage intensity had to be significantly reduced in over half of the patients because of marrow toxicity. Splenectomized patients received a higher dose intensity than those in whom the procedure was not performed.
A new technique for recording compliance of human hand veins.
Authors: Aellig WH
Published: July 2012

1 A new technique for determining venous compliance at a standardized congestion pressure has been developed based on the optical method described by Nachev, Collier & Robinson (1971). It uses a linear variable differential transformer for a direct and continuous recording of venous compliance. 2 This method has been used to establish dose‐ response curves for the constrictor effects of noradrenaline, adrenaline, 5‐hydroxytryptamine and dihydroergotamine after direct local infusion. 3 A parallel shift to the right of the noradrenaline dose‐response curves was observed after local infusion of phentolamine, showing that the method can be used also to study interactions between agonists and antagonists on human veins in vivo. The usefulness of this technique for investigating the effects of orally administered drugs has also been established. The venoconstrictor action of dihydroergotamine reached its maximum after 1.5 h and remained almost constant for the period of observation (8 h).
The reliability of 5‐hydroxytryptamine induced platelet aggregation responses in schizophrenic patients treated with neuroleptic drugs.
Authors: Knox JM , Orr MW , Allen R , Gelder MG , Grahame‐Smith DG
Published: July 2012

1 The reliability of 5‐hydroxytryptamine induced platelet aggregation responses in psychiatric patients treated with neuroleptic drugs was investigated by examining the effects of a number of technical factors which could account for the variability of responses observed in some patients. 2 Variation in incubation time, temperature, aggregometer stirrer speed, and in the time interval between withdrawal of the blood sample and testing, had no significant effects on the consistency of responses. 3 Dilution of platelet rich plasma (PRP) led to enhanced platelet aggregation responses becoming non‐enhanced. 4 Overcentrifugation of blood samples during the preparation of PRP caused a decrease in the incidence of enhanced platelet aggregation responses observed in chronic schizophrenic patients receiving chlorpromazine. 5 The reliability of platelet aggregation responses as indices of the action of neuroleptic drugs in psychiatric patients remains doubtful.
Plasma diazepam and desmethyldiazepam concentrations during long‐term diazepam therapy.
Authors: Greenblatt DJ , Laughren TP , Allen MD , Harmatz JS , Shader RI
Published: July 2012

1 Factors influencing steady‐state plasma concentrations of diazepam (DZ) and its major metabolite desmethyldiazepam (DMDZ) were assessed in 110 male Veterans Administration outpatient clinic patients (mean age 53 years). 2 Patients reportedly had taken DZ for 1 to 14 years (mean duration 5.1 years) at a mean daily dose of 20 mg (range 2 to 55 mg). 3 Steady‐state plasma concentrations of DZ (mean 329 ng/ml) and DMDZ (mean 389 ng/ml) were highly correlated (r = 0.80), with a mean DMDZ/DZ ratio of 1.26. 4 Weight‐corrected daily dose were significantly correlated with plasma level of DZ (r = 0.32), DMDZ (r = 0.38) and the sum of DZ plus DMDZ (r = 0.37), but explained a small fraction of individual variation. 5 Duration of therapy, smoking habits, alcohol consumption, and number of other drugs coingested were not significantly related to plasma level.
Prediction of phenytoin dosage in relation to the variability of phenytoin plasma concentration.
Authors: Van der Velde EA , Driessen O
Published: July 2012

1 In a model study the influence of some variables on the accuracy of predictions of phenytoin doses which should produce desired plasma concentrations were studied. All predictions were extrapolations from low test doses with concurrent observations of plasma concentrations. 2 The variables in introduced were:‐Variability in observed plasma concentration;‐Variability in applied test doses;‐Variability in patient characteristics as expressed in Km and Vmax values. 3 The model study generated the same sort of result as a previous one, executed in practice (Driessen. Van der Velde + Hoppener, 1980), i.e. predictions are often inaccurate and of the method tested (Richens & Dunlop, 1975; Ludden, Hawkins, Allen & Hoffman, 1976; Martin, Tozer, Sheiner & Riegelman, 1977; Rambeck, Boenigk, Dunlop, Mullen, Wadsworth & Richens, 1980), Richens' first nomogram (Richens & Dunlop, 1975) is to be preferred.
Changes in blood pressure, plasma catecholamines and plasma renin activity during and after treatment with tiamenidine and clonidine.
Authors: Hansson BG , Hokfelt B
Published: July 2012

1 Tiamenidine (Hoe 440) is an imidazoline with blood pressure lowering properties. Its pharmacology resembles that of clonidine. 2 The effect of both drugs on blood pressure, plasma noradrenaline (NA), plasma adrenaline (Ad), urinary catecholamines and plasma renin activity (PRA) was assessed in four previously untreated male hypertensive patients in a cross over study. 3 The maximum daily dose of tiamenidine was 3 mg. The maximum daily dose of clonidine was 450 micrograms. 4 During treatment, blood pressure, systolic and diastolic, supine and erect, fell on average between 12 and 15%. Levels of NA, Ad, PRA were reduced during treatment. 5 During withdrawal of either drug there was rebound of blood pressure and NA, Ad, PRA, overshooting baseline levels. 6 The withdrawal effects caused by clonidine were similar for tiamenidine.
A specific radioenzymatic assay for dihydroxyphenylalanine (DOPA). Plasma dopa may be the precursor of urine free dopamine.
Authors: Brown MJ , Dollery CT
Published: July 2012

1 A sensitive radioenzymatic assay was developed, in which DOPA is enzymatically decarboxylated to dopamine and the latter converted to [3H]‐methoxytyramine in the presence of [3H]‐S‐adenosyl‐L‐methionine and catechol‐o‐methyltransferase. 2 The assay was specific for DOPA, and was sensitive to 50 pg/ml. 3 Endogenous DOPA was found to be present in the plasma of eight human volunteers at a concentration of 10.46 +/− 2.42 nmol/l. 4 Simultaneous urine collections in the same subjects showed a free dopamine excretion of 68.88 +/− 17.70 nmol/h. There was significant correlation (P less than 0.01) between plasma DOPA concentration and urine free dopamine excretion (r = 0.84). 5 After the oral administration of 250 mg levodopa, plasma DOPA and urine dopamine both increased by a similar proportion (98 +/− 8.4‐fold, and 93.4 +/− 6.9‐fold respectively). These compare with an increase in plasma dopamine of only 26 +/− 15‐fold (P less than 0.01). 6 Following the orale dose DOPA, the increase in plasma DOPA, but not plasma dopamine, could account for the increase in urine dopamine. The calculated clearance of plasma DOPA by renal decarboxylation to dopamine was 114 +/− 20 ml/min. 7 This is not significantly different from the apparent clearance of endogenous DOPA by renal decarboxylation to dopamine, and suggests that there is adequate renal decarboxylase activity for DOPA to be the precursor for renal dopamine formation.
Spironolactone in thiazide‐induced hypokalaemia: variable response between patients.
Authors: Ramsay LE , Hettiarachchi J
Published: July 2012

1 The influence of spironolactone 25, 50, 100 and 200 mg daily, and placebo, on plasma potassium and other variables was examined in a random crossover study of 15 hypertensive patients taking bendrofluazide 10 mg daily. 2 Spironolactone produced significant dose‐ related increases in plasma potassium and aldosterone, and reductions in plasma sodium and bicarbonate. 3 In 14 compliant patients plasma concentrations of the major metabolite canrenone were related linearly to the dose of spironolactone, and there was less than twofold variation between patients. The plasma canrenone concentration correlated negatively with body weight (r = −0.77, P less than 0.001). 4 The plasma potassium response to spironolactone varied sevenfold between compliant patients. The response correlated negatively with placebo plasma potassium (r = −0.62, P less than 0.02), positively with plasma canrenone (r = +0.55, P less than 0.05), but was unrelated to plasma aldosterone (r = −0.22). In one patient relative resistance to spironolactone was attributed to exaggerated secondary hyperaldosteronism induced by the drug. 5 The variability in response to spironolactone between patients is such that fixed dose thiazide‐ spironolactone combination tablets are unlikely to prevent hypokalaemia reliably.
Morphine‐like insomnia from heroin in nondependent human addicts.
Authors: Kay DC , Pickworth WB , Neider GL
Published: July 2012

1 This study was performed because dose‐related effects of heroin on human sleep had not been described previously, and to discover if heroin produces a morphine‐like insomnia. 2 After three adaptation nights, the sleep of seven male nondependent opiate addicts was studied following i.m. doses of heroin (3, 6, 12 mg/70 kg), morphine (10, 20 mg/70 kg) or placebo at weekly intervals in a randomized double‐blind crossover design. 3 Heroin produces a dose‐related increase in wakefulness, drowsiness episodes, muscle tension, and shifts in sleep‐ waking states. 4 Heroin produces a dose‐related decrease in total sleep, sleep efficiency, delta sleep and REM sleep (REMS). 5 Heroin is about twice as potent as morphine in producing this type of insomnia. 6 'Morphine insomnia' appears to be a characteristic initial effect of several opioids, at least in nondependent opiate addicts, and might serve as a model insomnia for evaluation of hypnotics.
Pharmacokinetics of digoxin in patients subjected to the quinidine‐ digoxin interaction.
Authors: Schenck‐Gustafsson K , Dahlqvist R
Published: July 2012

1 This study was designed to evaluate pharmacokinetically the digoxin‐ quinidine interaction in patients with atrial fibrillation. 2 Five patients on maintenance digoxin therapy were given [3H]‐digoxin as a single i.v. dose before and during quinidine therapy and the elimination of [3H]‐digoxin from plasma and excretion in urine were determined. 3 The mean steady state plasma concentration of digoxin increased from 0.7 to 1.3 nmol/l after quinidine administration. 4 The apparent volume of distribution of digoxin decreased on the average 38%. Renal clearance and the total body clearance of digoxin decreased 51 and 56% respectively (mean values). Also non renal clearance was reduced. The fraction of digoxin excreted unmetabolised in urine did not change during quinidine treatment. The mean elimination half life of digoxin increased from 49 to 72 h during quinidine. 5 In two patients the DC‐shock did not cause a conversion to sinus rhythm. However, the quinidine induced changes in the pharmacokinetics of digoxin in these patients did not differ from the others. 6 Quinidine appears to decrease the amount of digoxin distributed to body tissue(s). In addition, the reduction of renal clearance of digoxin and the observed unchanged clearance of creatinine suggests an inhibition of the renal secretion of digoxin.
The effect of quinidine and its metabolites on the electrocardiogram and systolic time intervals: concentration‐effect relationships.
Authors: Holford NH , Coates PE , Guentert TW , Riegelman S , Sheiner LB
Published: July 2012

1 A combined pharmacokinetic and pharmacodynamic model has been used to analyze the relationship between electrocardiographic (ECG) and systolic time intervals (STI) and changes in plasma concentration of quinidine after oral and i.v. doses in ten normal subjects. 2 The major effects of quinidine were on cardiac repolarization. Contrary to previous descriptions, we found no important change in the U wave, but the T wave was split into two peaks. The amplitude of these two peaks (T and T') was reduced, and the QT' peak and QT intervals were prolonged. The QT peak interval and systolic intervals did not change appreciably. There were small increases in the PQ and QRS intervals. 3 The effect of quinidine on the QT interval could be explained by a linear pharmacodynamic model. The equilibration between plasma and effect site had a half‐time of 8 min. The slope of the pharmacodynamic model was 20.3 ms . mg 1(‐1) after i.v. dosing and 33.5 ms . mg 1(‐1) after oral dosing. 4 The difference in effect model slopes suggests pharmacologically active metabolites of quinidine are formed during absorption from the gut. 5 The total effect of a single oral dose of quinidine appears to be the same as the same dose given intravenously, even though only 70% of the oral dose reaches the systemic circulation as quinidine.
Haemodynamic responses to intravenous cimetidine in subjects with normal lung function and in subjects with chronic airway obstruction.
Authors: Lee PK , Lai CL , Lok AS , Tse TF , Lai KN , Chow SF , Lam KC
Published: July 2012

1 The haemodynamic responses to a bolus intravenous injection of 400 mg cimetidine were studied in eight subjects with normal lung function and sixteen with chronic obstructive airway disease (COAD), under continuous systemic and pulmonary arterial monitoring. In all subjects there were significant immediate but transient (less than 10 min) drops in the systemic and pulmonary arterial pressures (both systolic and diastolic), the systemic vascular resistance and total pulmonary resistance. The percentage drops were significant more marked in the COAD group in the following: systemic arterial pressures (systolic and diastolic), systemic vascular resistance and total pulmonary resistance. The cardiac output showed no significant change in the group with normal lung function but rose significantly in the COAD group. None of the subjects had any symptoms associated with the haemodynamic changes. 2 These results can be explained by a generalized vasodilatory effect of cimetidine, but the relationship to its H2‐ receptor blocking effect is undetermined. Hypoxia and/or hypercapnia may sensitize an individual to the vasodilatory effect of cimetidine.
Plasma protein binding of azapropazone in patients with kidney and liver disease.
Authors: Jahnchen E , Blanck KJ , Breuing KH , Gilfrich HJ , Meinertz T , Trenk D
Published: July 2012

1 The free fraction of azapropazone in the plasma of 37 healthy volunteers ranged from 0.0027 to 0.0070 (0.0044 +/− 0.0009, mean +/‐ s.d.). The principal binding protein was found to be albumin. 2 In 27 patients with various degrees of renal failure the free fraction values of azapropazone were markedly enhanced (0.0260 +/− 0.0239, mean +/‐ s.d.) and increased more than tenfold in some patients. There was a weak correlation (r = 0.46, P less than 0.05) between the free fraction and the clearance of endogenous creatinine. Such correlation was not found for serum creatinine, serum albumin, serum uric acid and serum urea nitrogen. 3 In 32 patients with chronic liver disease the free fraction values of azapropazone were also markedly higher (0.0210 +/− 0.0242, mean +/‐ s.d.) than in healthy subjects. There were statistical significant correlation between free fraction values and the prothrombin complex activity in the plasma (r = 0.40, P less than 0.05) and the total bilirubin concentration in the plasma (r = 0.90, P less than 0.001), respectively. Such correlation was not found for serum albumin, serum glutamic oxalacetic transaminase, serum gamma‐glutamyl transpeptidase and serum alkaline phosphatase. 4 In patients with kidney and liver disease the free fraction values of azapropazone correlated well with those of the anticoagulant drug phenprocoumon (r = 0.93, P less than 0.001). However, the binding of the latter drug was less impaired. Bilirubin, when added in vitro, displaced both drugs from plasma proteins but this displacing effect was much smaller than the binding changes observed in patients with liver disease. 5 Kidney and liver disease caused a marked impairment of the plasma protein binding of azapropazone. In patients with kidney disease the degree of impairment of azapropazone binding cannot or only poorly (creatinine clearance) be predicted from the biochemical parameters of kidney function whereas in patients with chronic liver disease the total bilirubin concentration in the plasma may serve as an index of the binding defect.
Plasma concentrations and protein binding of disopyramide and mono‐N‐ dealkyldisopyramide during chronic oral disopyramide therapy.
Authors: Aitio ML
Published: July 2012

1 The plasma levels of disopyramide and mono‐N‐dealkyldisopyramide were measured from 118 patients, and the protein binding of both drugs from 50 patients during chronic oral disopyramide therapy. 2 No significant correlation was seen between the daily dose of disopyramide and the achieved plasma drug concentration. 3 The concentration of mono‐N‐ dealkyldisopyramide in the plasma was about one third of that of disopyramide in patients with normal renal function. 4 The mean plasma levels of disopyramide and mono‐N‐dealkyldisopyramide were high in patients with renal impairment. In patients with simultaneous therapy with enzyme inducing drugs the mean levels of disopyramide were low and those of mono‐N‐dealkyldisopyramide high. 5 In patients with effective treatment of ventricular arrhythmias the levels of disopyramide were significantly higher than in those with ineffective treatment; the difference was not significant in supraventricular arrhythmias. Patients with side‐effects had slightly though not significantly higher disopyramide levels than patients without side‐effects; mono‐N‐ dealkyldisopyramide concentrations were identical. 6 The average protein binding of disopyramide was 82%, and that of mono‐N‐ dealkyldisopyramide 22‐35%. Although a concentration dependent binding of disopyramide was seen within an individual, the average protein binding did not vary significantly at different concentrations of all samples analyzed. The protein binding was not altered in renal insufficiency, but was slightly decreased by high concentrations of mono‐N‐dealkyldisopyramide.
Methods of assessment of antiepileptic drugs.
Authors: Milligan N , Richens A
Published: July 2012

Epilepsy is a symptom with protean manifestations and as such it is a difficult disease in which to carry out a therapeutic trial. The methods available to research workers for the assessment of new antiepileptic drugs are hampered by the fact that epilepsy is a fluctuant condition. Although it is a chronic disorder open to study using cross‐over trials and within‐patient comparisons, accurate assessment cannot be easily made at any one point in time. Research workers are therefore automatically placed at a time factor disadvantage and this is especially so for those searching for quick methods of evaluating new compounds. The need for a quick and reliable method of assessing a new antiepileptic drug has long been appreciated. This article will discuss the methods currently available and we will begin by considering the most commonly used method of assessment with particular reference to some of the problems involved in conducting a controlled clinical trial in epilepsy.
β‐Adrenoceptor blockers and the blood‐brain barrier
Authors: Neil‐Dwyer G , Bartlett J , McAinsh J , Cruickshank JM
Published: July 2012

1 This study on 21 neurosurgical patients was set up to investigate the extent to which four chronically administered β‐adrenoceptor blockers, propranolol, oxprenolol, metoprolol and atenolol, cross the blood‐brain barrier and enter the cerebrospinal fluid (CSF) and brain tissue. The concentration in the CSF of the three lipophilic β‐adrenoceptor blockers, propranolol, oxprenolol and metoprolol, approximated to the free drug concentration in the plasma, and was a poor predictor of brain concentration. These three lipophilic β‐adrenoceptor blockers appeared in brain tissue at concentrations 10‐20 times greater than that of hydrophilic atenolol. The approximate brain/plasma ratio for propranolol was 26, for oxprenolol 50, for metoprolol 12 and for atenolol 0.2.

2 The low concentration of atenolol in brain tissue is possibly responsible for the low incidence of central nervous system‐related side effects in patients on this agent compared to lipophilic β‐adrenoceptor blockers.
Intrathyroidal iodide binding rates and plasma methimazole concentrations in hyperthyroid patients on small doses of carbimazole.
Authors: Low LC , McCruden DC , Alexander WD , Hilditch TE , Skellern GG , Knight BI
Published: July 2012

1 The effect of small doses of carbimazole on the binding rate constant of intrathyroidal iodide, plasma methimazole concentrations and circulating thyroid hormone concentrations in five hyperthyroid patients is presented. 2 In all patients there was a marked reduction in iodide binding with carbimazole doses as low as 5 to 10 mg daily. 3 In three patients little further reduction in the observed binding rate occurred with daily doses in excess of 10 mg despite progressive increases in plasma methimazole concentrations. 4 At the end of 4 weeks' treatment with 10 mg carbimazole daily, the reduction in thyroid hormone concentrations and clinical improvement were such as to suggest that this dose may be an effective starting dose in many patients.
Effect of intravenous injection of rimiterol in asthma.
Authors: Tarala RA , Martyn V , Paterson JW
Published: July 2012

1 The effect of i.v. rimiterol was compared with aerosol rimiterol in twelve asthmatic patients. 2 A cumulative dose of rimiterol (1050 microgram) given in six separate injections over 90 min resulted in a mean increase in peak expiratory flow rate (PEFR) of 50.6% and FEV1 of 53.7%. 3 Comparison of the degree of bronchodilation to the same dose of rimiterol administered intravenously or by aerosol, suggested that on average the potency ratio was 10:1, i.e. ten times the aerosol dose was required to produce the equivalent bronchodilator effect. 4 Palpitations, tremor and postural hypotension were common during the first minute after the drug was injected intravenously, but did not occur after aerosol administration. 5 It is suggested that rimiterol by intravenous injection is a useful addition to the treatment of acute asthma.
Development of tolerance to oral salbutamol in the third trimester of pregnancy: a study of circulatory and metabolic effects.
Authors: Wager J , Fredholm BB , Lunell NO , Persson B
Published: July 2012

1 The purpose of the study was to investigate whether a development of tolerance does occur or not to salbutamol‐induced cardiovascular and metabolic effects after oral long term treatment in pregnancy. 2 Twenty‐ three women in late pregnancy were given an oral dose of 4 mg salbutamol in the morning after an overnight fast. Ten of the women had not been exposed to beta‐adrenoceptor agonists earlier in their pregnancy (group A). Thirteen of the women had been treated with salbutamol in a dose of 4 mg four times a day for 12 to 33 days preceding the study (group B). 3 Blood samples were collected every 30 min for 120 min and analyzed for cyclic AMP, insulin, C‐peptide, glucose, lactate, glycerol, non‐esterified fatty acids (NEFA) and 3‐ hydroxybutyrate (3‐HB). Heart rate and blood pressure were recorded simultaneously. 4 In group A there was significant increase in plasma cyclic AMP and increased glycogenolysis, lipolysis and insulin secretion. In this group there were also significant cardiovascular effects, that is, an increase of heart rate and decrease of diastolic blood pressure. 5 In group B the effects of salbutamol were significantly less pronounced, indicating a development of tolerance. 6 We conclude that the metabolic side‐effects are not sufficient reason to withhold beta‐adrenoceptor agonists to healthy pregnant women with threatened premature labour, since tolerance rapidly develops to these actions.
Effects of salbutamol, ipratropium bromide and disodium cromoglycate on breathlessness induced by exercise in normal subjects.
Authors: Stark RD , Gambles SA
Published: July 2012

1 Healthy volunteers undertook submaximal graded exercise while objective measurements of cardio‐respiratory function were made and breathlessness was assessed with serial visual analogue scales. 2 A useful and consistent relationship existed between breathlessness and ventilation for individual subjects. 3 Drugs were examined in this system to test whether they modified the relationship between ventilation and breathlessness such that less breathlessness occurred for a given level of ventilation. 4 Salbutamol, ipratropium bromide and disodium cromoglycate given by inhalation did not reduce breathlessness in healthy subjects during exercise.
Comparison of prizidilol hydrochloride (SK & F 92657), a new antihypertensive agent with beta‐adrenoceptor antagonist and vasodilator activity with propranolol and hydralazine in normal volunteers.
Authors: Steiner JA , Clancy A , Manghani KK , James IM
Published: July 2012

1 Some cardiovascular pharmacology of prizidilol hydrochloride, a new antihypertensive compound with precapillary vasodilator and beta‐ adrenoceptor antagonist activity, in man is described. 2 To investigate further the pharmacological profile of this drug the effects of a single oral dose of 400 mg prizidilol hydrochloride were compared with propranolol 40 mg in combination with either 25 mg or 50 mg of hydralazine for up to 6 h after dosing, in a placebo controlled in eight healthy subjects. 3 Prizidolol hydrochloride significantly reduced supine and standing diastolic blood pressure and was more effective than propranolol combined with either dose of hydralazine in this respect. 4 Supine heart rate was significantly increased after prizidilol hydrochloride, but was not significantly changed after propranolol combined with either dose of hydralazine. The reasons for the increase in supine heart rate after prizidolol are discussed. 5 beta‐adrenoceptor antagonism was assessed in terms of inhibition of exercise induced increases in heart rate and systolic blood pressure. At the doses used, prizidolol hydrochloride was less effective than propranolol and hydralazine combined, particularly during the first 3 h after dosing.
Pharmacokinetics of the enantiomers of acenocoumarol in man.
Authors: Godbillon J , Richard J , Gerardin A , Meinertz T , Kasper W , Jahnchen E
Published: July 2012

1 The pharmacokinetics of R(+)‐, S(‐)‐ and R,S(+/‐)‐acenocoumarol were studied in healthy volunteers after administration of single oral and intravenous doses. 2 After both oral and i.v. administration of either enantiomer in a dose of 0.25 mg/kg, the concentrations of R(+) found in the plasma were much higher than those of S(‐). This indicates that the observed differences are not related to stereoselective absorption. 3 After intravenous administration of 25 mg of each enantiomer and the racemate, the total plasma clearance of S(‐) was about 10 times that of R(+). The clearance of the racemate was between that of the enantiomers. 4 The apparent elimination half‐life of S(‐) was much shorter than those of R(+) and the racemate, which were similar. 5 The apparent volume of distribution VdSS of S(‐) acenocoumarol was 1.5 to 2 times that of R(+). 6 Measurements of the extent of binding to serum proteins, made in vitro at much higher concentrations than those observed in vivo, revealed no differences between the two enantiomers and the racemate. 7 The results indicate that the greater anticoagulant potency of R(+) compared with S(‐) acenocoumarol can be explained mainly by stereoselective differences in their metabolic clearance.
Clobazam kinetics in the elderly.
Authors: Greenblatt DJ , Divoll M , Puri SK , Ho I , Zinny MA , Shader RI
Published: July 2012

1 The effects of age and sex on the disposition of clobazam (CBZ), a 1.5‐benzodiazepine derivative, were evaluated in a series of 29 healthy volunteers aged 18 to 72 years, who ingested single 20 mg oral doses. CBZ kinetics were determined from multiple plasma concentrations measured during 7 days after the dose. 2 CBZ was rapidly absorbed, with peak levels reached an average of 1.5 h after dosing (range 0.5–2.5 h). Mean absorption half‐life was 19.7 min. Absorption kinetics were not influenced by age of sex. 3 Elimination half‐life ranged from 11 to 77 h, and was significantly longer in elderly v young males (48 v 17 h, P less than 0.01). In women, half‐life also increased with age, but differences between young and elderly women were less striking (31 v 49 h, P less than 0.05). 4 Volume of distribution (Vd) was influenced by age and sex. Vd became larger with age regardless of sex, and within each age group was larger in women than in men. Total clearance was unrelated to age in women, but declined significantly with age in men (P less than 0.01). 5 The mean free fraction for CBZ in plasma was 11.5% (range 8.6–15.0%), and tended to increase with age, partly due to a significant age‐related decline in plasma albumin concentration (r = −0.68, P less than 0.001). Correction of Vd and clearance for individual differences in binding did not alter their relation to age and sex. 6 As in the case of other benzodiazepines biotransformed by oxidative pathways, the capacity for N‐demethylation of CBZ declines with age in men, but age has a minimal effect on CBZ clearance in women.
Pharmacokinetics of phenytoin in children.
Authors: Blain PG , Mucklow JC , Bacon CJ , Rawlins MD
Published: July 2012

1 Apparent Vmax and Km for phenytoin were estimated in 40 children (aged 8–33 months) and 21 adults (aged 18–66 years). 2 The derived values of Vmax and Km were used to predict the plasma and salivary concentrations of phenytoin following a change in dose. There was a highly significant correlation between observed and predicted steady‐ state concentration in both children and adults (P less than 0.001). 3 The apparent Km was similar in children (7.5 +/‐ 1.2 mg/l) and adults (9.4 +/‐ 2.3 mg/l). 4 Vmax differed significantly (P less than 0.001) between children (20.4 +/‐ 2.1 mg kg‐1 day‐1) and adults (8.7 +/‐ 0.7 mg kg‐1 day‐1). 5 After correction for differences in the ratio of liver weight to body weight in children and adults, Vmax was similar in the two groups.
Ethanol ‘dose‐dependent’ elimination: Michaelis‐Menten v classical kinetic analysis.
Authors: Rangno RE , Kreeft JH , Sitar DS
Published: July 2012

1 To compare classical linear regression techniques and a Michaelis‐ Menten elimination model eight normal human volunteers each received three intravenous doses (0.375, 0.5, and 0.75 g/kg) of ethanol and four of the subjects each received four oral doses (0.5, 0.65, 0.95, 1.25 g/kg) of ethanol. 2 Computerized analysis of the time‐plasma concentration profiles using a two‐compartment Michaelis‐Menton elimination model yielded a median absorption constant of 1.29 h‐1; volume of distribution of 0.47 l/kg; Vmax of 0.12 g h‐1 kg‐1; and Km of 0.03 g/l. Classical techniques resulted in a slope of 0.20 g l‐1 h‐1, volume of distribution of 0.55 l/kg, and a B60 of 0.11 g h‐1 kg‐1. 3 Transient post‐prandial decreases in elimination slope occurred at higher oral doses. A trend of increasing slope with increasing oral dose was seen at concentrations well above the Km. Time to sobriety (0.8 g/l) increased nonlinearly with increasing peak concentration. 4 Maximal ethanol elimination rates are determined equally well by the two techniques. Classical analyses overestimate the volume of distribution of ethanol by 17%. Neither technique helps explain the post‐prandial changes in slope or increasing slope with dose at high concentrations.