bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of pindolol and propranolol on renal function of patients with hypertension.
Authors: Pasternack A , Porsti P , Poyhonen L
Published: July 2012

1 Pindolol and propranolol were administered orally in equipotent antihypertensive doses to 14 subjects with mild to moderate hypertension in an open cross‐over study. 2 Pindolol caused a smaller decrease in plasma renin activity and heart rate than propranolol. 3 Glomerular filtration rate and effective renal plasma flow remained unchanged during therapy with either agent.
alpha‐Methyldopa, alpha‐methyldopamine an alpha‐methylnoradrenaline: substrates for the thermolabile form of human platelet phenol sulphotransferase.
Authors: Mwaluko G , Weinshilboum R
Published: July 2012

1 Sulphate conjugation catalyzed by phenol sulphotransferase (PST) is an important pathway in the catabolism of alpha‐methyldopa (MD). Variations in PST activity in an easily obtained tissue such as the human platelet might reflect individual differences in the sulphate conjugation of MD in other organs and tissues. There are at least two forms of human platelet PST, a thermolabile form for which dopamine is a substrate and a thermostable form for which low concentrations of phenol can serve as a substrate. 2 MD, alpha‐methyldopamine (MDA) and alpha‐methylnoradrenaline (MNA) were tested as substrates for human platelet PST. All three were substrates for the thermolabile form of the enzyme and none were substrates for the thermostable form of PST. Apparent Michaelis‐Menten (Km) values for MD, MDA and MNA were 5.5, 0.014 and 0.28 mM, respectively. Apparent Km values for 3'‐ phosphoadenosine‐5'‐phosphosulphate, the sulphate donor for the reaction, were 0.08, 0.13 and 0.10 microM, respectively, for the three catechol substrates. The pH optima for the reaction were 7.5 for MD and 6.5 for both MDA and MNA. 3 When platelet homogenates from 20 individual subjects were tested, there were significant correlations between PST activities measured with dopamine and those measured with MD, MDA and MNA (r = 0.54, 0.98 and 0.93, P less than 0.02, less than 0.001, and less than 0.001, respectively), but not between activities measured with low concentrations of phenol and those measured with MD, MDA and MNA (r = 0.021, 0.045 and 0.046, respectively). There results were also compatible with the conclusion that MD, MDA and MNA were substrates for the thermolabile form of platelet PST. 4 These observations will make it possible to test the hypothesis that variations in the activity of the thermolabile form of platelet PST may reflect individual differences in the sulphate conjugation of MD, MDA and MNA.
The minimum effective analgetic blood concentration of pethidine in patients with intractable pain.
Authors: Mather LE , Glynn CJ
Published: July 2012

1 Pethidine infusions were performed in 16 patients with intractable pain in order to define a minimum effective analgetic blood concentration (MEAC) range. 2 Pethidine blood concentrations at the return of pain following a period of analgesia were considered to provide a more useful estimation of the MEAC than that at the onset of analgesia. 3. The MEAC range found in 15 of the 16 patients was 0.10 mg/l to 0.82 mg/l (median 0.25 mg/l). The intravenous dose of pethidine used in this study did not provide analgesia in one patient. 4 If the MEAC was greater than 0.40 mg/l in any patient, then additional techniques were required to provide adequate long term analgesia, e.g. destructive neurolytic techniques or antidepressant therapy. 5 The pharmacokinetic properties of pethidine found in the majority of these patients were in the range considered to be normal. 6 The clinical pharmacokinetic properties of pethidine found in the majority of these patients were in the range considered to be normal. 6 The clinical pharmacokineticist has in important role to play in the investigation, diagnosis and treatment of patients with intractable pain by detecting those patients with atypical pharmacokinetic and/or pharmacodynamic characteristics towards analgesic drugs.
The effect of systemic prednisolone on arachidonic acid, and prostaglandin E2 and F2 alpha levels in human cutaneous inflammation.
Authors: Kobza Black A , Greaves MW , Hensby CN
Published: July 2012

1 In order to test the proposal that the anti‐inflammatory effect of corticosteroids is attributable to inhibition of release of the prostaglandin precursor, arachidonic acid, the effect of systemic prednisolone on arachidonic acid and prostaglandin levels in abdominal skin of six patients receiving this treatment for alopecia totalis, was studied. 2 Inflammation was produced in an area of abdominal skin by topical application of 5% w/w tetrahydrofurfuryl nicotinate (THFN) cream. 3 The erythema produced was assessed visually, and exudate recovered from normal and inflamed skin, by a suction bulla technique. 4 Arachidonic acid and PGE2 and PGF2 alpha levels, as measured by gas chromatograph‐mass spectrometry (GC‐MS) were significantly elevated in the reddened (THFN) treated skin, compared with control areas. 5 After prednisolone treatment both arachidonic acid and prostaglandin levels in THFN‐treated areas were suppressed near to values obtained from untreated skin, before prednisolone therapy. There was partial reduction of THFN induced erythema in three out of six subjects. Levels of arachidonic acid on control skin were not affected by the steroid. 6 These results provide direct evidence that steroids inhibit prostaglandin formation by blocking evoked rise in the concentration of free arachidonic acid. The relationship of this effect, in human skin, to the anti‐inflammatory action of systemic steroids is uncertain.
The effect of a combination of timolol, hydrochlorothiazide and amiloride on 24 hour blood pressure control using ambulatory intra‐ arterial monitoring.
Authors: Hornung RS , Gould BA , Kieso H , Raftery EB
Published: July 2012

1 The effectiveness of fixed combination tablets of timolol 10 mg, hydrochlorothiazide 25 mg and amiloride 2.5 mg (Moducren) once daily in the control of blood pressure has been assessed in fully ambulant hypertensives by the technique of continuous intra‐arterial recording. Highly significant blood pressure reduction (P less than 0.001) was obtained consistently throughout the whole day, confirming the potency and usefulness of the preparation for those patients who need more than one drug to control their blood pressure. 2 Blood pressure responses to both isometric and dynamic forms of exercise were also significantly lowered by combination therapy. 3 The addition of a diuretic to a beta‐ adrenoceptor blocker appears to be an advantage if the aim of treatment in hypertension is 24 h blood pressure control.
Diuretic induced hypokalaemia: relationship to dosage interval and plasma aldosterone.
Authors: McInnes GT , Shelton JR , Harrison IR , Perkins RM , Rigby GV
Published: July 2012

Plasma potassium and aldosterone responses to 9 days treatment with hydrochlorothiazide (100 mg/day) alone or in combination with spironolactone (100 mg/day), prescribed once daily or in doses 12 h apart, were examined in a double‐blind, crossover study in twelve healthy subjects. Plasma potassium concentrations were lower when the drugs were administered 12 h apart (P less than 0.01). Spironolactone attenuated significantly hydrochlorothiazide induced hypokalaemia–mean rise in plasma potassium, 0.36 mmol/l (P less than 0.001). The increase in plasma aldosterone was greater following combination therapies (P less than 0.001), but there were no significant differences between once daily and twice daily regimens. We conclude that plasma potassium concentration is better maintained when diuretics are given once daily and that this is not related closely to differences in plasma aldosterone responses.
Codeine added to paracetamol induced adverse effects but did not increase analgesia.
Authors: Skjelbred P , Lokken P
Published: July 2012

1 In a double‐blind crossover study identical oral surgical procedures were performed on two separate occasions in 24 outpatients. 2 At one operation they were given tablets containing paracetamol + codeine phosphate (400 mg + 30 mg), and at the other plain paracetamol (400 mg). The day of operation 2 tablets were taken 3, 6 and 9 h after surgery, the following two days 1 tablet four times daily. 3 Several measurements/assessments were recorded for a paired comparison of the postoperative courses. 4 No increase In the analgesic effect could be demonstrated by addition of codeine to paracetamol. 5 On the day of operation 18 patients reported adverse effects like nausea, dizziness and drowsiness with paracetamol + codeine, while only 3 patients experienced side effects with paracetamol alone (P less than 0.001). 6 Measurements revealed almost identical swelling after the two operations. 7 Compared with results obtained in previous studies, the present findings indicate that paracetamol may exert anti‐inflammatory activity and reduce postoperative swelling, even when given 3 h after surgery. 8 On the day of operation and the following two days 20 patients preferred the treatment with plain paracetamol, while only 4 favoured paracetamol + codeine (P less than 0.001).
Responsiveness to beta‐adrenergic receptor stimulation: the effects of age are cardioselective.
Authors: Kendall MJ , Woods KL , Wilkins MR , Worthington DJ
Published: July 2012

1 To examine the influence of age on beta‐adrenergic receptor mechanisms, we have observed the cardiovascular, bronchial and metabolic effects of an intravenous infusion of the beta‐adrenoceptor agonist terbutaline in healthy young and elderly female subjects (mean ages 20.9 and 72.1 years respectively). 2 There was a highly significant fall in systolic blood pressure in the elderly, in contrast to the rise in systolic pressure seen in the young subjects. A similar fall in diastolic pressure occurred in both groups, indicating comparable beta‐adrenoceptor‐mediated vasodilatation. The fall in mean arterial pressure was significantly greater in the old than in the young subjects. The increase in heart rate was significantly less in the elderly. 3 Changes in plasma glucose and potassium during the infusion were similar in the two groups. 4 The observed abnormality of myocardial sensitivity to beta‐adrenergic receptor stimulation, which is not associated with a generalized blunting of beta‐adrenoceptor mediated effects, may significantly impair autonomic cardiovascular regulation in the elderly.
The effect of once daily beta‐adrenoceptor blocker‐thiazide diuretic combination on the ambulatory blood pressure.
Authors: Gould BA , Hornung RS , Kieso H , Mann S , Raftery EB
Published: July 2012

1 We have assessed the efficacy of Viskaldix, a combination of pindolol 10 mg and clopamide 5 mg using continuous intra‐arterial ambulatory blood pressure monitoring. 2 Fourteen of the sixteen patients entered were studied on no therapy and following a minimum of 6 weeks at a constant dosage of Viskaldix. 3 Viskaldix produced a marked and consistent reduction of the blood pressure over the 24 h. The diurnal variation in the heart rate was decreased. 4 The results were compared with those of a similar study with once‐daily pindolol where there was control during the day but not in the early morning when the blood pressures rose rapidly.
The effect of propranolol on luteinising hormone and prolactin plasma concentrations in hypertensive women.
Authors: Dart AM , McHardy K , Barber HE
Published: July 2012

1 Chronic propranolol treatment has been previously shown to lower the plasma concentrations of LH and prolactin in normal male volunteers. 2 The effect of 2 weeks treatment with propranolol (80 mg twice daily) on the plasma concentrations of LH and prolactin has now been investigated in five post menopausal hypertensive women. 3 There was no significant effect of propranolol treatment on the basal plasma concentrations of either hormone. Both hormones showed significant increases in plasma concentration following GnRH stimulation and these increases were also unaffected by propranolol treatment.
Microsomal enzyme induction in children: the influence of carbamazepine treatment on antipyrine kinetics, 6 beta‐hydroxycortisol excretion and plasma gamma‐glutamyltranspeptidase activity.
Authors: Moreland TA , Park BK , Rylance GW
Published: July 2012

1 The influence of carbamazepine (CBZ) therapy on saliva antipyrine kinetics, urinary 6 beta‐hydroxycortisol excretion and plasma gamma‐ glutamyltranspeptidase activity was determined in nine children aged 6‐ 14 years. 2 During 5 weeks of CBZ therapy the mean (+/‐ s.d.) antipyrine clearance increased from 65 +/‐ 12 ml kg‐1 h‐1 to 143 +/‐ 34 ml kg‐1 h‐1 (P less than 0.001) and the mean half‐life declined from 6.24 +/‐ 1.23 h to 2.78 +/‐ 0.59 h (P less than 0.001). The apparent volume of distribution of antipyrine did not change during CBZ treatment. 3 Urinary 6 beta‐hydroxycortisol excretion increased markedly during the study period from 5.10 +/‐ 1.77 micrograms day‐1 kg‐ 1 to 17.85 +/‐ 6.75 micrograms day‐1 kg‐1 (P less than 0.01). 4 Plasma gamma‐glutamyltranspeptidase activity increased in eight out of nine children during CBZ therapy but the change was not statistically significant. 5 CBZ appears to have a marked enzyme inducing effect in young epileptics as indicated by antipyrine kinetics and 6 beta‐ hydroxycortisol excretion.
Clinical and haemodynamic effects of low dose captopril in severe chronic heart failure.
Authors: Sharpe DN , Coxon RJ
Published: July 2012

1 The clinical and haemodynamic effects of low doses of the oral converting‐enzyme inhibitor captopril were studied in 18 patients with severe chronic heart failure. Increasing doses of 1 mg, 2.5 mg, 6.25 mg, 12.5 mg, and 25 mg captopril were given at two hour intervals with haemodynamic monitoring. Graded haemodynamic improvement (increased stroke volume index and reduced mean pulmonary capillary wedge pressure) occurred from one hour with reduction of blood pressure closely associated. 2 Maximal haemodynamic improvement for the group was seen at six and seven hours after the 6.25 mg and 12.5 mg doses, when stroke volume index was increased by 35% and mean pulmonary capillary wedge pressure reduced by 40% from control. Captopril 12.5 mg‐ 50 mg eight hourly was continued long‐term but withdrawn in two patients with symptomatic hypotension and one patient with altered taste. 3 Four patients died and one was non‐compliant with therapy. At three months 10 patients showed significant improvement in symptoms, treadmill exercise duration, and echocardiographic indices of left ventricular size and function. The results of repeat haemodynamic measurements were similar to optimal measurements obtained during the initial study. 4 At two years six patients remained alive, five having maintained their symptomatic improvement. Thus small doses of captopril produce haemodynamic improvement in heart failure with a closely associated reduction of blood pressure. Symptomatic and haemodynamic benefit is maintained with long‐term treatment.
The effect of pretreatment with cimetidine on the bioavailability and disposition of atenolol and metoprolol.
Authors: Houtzagers JJ , Streurman O. , Regardh CG
Published: July 2012

1 Plasma levels of atenolol and metoprolol and their effects on exercise heart rate have been studied after oral administration of single doses of 100 mg of the two drugs in ordinary tablets alone and during concomittant cimetidine medication of 1 g per day. 2 Cimetidine caused no significant changes in the bioavailability of any of the two beta‐adrenoceptor blockers and the rate of elimination of metoprolol was unaffected by the histamine H2‐receptor blocker. A slight but significant increase in the elimination half‐life from 6.5 +/‐ 0.6 to 7.9 +/‐ 0.6 (P less than 0.05) was noted for atenolol after pretreatment with cimetidine. The beta‐adrenoceptor blocking effect was about the same for the used doses of atenolol and metoprolol and it was not changed during cimetidine therapy.
Tooth pulp stimulation: a method of determining the analgesic efficacy of meptazinol in man.
Authors: Gabka J. , Price RK
Published: July 2012

A dose‐ranging study of meptazinol was carried out using the pain threshold to electrical tooth pulp stimulation in healthy volunteers as the pain model. A well defined dose‐response curve was found for oral meptazinol (50 mg, 100 mg, 150 mg and 200 mg) and placebo. The methodology and results are discussed in terms of subsequent clinical experience with meptazinol.
Effect of pirprofen on glibenclamide kinetics and response.
Authors: Morrison PJ , Rogers HJ , Spector RG , Bradbrook ID , John VA
Published: July 2012

Pirprofen (a new non‐steroidal anti‐inflammatory agent), 200 mg 8 hourly, or placebo was administered orally to eight normal volunteers to investigate its effect on the pharmacokinetics and glucose and insulin responses after 1 mg i.v. glibenclamide. No significant changes were produced in these measures and in vitro studies showed no displacement of glibenclamide by pirprofen from plasma protein binding.
Plasma binding of disopyramide and mono‐N‐dealkyldisopyramide.
Authors: Bredesen JE , Pike E. , Lunde PK
Published: July 2012

1 Measuring total plasma levels of disopyramide (DP) and the main metabolite mono‐N‐dealkyldisopyramide (MND) in patients on maintenance therapy with DP has shown concentrations of MND comparable with those of DP, with wide intersubject variations. 2 A method which permits simultaneous measurement of unbound fraction of DP and MND has been developed. 3 In healthy subjects the unbound fraction of both DP and MND was concentration dependent, i.e. increased with higher concentrations of DP or MND. 4 The plasma protein binding of DP is altered by varying concentrations of MND. Clinically relevant concentrations of MND may increase the unbound fraction of DP approximately twofold. 5 The plasma protein binding of MND is also altered by varying concentrations of DP. Variation in the concentration of DP from the lower to the upper part of the therapeutic range may cause a 1.5‐fold increase in the unbound fraction of MND. 6 In the assumed therapeutic range of 6‐15 mumol DP/L, the interpatient variance of unbound DP concentration might be ten‐fold or even higher. The present findings indicate the need for monitoring unbound drug concentrations in any attempt to establish plasma concentration/effect relationship.
Antihistamines and visual function: studies on dynamic acuity and the pupillary response to light.
Authors: Nicholson AN , Smith PA , Spencer MB
Published: July 2012

1 Effects of three antihistamines, triprolidine (10 mg) in a sustained release form, astemizole (10 mg) and terfenadine (60 mg), have been studied on dynamic visual acuity and on the response of the pupil to light, together with critical flicker fusion, digit symbol substitution and cancellation, and subjective assessment of mood. The study was double‐blind and effects were observed from 0.5‐4.0 h after ingestion. 2 Triprolidine impaired dynamic acuity and reduced the threshold for subjective fusion of a flickering light, but there were no changes with astemizole or terfenadine. The diameter of the pupil and its response to light were not changed by the drugs. 3 Performance on digit symbol substitution and cancellation was not altered by the drugs. 4 Astemizole and terfenadine are promising antihistamines for those involved in skilled activity.
The influence of a cooked meat meal on creatinine plasma concentration and creatinine clearance.
Authors: Mayersohn M , Conrad KA , Achari R
Published: July 2012

1 The influence of a meal containing cooked meat (225 g) on creatinine plasma concentration, creatinine urinary excretion and creatinine clearance was determined in six healthy male subjects. 2 The meat meal produced an average 52% increase in creatinine plasma concentration within 1.5 to 3.5 h after ingestion. The 24 h area under the creatinine plasma concentration‐time curve increased by about 19%. Urinary creatinine excretion during 24 h increased by an average of 13%. Creatinine clearance was not altered in response to the meal of cooked meat.
Dazoxiben, a thromboxane synthetase inhibitor, in the treatment of Raynaud's syndrome: a double‐blind trial.
Authors: Belch JJ , Cormie J , Newman P , McLaren M , Barbenel J , Capell H , Leiberman P , Forbes CD , Prentice CR
Published: July 2012

1 UK‐37248 (dazoxiben), an orally active thromboxane synthetase inhibitor, was evaluated in a double‐blind trial of patients with severe Raynaud's syndrome. 2 Twenty patients were enrolled in the study. Eleven of these patients received dazoxiben 400 mg day and nine received matching placebo capsules. Treatment was given for 6 weeks and the patients reviewed at 2 weekly intervals during the study. 3 Assessment of response was judged by clinical symptoms and hand temperature measurements. Haematological and haemostatic studies were also carried out. 4 Results show a significant clinical improvement in patients receiving dazoxiben for six weeks. Hand temperature measurements, and haematological and haemostatic blood tests remained unchanged, however, apart from the expected lowering in plasma thromboxane B2 levels. 5 The mechanism of action of the drug would appear not to be mediated through increased prostacyclin production and further studies are under way to determine how improvement has been obtained in these patients.
Selective inhibition of thromboxane synthesis during experimental endotoxemia in the goat: effects on pulmonary haemodynamics and lung lymph flow.
Authors: Harlan J , Winn R , Hildebrandt J , Harker L
Published: July 2012

1 The effects of a selective thromboxane synthetase inhibitor, dazoxiben (UK 37248), on haemodynamics, eicosanoid levels, and lung vascular permeability were assessed in three unanesthetized goats with chronic lung lymph fistulae following infusions of E. coli endotoxin (1 microgram/kg). Each animal received an infusion of endotoxin in both a control and treatment trial. In the control trial endotoxin alone was infused. In the treatment trial endotoxin administration was preceded by a bolus intravenous infusion of dazoxiben 25 mg/kg followed by a maintenance infusion of 10 mg/kg/h. 2 In animals receiving endotoxin alone the peak elevation in pulmonary artery and wedge pressures, the initial increase in lymph flow, and the fall in cardiac output correlated with the peak elevation in plasma thromboxane B2 (TXB2) concentration at 30 min after endotoxin. Although TXB2 levels had returned to baseline by 3 h, lung lymph flow remained elevated for at least 6 h after endotoxin. The lymph/plasma protein ratio (L/P) did not fall. 3 In dazoxiben‐treated animals the rise in plasma concentrations of TXB2 after endotoxin was prevented and, in concert, the increase in pulmonary artery and wedge pressures, the fall in cardiac output, and the initial increase in lymph flow were greatly attenuated. The increase in lymph flow at 2‐6 h after endotoxin, however, was not prevented in dazoxiben‐treated animals, and again L/P did not change. 4 Plasma 6‐keto‐prostaglandin F1 alpha concentrations were not significantly altered by dazoxiben treatment except for an earlier peak. 5 We conclude that selective total inhibition of thromboxane synthesis can be achieved by dazoxiben. The inhibition ameliorates many of the adverse haemodynamic consequences of experimental endotoxaemia and reduces, but does not prevent pulmonary oedema formation. This seems to be due to an increase in lung microvascular permeability which is not mediated by TXA2.
Morphine metabolism in cancer patients on increasing oral doses‐no evidence for autoinduction or dose‐dependence.
Authors: Sawe J , Svensson JO , Rane A
Published: July 2012

Four cancer patients with severe chronic pain were treated with oral morphine with increasing doses during 5‐8 months. During this period the oral dose was increased 16‐23‐fold in each of the patients. Morphine, morphine‐3‐ and morphine‐6‐glucuronide were determined with high performance liquid chromatography in plasma and urine during steady‐state, at five or more occasions on different daily doses of morphine. The trough concentrations of morphine and its metabolites were linearly related to the given dose. The relation between the levels of morphine and the two glucuronides was constant in the individual patient and independent of dose and duration of treatment. The average molar ratio between the areas under the plasma concentration‐time curves (AUC) for morphine‐3‐glucuronide and morphine was 34.0 (range 23.0‐46.9). The corresponding value for the ratio between morphine‐6‐glucuronide and morphine was 3.9 (range 2.7‐5.6). Our results show that the conjugation of morphine with glucuronic acid is proportional to the dose during long‐term treatment with increasing doses, thus this metabolic pathway is not subject to auto‐induction, even after very long periods of continuous treatment with high doses.
Skeletal muscle digoxin binding in patients with renal failure.
Authors: Jogestrand T , Ericsson F
Published: July 2012

For digoxin analyses blood and skeletal muscle samples were taken from seven digoxin‐treated patients with chronic renal failure. The ratio between skeletal muscle and serum digoxin concentration in the patients with renal failure was not significantly different from the ratios in two control groups consisting of subjects with normal renal function. In the group of patients with renal failure there was no relationship between the glomerular filtration rate and muscle digoxin binding (specific plus unspecific). The present study does not indicate reduced skeletal muscle digoxin binding in patients with chronic renal failure.
Mexiletine disposition: individual variation in response to urine acidification and alkalinisation.
Authors: Mitchell BG , Clements JA , Pottage A , Prescott LF
Published: July 2012

The disposition of mexiletine has been studied in five subjects on two occasions with urine pH controlled at 5.0 and at 8.0. With acid urine total plasma clearance was similar in all subjects (462 to 497 ml min‐ 1) and the plasma half‐life ranged from 3.8 to 9.2 h (mean 6.7 h). With alkaline urine the total plasma clearance varied considerably (239 to 441 ml min‐1); the mean half‐life, 9.7 h, (range 7.6 to 12.7 h) was not significantly different from that in the acid urine study. Renal clearance fell greatly in every subject on alkalinisation of the urine. The total plasma clearance fell by a similar amount in two. In the remaining three the fall in total clearance was much smaller because of an increase in non‐renal clearance. The reduction in total plasma clearance only just achieved statistical significance. The increase in predicted steady‐state plasma mexiletine concentrations during infusion with change in urine pH from 5 to 8 varied between +5% and +95% (mean +39%). Changes in urine pH have a predictable effect upon renal clearance of mexiletine. However, disposition is changed in an unpredictable manner and inter‐subject variation in distribution volume and non‐renal clearance are important factors.
Plasma protein‐binding and CSF concentrations of valproic acid in man following acute oral dosing.
Authors: Rapeport WG , Mendelow AD , French G , MacPherson P , Teasdale E , Agnew E , Thompson GG , Brodie MJ
Published: July 2012

Simultaneous cerebrospinal fluid (CSF), total and free plasma valproic acid (VPA) concentrations were measured in 17 patients receiving two weight‐adjusted VPA doses as seizure prophylaxis prior to diagnostic myelography or cisternography. Free drug concentrations were similar when measured by equilibrium dialysis (ED) at 37 degrees C for 24 h (Dianorm) or by a novel ultrafiltration (UF) method (EMIT freelevel system 1, SYVA) (ED:2.3‐35.5 mg‐1; UF:1.3‐33.6 mg‐1; r = 0.78, P less than 0.002). There was wide variation in total VPA concentration (39‐ 154 mg‐1) and in free fraction (ED: 3.3‐25.6%; UF: 5.9‐24%). Concentration dependent protein binding was not demonstrated. CSF VPA varied between 4.2 and 25.6 mg‐1 and was accurately reflected by free plasma VPA concentrations (ED: r = 0.75, P less than 0.005: UF: r = 0.93, P less than 0.001). CSF concentration also correlated with the total plasma VPA (r = 0.76, P less than 0.005). The Emit freelevel system 1 provides a rapid measure of unbound VPA in the plasma which may be suitable for routine clinical use.
Investigation of diurnal changes in the disposition of theophylline.
Authors: Taylor DR , Duffin D , Kinney CD , McDevitt DG
Published: July 2012

The mechanism of observed temporal variations in plasma theophylline concentrations has been investigated. Eight healthy volunteers were given both oral and intravenous doses of theophylline (5 mg/kg) at 09.00 h and 21.00 h under controlled conditions. Regular plasma concentration measurements were made following each dose in order to determine the diurnal and nocturnal disposition of the drug. Plasma theophylline concentrations at 0.5 h following each oral dose were 6.9 +/‐ 0.8 micrograms/ml, a.m., and 3.9 +/‐ 0.6 microgram/ml, p.m. (P less than 0.05). Time to peak concentration was 1.69 +/‐ 0.28 h, a.m.; 2.13 +/‐ 0.23 h, p.m. (P less than 0.05). Values for ka were not significantly different, however. Overall bioavailability, volume of distribution and systemic clearances, calculated for the 12 h period after each dose, did not differ significantly between day and night. Diurnal variations in theophylline disposition do not appear to be the result of changes in metabolism or excretion, but may reflect minor differences in absorption.
Dose‐response studies on glycopyrrolate and atropine in conscious cardiac patients.
Authors: Preiss D , Berguson P
Published: July 2012

The dose‐heart rate response relationship for the two anticholinergics, atropine and glycopyrrolate, were studied in non‐anaesthetised patients about to undergo coronary artery surgery. Two methods were used, the administration of increasing doses to different groups of patients, and an incremental dose technique in the same patient. Both drugs increased heart rate in a dose‐related manner with glycopyrrolate being approximately twice as potent as atropine. Glycopyrrolate is as effective as atropine in correcting bradycardia prior to open heart surgery.
Exercise‐induced increments in plasma levels of propranolol and noradrenaline.
Authors: Hurwitz GA , Webb JG , Walle T , Bai SA , Daniell HB , Gourley L , Loadholt Boyd C , Gaffney TE
Published: July 2012

Exercise‐induced changes in the plasma levels of propranolol and noradrenaline were determined in nine volunteers. Total plasma propranolol levels were increased during submaximal treadmill exercise, with exercise‐induced increments of 13 +/‐ 4% at 4 h after the last dose, 18 +/‐ 7% at 9 h and 41 +/‐ 5% at 16 h. Exercise‐induced increments in plasma propranolol were observed after single as well as repeated doses. During exercise, increments in plasma propranolol were correlated temporally with changes in plasma noradrenaline. Exercise‐ induced increments in plasma noradrenaline were greater during propranolol administration than during placebo periods. The changes in plasma propranolol concentration during exercise may reflect a redistribution of propranolol at its site(s) of action.
Ranitidine disposition in patients with renal impairment.
Authors: Meffin PJ , Grgurinovich N , Brooks PM , Miners JO , Cochran M , Stranks G
Published: July 2012

Ranitidine disposition has been studied in 12 patients with renal impairment following 50 mg given intravenously and 150 mg given by mouth on separate occasions. The clearance of ranitidine from plasma (y) was correlated with creatinine clearance (x): y = 10.47 + 0.289x,r2 = 0.751, but there was no significant correlation of creatinine clearance with distribution volume or bioavailability. The mean (s.e. mean) distribution volume was 1.62 (0.08) 1/kg and the mean bioavailability 0.81 (0.05). These data suggest that in order to obtain similar ranitidine plasma concentrations in anephric patients and patients with normal renal function, the maintenance dose in the anephric patients should be 25‐30% of that for patients with normal renal function.
Effect of midazolam on sleep of insomniacs.
Authors: Vogel GW , Vogel F
Published: July 2012

We studied in a sleep laboratory the effects of bedtime 15 mg midazolam and 20 mg midazolam on the sleep and morning performance of healthy subjects with polygraphically verified sleep onset insomnia. Six subjects received 15 mg midazolam and six subjects received 20 mg midazolam for 14 consecutive nights which were preceded by a three‐ night placebo baseline and followed by a three‐night placebo period. The medications were administered in a double‐blind manner. The results were that both doses increased total sleep time, reduced sleep latency, reduced wake time after sleep onset and reduced the number of awakenings. There was no difference between the doses. Midazolam had its main effect by decreasing wake time in the first third of the night. We found no evidence of tolerance, drug withdrawal rebound insomnia, or drug‐induced morning performance decrements. We did find evidence of an anterograde amnesia produced by the drug.
Pharmacokinetics of oral brotizolam in patients with liver cirrhosis.
Authors: Jochemsen R , Joeres RP , Wesselman JG , Richter E , Breimer DD
Published: July 2012

Disposition of oral brotizolam (0.5 mg) was studied in male patients with liver cirrhosis (patients) and in other patients (control) matched for age, weight, smoking and drinking habits. Absorption of brotizolam was relatively rapid in both groups with a median peak time (range) of 1.0 (0.5‐2.0) h. Peak concentrations were also similar with median values of 7.1 (3.2‐10.7) ng/ml in patients and 9.4 (2.9‐19.0 ng/ml) in controls. Elimination half‐life was longer in patients than in controls. The median values were 12.8 (9.4‐25) h and 6.9 (4.4‐8.4) h respectively (P less than 0.01). In two patients hardly any drug elimination was observed, indicating severe impairment of drug metabolizing activity. The prolongation of the elimination half‐life was likely to be due to a decrease in clearance (45 ml/min in patients compared with 64 ml/min in controls), and an increase in volume of distribution (0.62 l/kg and 0.39 l/kg respectively). Median values of protein unbound fraction of brotizolam were 9.2 (7.8‐10.4) % in controls and 12.4 (10.4‐18.9) % in patients. Clearance of unbound drug was 612 ml/min and 380 ml/min respectively.
Residual effects of flurazepam and brotizolam on psychomotor performance.
Authors: Krueger H , Muller‐Limmroth W
Published: July 2012

Residual effects of brotizolam (0.25 mg) and flurazepam (30 mg) were studied in healthy young adults. Performance and subjective assessments were observed from 7 to 8 h after overnight ingestion, and effects were compared with that of placebo. Visuo‐motor coordination, visuo‐mental processing time, visuo‐motor reaction time and reading errors were not impaired with brotizolam. There were residual effects with 30 mg flurazepam. Visuo‐motor coordination, visuo‐mental processing time, visuo‐motor reaction time, and reading errors were impaired compared with placebo and 0.25 mg brotizolam. Subjective assessments of performance correlated with measured performance. There was a decrease with flurazepam (visuo‐motor coordination and visuo‐mental processing time) compared with placebo.
Lack of evidence for polymorphism in metoprolol metabolism.
Authors: Jack DB , Wilkins M. , Quarterman CP
Published: July 2012

The claim for polymorphism in the metabolism of metoprolol is based on a logical fallacy. A frequency distribution of metoprolol AUC data is presented and, although highly skewed, no evidence of more than a single population is apparent. Plasma and urine metoprolol and metabolite data are also presented to support this.
The acute effects of nifedipine on red cell deformability in angina pectoris.
Authors: Waller DG , Nicholson HP , Roath S
Published: July 2012

In a randomised double‐blind study, the effects on red cell deformability of a single sublingual dose of nifedipine were compared with placebo in eight patients with stable angina pectoris. Red cell deformability, measured by filtration and centrifugation techniques, was significantly increased at rest in all eight patients 1 h after nifedipine, while no change occurred after placebo. The improvement in deformability after nifedipine was maintained at the end of a period of exercise and unchanged from resting values after placebo. The results suggest that the increased deformability of red cells after nifedipine could contribute to the therapeutic effects of the drug in myocardial ischaemia.
Severe megaloblastic anaemia associated with abnormal azathioprine metabolism.
Authors: Lennard L , Murphy MF , Maddocks JL
Published: July 2012

Severe anaemia is a rare, unexplained, side effect of azathioprine therapy. We report here such a case associated with a previously unreported abnormality in azathioprine metabolism. A 57 year old man on azathioprine therapy, for a presumed collagen vascular disease, developed severe megaloblastic anaemia. This resolved on cessation of azathioprine treatment. A very high concentration of an azathioprine metabolite, 6‐thioguanine nucleotide, was found in the patient's red blood cells and this was confirmed by subsequent rechallenge with a single dose of 50 mg azathioprine.
Anticholinergic activity in the serum of patients receiving maintenance disopyramide therapy.
Authors: Iisalo E , Aaltonen L
Published: July 2012

The steady state serum levels of disopyramide and its metabolite, mono‐ N‐dealkylated disopyramide (MND) were measured by gas‐liquid chromatography in 40 patients receiving maintenance disopyramide treatment. The levels were mean 3.11 micrograms/ml +/‐ 0.28 (s.e. mean) and 0.9 micrograms/ml +/‐ 0.13 (s.e. mean), respectively. A radioreceptor assay was used for the quantitation of the anticholinergic activity of disopyramide and its metabolite in the same serum samples. The serum levels of anticholinergic activity varied between 0 and 6.7 ng/ml when measured as atropine equivalent (mean 1.88 +/‐ 0.26, s.e. mean, ng/ml). After a single oral dose of disopyramide the serum anticholinergic activity was, however, not detectable or very low. There was a significant correlation between disopyramide concentrations in serum and the serum anticholinergic activity (r = 0.655, P less than 0.001). No correlation was found between MND concentrations and the anticholinergic activity arguing against the role of MND causing antimuscarinic side effects. The affinity of MND for the muscarinic receptors in vitro was also lower than that of disopyramide.
Pethidine binding in whole blood: methodology and clinical significance.
Authors: La Rosa C , Morgan DJ , Mather LE
Published: July 2012

A three‐compartment equilibrium dialysis method was developed for the simultaneous and direct determination of drug binding in whole blood and in plasma and of the blood to plasma concentration ratio (b/p). The unbound fraction of pethidine in the blood of six healthy volunteers (0.63, s.d. 0.09, n = 23 determinations) was significantly different from that in the blood of six patients (0.72, s.d. 0.08, n = 24 determinations). There was no significant difference in the b/p of six patients (0.84, s.d. 0.09, n = 24 determinations) and six volunteers (0.90, s.d. 0.14, n = 23 determinations). The observed unbound fraction of pethidine in blood (0.6 to 0.7) was considerably lower than previously reported. As this value for the unbound fraction (0.6 to 0.7) is similar to the reported estimated hepatic extraction ratio of the drug in man, it is proposed that pethidine elimination should be described as ‘capacity limited, binding sensitive’ rather than ‘flow‐ limited’.
Azathioprine and 6‐mercaptopurine (6‐MP) suppress the human mixed lymphocyte reaction (MLR) by different mechanisms.
Authors: Al‐Safi SA , Maddocks JL
Published: July 2012

6‐MP inhibitory effects on the MLR were reversed by AIC (46%), adenine (32%), hypoxanthine (89%), adenosine (86%) and inosine (93%). AIC, adenine, hypoxanthine and inosine had no effect on azathioprine inhibition of the MLR. Adenosine at 10 microM caused 29% reversal and had no effect at 100‐400 microM on azathioprine inhibition of the MLR. Reversal of 6‐MP suppression of the MLR was decreased with the delay of adenosine addition. Guanine, xanthine and guanosine caused no reversal of 6‐MP or azathioprine inhibitory effects on the MLR. These results show that azathioprine and 6‐MP suppress the MLR by different mechanisms.
Renal actions of a uricosuric diuretic, racemic indacrinone, in man: comparison with ethacrynic acid and hydrochlorothiazide.
Authors: Brooks BA , Lant AF , McNabb WR , Noormohamed FH
Published: July 2012

The effects of indacrinone (IND) have been investigated in a two part study. First, a total of 36 clearance studies have been performed in 14 healthy volunteers, under conditions of either maximal hydration or hydropenia, to compare the renal sites of action of single oral doses of IND, 20 mg, ethacrynic acid (EA), 100 mg, and hydrochorothiazide (HCTZ), 100 mg. Under conditions of maximal water hydration, IND increased fractional Na+ excretion from a mean of 1.19 +/‐ 0.05 to 4.93 +/‐ 0.67% of GFR. This was similar to the response seen with HCTZ, which increased fractional Na+ clearance up to 3.16 +/‐ 0.17% of GFR; EA increased fractional Na+ excretion up to 14.5 +/‐ 2.5% of GFR. The mean reduction in fractional free‐water clearance (CH2O/GFR X 100%) invoked by IND, (delta = −34.8% of control) was similar to that produced by EA, (delta = −27.2% of control), and by HCTZ, (delta = ‐ 26.6% of control). During hydropenia with superimposed mannitol diuresis, both IND and EA caused a fall in fractional free‐water reabsorption (TcH2O/GFR X 100%), delta IND = −20.3% of control, delta EA = −70.1% of control. HCTZ produced a significant increase in fractional free‐water reabsorption, delta HCTZ = −20.7% of control. In all studies, single doses of IND were both uricosuric and hypouricaemic. Fractional urate excretion increased from a mean 6.7 +/‐ 0.1 to 15.2 +/‐ 2.1% of GFR whilst plasma urate concentration fell from a mean of 0.36 +/‐ 0.03 to 0.34 +/‐ 0.03 mM (P less than 0.05) within 2‐ 3 h post drug. HCTZ and EA, in single doses, had little effect on urate excretion. In the second part of the study, a total of 16 healthy volunteers received either IND, 10 mg, or HCTZ 50 mg, orally for 8 days, whilst on a diet of controlled electrolyte content. Both drugs were well tolerated by both sets of subjects with no adverse clinical or pathological findings. Both IND and HCTZ caused a significant reduction in weight and standing systolic blood‐pressure during the first 48 h of therapy. At the doses administered, IND and HCTZ displayed similar diuretic responses with respect to water, Na+, Cl‐, Ca2+ and PO4(3‐) excretion. IND produced less kaliuresis than HCTZ during the first treatment day but cumulative K+ loss was similar for both drugs over the eight days of therapy. Fractional urate excretion after IND remained elevated throughout the 8 days of therapy and the subjects remained isouricaemic for 7 days.(ABSTRACT TRUNCATED AT 400 WORDS)
Prediction of metabolic drug interactions involving beta‐adrenoceptor blocking drugs.
Authors: Park BK
Published: July 2012

There is evidence, from human and animal studies, that drug‐ metabolising enzymes exist in multiple forms, the individual enzymes having selective, but not specific, substrate requirements. Consequently drug interactions may arise when two drugs bind to the same enzyme. The degree of enzyme inhibition will be partly dependent on the relative affinities of the drugs for the enzyme and on their rates of turnover. The decrease in drug clearance produced by enzyme inhibition is dependent on the fraction of the drug normally metabolised by the inhibited pathway(s). Cimetidine, a P‐450 enzyme inhibitor, increases the systemic bioavailability of propranolol and labetalol, which undergo extensive metabolism, but does not affect the clearance of atenolol, which is excreted largely unchanged. In this situation, both the extent and type of biotransformation are important. Thus, cimetidine has no effect on the clearance of penbutolol, even though the drug is eliminated almost entirely by biotransformation. The major metabolite is penbutolol glucuronide, and it has been shown recently that cimetidine does not inhibit glucuronylation. Beta‐ adrenoceptor blockers also act as enzyme inhibitors themselves. For example, antipyrine clearance is decreased by propranolol and to a lesser extent by metoprolol, whereas atenolol has no effect. It has been suggested, therefore, that there is a relationship between the lipid‐solubility of beta‐adrenoceptor blockers and their ability to inhibit drug metabolism. The clearance of lipophilic beta‐adrenoceptor blockers is dependent on hepatic enzyme activity, and is therefore sensitive to enzyme induction. For drugs with high hepatic clearance and subsequent high presystemic elimination, a moderate increase in the extraction ratio will produce a marked decrease in systemic bioavailability. (ABSTRACT TRUNCATED AT 250 WORDS)
Diazepam/beta‐adrenoceptor antagonist interactions.
Authors: Hawksworth G , Betts T , Crowe A , Knight R , Nyemitei‐Addo I , Parry K , Petrie JC , Raffle A , Parsons A
Published: July 2012

The effects of diazepam on the pharmacokinetics and pharmacodynamics of two lipophilic beta‐adrenoceptor antagonists (propranolol and metoprolol) and a hydrophilic beta‐adrenoceptor antagonist (atenolol) were compared in 12 subjects. Administration of propranolol and metoprolol produced small increases in the AUC0‐8h for diazepam compared with placebo (P less than 0.05 for metoprolol). Atenolol had no significant effect on the AUC0‐8h for diazepam. The increase in the AUC0‐8h was accompanied by increases in the plasma concentrations of N‐ desmethyldiazepam. Diazepam had no significant effect on the pharmacokinetics of either propranolol or atenolol. The pharmacokinetic interaction could be attributed to inhibition of diazepam metabolism by the lipophilic beta‐adrenoceptor antagonists. The pharmacodynamic studies showed that when compared with placebo or atenolol there was a significant impairment of kinetic visual acuity (KVA) when diazepam was co‐administered with metoprolol. Although there was a significant correlation (P less than 0.02) between plasma concentrations of diazepam and impairment of KVA, the pharmacodynamic interactions may not be due solely to the small pharmacokinetic interaction observed.
Beta‐adrenoceptor blocker pharmacokinetics and the oral contraceptive pill.
Authors: Kendall MJ , Jack DB , Quarterman CP , Smith SR , Zaman R
Published: July 2012

Higher AUC and Cmax values were obtained for metoprolol, oxprenolol and propranolol in groups receiving the low‐dose oestrogen‐ethinyl oestradiol oral contraceptive, but statistical significance was reached only with metoprolol AUC. The oral contraceptive had the opposite effect on acebutolol AUC and Cmax but this was not significant. The oral contraceptive had no detectable effects on the tmax and t 1/2 values of any of the beta‐adrenoceptor blockers.