bluuebunny/crossref_metadata_2025 huggingface dataset:
Sex‐related differences in the plasma protein binding of lignocaine and diazepam.
Authors: Routledge PA , Stargel WW , Kitchell BB , Barchowsky A , Shand DG
Published: July 2012

1 The percentage of lignocaine free in the plasma of ten females receiving oral contraceptive medication was significantly greater than in 17 males of similar age (18–42 years). 2 In the same subjects the percentage of diazepam free in plasma was significantly greater in the contraceptive treated group than in 11 contraceptive‐free females and significantly greater in contraceptive‐free females than in males. 3 The differences in lignocaine binding were almost completely attributable to changes in alpha 1‐acid glycoprotein concentration, which is reduced by oestrogens. The binding of diazepam was significantly related to albumin, alpha 1‐acid glycoprotein and non‐ esterified fatty acid concentrations which together were related to 55% of the variation in the binding of this basic compound.
The effects of neuroleptic drugs on 5‐hydroxytryptamine induced platelet aggregation in schizophrenic patients.
Authors: Orr MW , Knox JM , Allen R , Gelder MG , Grahame‐Smith DG
Published: July 2012

1 The effects of treatment with a range of neuroleptic drugs on 5‐ hydroxytryptamine (5‐HT) induced platelet aggregation in vivo were examined in a group of recently admitted psychiatric patients and in a larger group of chronic schizophrenic patients. 2 Five of seven recently admitted patients treated with chlorpromazine showed enhanced aggregation. Four of seven patients treated with fluphenazine, flupenthixol, trifluoperazine and haloperidol showed enhancement. 3 Enhanced aggregation responses were observed in only 20% of chronic schizophrenic patients being treated with a neuroleptic drug. 4 The relationship between changes in platelet aggregation and clinical changes in recently admitted patients was variable and platelet aggregation responses were not predictive of response to treatment. 5 Chronic schizophrenic patients with enhanced aggregation showed significant week to week variation in platelet aggregation response. Variability of responses was not related to the drug used or to the dose administered. There was some evidence that higher plasma concentrations of neuroleptic drugs were associated with enhanced platelet aggregation responses. 6 Treatment with neuroleptic drugs leads to enhancement of platelet aggregation responses induced by 5‐HT. The frequency and reliability with which such responses can be elicited is unpredictable and the value of platelet aggregation responses as an empirical guide to treatment with neuroleptic drugs is therefore open to question.
Comparative pharmacokinetics of theophylline and aminophylline in man.
Authors: Aslaksen A , Bakke OM , Vigander T
Published: July 2012

1 The pharmacokinetics of theophylline and aminophylline was compared after oral administration and intravenous infusion. 2 Theophylline (250 mg) and aminophylline (390 mg) were taken orally by eight healthy volunteers in a randomized cross‐over study. 3 In another cross‐over study theophylline and aminophylline were administered intravenously to six healthy volunteers at a dose corresponding to 5 mg/kg pure theophylline. 4 The protein binding of the theophylline in serum collected during the intravenous study was studied by ultrafiltration. The serum concentration of theophylline was measured by high pressure liquid chromatography. 5 Almost identical concentration‐time curves were found for theophylline and aminophylline in both of the studies. No significant difference was found in the pharmacokinetic parameters or protein binding with the two preparations.
A comparison of the effects of hydrallazine, diazoxide, sodium nitrite and sodium nitroprusside on human isolated arteries and veins.
Authors: Moulds RF , Jauernig RA , Shaw J
Published: July 2012

1 Human common palmar digital arteries and dorsal metacarpal veins have been studied in vitro to investigate the responses of arterial and venous muscle to hydrallazine, diazoxide, nitroprusside and sodium nitrite. 2 Tissues were removed at autopsy, cut into helical strips and suspended in organ baths under identical conditions. The contractile response to noradrenaline was tested in the presence of the same concentrations of the vasodilator drugs in arteries and veins. 3 Hydrallazine antagonised contraction of arteries, but not veins to noradrenaline. Diazoxide, nitroprusside or sodium nitrite antagonised responses in both arteries and veins. Diazoxide and nitrite were more effective on arteries and nitroprusside was more effective on veins. 4 These results are in accord with clinical observations and confirm that there are differences in the susceptibility of human arterial and venous smooth muscle to vasorelaxant drugs.
Observation on the efficacy and pharmacokinetics of betaxolol (SL 75212), a cardioselective beta‐adrenoceptor blocking drug.
Authors: Balnave K , Neill JD , Russell CJ , Harron DW , Leahey WJ , Wilson R , Shanks RG
Published: July 2012

1 Observations were made in five subjects who exercised before and at 2, 3, 6, 8, 24, 33 and 48 h after the oral administration of placebo and 5, 10, 20 and 40 mg betaxolol. 2 The exercise heart rate remained constant at all times after the placebo. All doses of betaxolol significantly reduced the exercise tachycardia at all times. The maximum effect (34.4 +/− 2.2%) occurred after 40 mg. 3 There was a small decline in effect from the peak to 24 h when 40 mg produced a 23.3 +/− 2.7% reduction and a further decline to 48 h when there was a 14.6 +/− 1.8% reduction. 4 Plasma levels of betaxolol were measured in these studies. The peak plasma concentration occurred between 3 and 8 h with different doses. The plasma elimination half‐lives after 10, 20 and 40 mg were 11.4 +/− 2.5, 15.9 +/− 4.9 and 15.1 +/− 3.1 h. 5 The effects of 40 mg betaxolol, 200 mg atenolol, 160 mg propranolol, 160 mg oxprenolol, 400 mg sotalol and placebo on an exercise tachycardia were compared in five subjects who received all treatments in random order. 6 There was no significant difference in the maximum reduction produced in an exercise tachycardia by the different drugs. 7 The effect of all drugs decreased with time. The effect of oxprenolol had worn off at 24 h but at 48 h only atenolol and betaxolol produced significant reductions in the exercise tachycardia. 8 Plasma concentrations of the different drugs were measured and plasma elimination half‐lives determined. The half‐life for betaxolol was 24.5 h which was longer than that for any of the other drugs. 9 These observations show that betaxolol is a potent beta‐adrenoceptor antagonist with a long duration of effect on an exercise tachycardia and a long plasma elimination half‐ life.
Total and free serum haloperidol levels in schizophrenic patients and the effect of age thioridazine and fatty acid on haloperidol‐serum protein binding in vitro.
Authors: Rowell FJ , Hui SM , Fairbairn AF , Eccleston D
Published: July 2012

1 Using radioimmunoassays, steady‐state levels of total and free haloperidol (obtained by ultrafiltration and dialysis) have been determined in twenty‐two patients on long term treatment receiving doses from 3 to 45 mg per day. 2 For the group, both total serum concentration and free drug concentration showed significant correlations (P less than 0.001) with daily dose. 3 No significant correlation was observed between age of the patient and percentage free haloperidol in serum. 4 In vitro experiments using sera from twenty‐ three healthy volunteers showed significant negative correlations (P less than 0.01) between age and percentage free haloperidol. 5 Thioridazine and oleic acid significantly enhanced the percentage of free haloperidol in normal human sera in vitro.
Effect of a new angiotensin converting enzyme inhibitor MK 421 and its lysine analogue on the components of the renin system in healthy subjects.
Authors: Brunner DB , Desponds G , Biollaz J , Keller I , Ferber F , Gavras H , Brunner HR , Schelling JL
Published: July 2012

1 MK 421 and its lysine analogue are two new inhibitors of angiotensin converting enzyme. Ten mg of both compounds were each given p.o. to 12 normotensive volunteers to determine their effect on the various components of the renin angiotensin aldosterone system. 2 Plasma converting enzyme activity decreased to very low levels within 3 to 4 h to recover only slowly over the next 72 h. Plasma angiotensin II and aldosterone also fell but returned to baseline within 24 h, whereas plasma renin activity rose reflecting the low angiotensin II levels. 3 There was a close correlation between both angiotensin II and aldosterone levels and the logarithm of plasma converting enzyme activity demonstrating that angiotensin II and aldosterone fell only when converting enzyme activity was reduced to very low levels. 4 Mean hourly urinary sodium excretion increased markedly 6 to 10 h post‐drug, while blood pressure decreased slightly. Both drugs were well tolerated. 5 Thus 10 mg of MK 421 or its lysine analogue given orally are effective and long acting angiotensin converting enzyme inhibitors.
Physiological and pharmacological variability in estimated hepatic blood flow in man.
Authors: Daneshmend TK , Jackson L , Roberts CJ
Published: July 2012

1 Changes in hepatic blood flow have been estimated by measurement of single‐dose indocyanine green kinetics in groups of healthy individuals. 2 The effects of change in posture, exercise and ingestion of milk on estimated hepatic blood flow have been assessed. 3 The erect posture and exercise significantly decreased ICG clearance. However, no consistent change was noted after ingestion of milk. 4 The effects of the adrenoceptor blocking drugs phenoxybenzamine, propranolol and labetalol on hepatic blood flow were also assessed. 5 Propranolol and labetalol caused a significant fall in ICG clearance in the supine position. Phenoxybenzamine did not show a consistent change. 6 Posture, exercise and adrenoceptor blockade appear to be important variables affecting hepatic blood flow. They should be considered when kinetics of high‐clearance drugs are measured, and may provide a useful model for the assessment of the effects of alterations in hepatic blood flow on the clearance of drugs.
The effects of chronic oral cimetidine therapy on the cardiovascular system in man.
Authors: Saltissi S , Crowther A , Byrne C , Coltart DJ
Published: July 2012

1 The demonstration of histamine (H2) receptors in the cardiovascular system in man and the widespread use of the specific H2 receptor antagonist cimetidine for the treatment of peptic ulcer has necessitated assessment of the cardiovascular effects of this drug during oral therapy in man. 2 Consequently, nineteen patients with a history of peptic ulcer but in symptomatic remission underwent a double‐ blind crossover trial of oral cimetidine v placebo, each treatment period lasting 4 weeks. No significant difference in various cardiac parameters at rest (heart rate, blood pressure, ECG) or following a maximal treadmill exercise test (time‐into‐protocol, maximum heart rate and blood pressure) was found between the groups. Similarly, cimetidine produced no change in the incidence of ventricular ectopics or in heart rate on 24 h ambulatory monitoring and had no effect on left ventricular volume or contractility as measured by echocardiography. 3 Thus oral administration of cimetidine in a dose of 400 mg four times daily was associated with no demonstrable cardiovascular changes. In addition, since this dose is thought compatible with cardiovascular H2 receptor blockade this study favours the lack of a physiological role for these receptors in man.
Acetanilide and paracetamol pharmacokinetics before and during phenytoin administration: genetic control of induction?
Authors: Cunningham JL , Evans DA
Published: July 2012

1 Steady state plasma concentrations (SSPCs) of acetanilide (AA) and its metabolite, paracetamol (PL), were studied in 27 healthy volunteer subjects before and at the end of an 11‐day exposure to phenytoin (DPH). Plasma concentrations of DPH were estimated. Plasma concentrations of DPH varied from 5.1 to 20.4 μg ml−1 (mean ± s.e.mean 12.2 ± 0.9). 2 The SSPC of AA before exposure to DPH varied from 0.06 to 0.67 μg ml−1 (mean ± s.e.mean 0.24 ± 0.02), and following exposure from 0.03 to 0.47 μg ml−1 (mean ± s.e. mean 0.15 ± 0.02). 3 The SSPC of PL before exposure to DPH varied from 1.2 to 4.4 μg ml−1 (mean ± s.e.mean 2.7 ± 0.13), and following exposure from 1.1 to 3.8 μg ml−1 (mean ± s.e.mean 2.2 ± 0.13). 4 SSPCs of AA and of PL decreased significantly during DPH administration (P<0.01 for AA, P<0.001 for PL). 5 Correlations were observed between the SSPCs of the drugs measured, suggesting a common influence on their kinetics. 6 Similarity was observed between the changes in plasma levels of AA and PL following DPH ingestion. There was, however, wide inter‐subject variability in this regard. In some subjects no change was observed even though they had DPH demonstrable in their plasma. Consequently it may be speculated that the effects of DPH may be under genetic control.
Effects of caroxazone, a reversible monoamine oxidase inhibitor, on the pressor response to oral tyramine in man
Authors: Martini A , Bonollo L , Nicolis FB , Sega R , Palermo A
Published: July 2012

1 A double‐blind, placebo‐controlled study was carried out in order to investigate the effects of caroxazone, a new antidepressant drug endowed with a reversible short‐lasting MAO‐inhibitory activity in man, on the blood pressure response to tyramine administered by the oral route. 2 The study was carried out in 9 healthy volunteers who were randomly assigned to treatment with caroxazone 200 mg three times daily (7 subjects) or with indistinguishable placebo (2 subjects). 3 The sensitivity to tyramine was assessed in each subject both before and after the 7‐9 days of treatment. 4. While placebo did not modify the pressor response to tyramine, the threshold dose of tyramine which induced a rise in systolic blood pressure was lowered by about four‐ fold in 6 out of the 7 subjects treated with caroxazone. In the seventh subject the observed potentiation of peroral tyramine was not quantitatively evaluable. 5 Challenges performed in three subjects after discontinuation of treatment with caroxazone show that the effects of the compound are short‐lasting, since the sensitivity to tyramine seems to regain the baseline value within 1‐2 days. 6 Even if caroxazone potentiates peroral tyramine to a relatively low degree, a tyramine poor diet is recommended for patients during caroxazone treatment. 7 The reversibility of the MAO‐inhibitory action of caroxazone is confirmed by the rapid return to normal values in the response to tyramine after discontinuation of treatment. This property of caroxazone would allow patients to return to a free diet in much less time than the safety limit of 2 weeks recommended for the currently used irreversible MAO‐inhibitors.
Dose‐related effects of phenobarbitone on human sleep‐waking patterns.
Authors: Karacan I , Orr W , Roth T , Kramer M , Thornby J , Bingham S , Kay D
Published: July 2012

1 Twenty‐four healthy male subjects had two consecutive drug nights at 2‐week intervals using placebo and 80, 140 and 240 mg doses of phenobarbitone in a double‐blind cross‐over design. 2 Phenobarbitone produced significant dose‐related decreases in sleep latency and number of awakenings, along with increased total sleep time. 3 Both subjective and objective measures of sleep indicated the presence of cumulative (first v second night) effects of phenobarbitone, especially decreases in the number of awakenings and in delta waveform activity. 4 Measures of REM sleep were highly sensitive to phenobarbitone. The high dose decreased REM density to 30% of baseline on the first night and to 18% on the second night. 5 EEG alpha activity was decreased, beta activity was increased and sigma spindle activity was unaffected by phenobarbitone during sleep. 6 Subjects experienced some impairment of cognitive performance along with residual sedation the following morning.
Dissociation of histamine release and clinical improvement following treatment of acquired cold urticaria by prednisone.
Authors: Black AK , Keahey TM , Eady RA , Greaves MW
Published: July 2012

1 Corticosteroids are known to suppress evoked histamine release from human skin in vitro. Therefore the effect of prednisone, on cold evoked histamine release and clinical response was studied in six patients with acquired cold urticaria. 2 Following cold challenge all six patients developed an immediate urticarial response of the forearm and elevation of histamine levels, measured by superfusion cascade bioassay of the venous blood draining the forearm. 3 After treatment with prednisone, in an oral dose of 20‐25 mg for 1 to 5 days, a suppression of evoked histamine release occurred in all but one patient. However, there was no corresponding decrease of erythema or oedema, though pruritus was improved in most patients. 4 The lack of clinical improvement in erythema and oedema, despite reduction in histamine levels, suggests that histamine may not be the principal mediator of the vascular response to cold challenge in acquired cold urticaria.
The effect of labetalol and propranolol on the pressor response to sexual arousal in women.
Authors: Riley AJ , Riley EJ
Published: July 2012

1 The effect of a single oral dose of labetalol (100 mg), propranolol (80 mg) and placebo on the pressor response to sexual autostimulation has been studied in six female volunteers. 2 Labetalol but not propranolol significantly reduced the increase in blood pressure that occurred at orgasm. 3 The subjective features of the sexual response were assessed by each subject using visual analogue scales. 4 Subjects reported a significant reduction in vaginal lubrication with labetalol compared to both placebo and propranolol. 5 No other effects were noted.
Circulatory and metabolic effects of a combined alpha‐ and beta‐ adrenoceptor blocker (labetalol) in hypertension of pregnancy.
Authors: Lunell NO , Hjemdahl P , Fredholm BB , Nisell H , Persson B , Wager J
Published: July 2012

1 Seven women with hypertension of pregnancy were given the combined alpha‐ and beta‐adrenoceptor blocking drug labetalol (50 mg i.v.) in their last trimester. Acute effects were studied for 3 h after administration. 2 Systolic and diastolic blood pressures were significantly reduced from 143 +/‐ 4 (s.e. mean) to 127 +/‐ 5 mmHg and from 101 +/‐ 2 to 88 +/‐ 2 mmHg, respectively. Maternal heart rate fell significantly from 77 +/‐ 5 to 68 +/‐ 3 beats/min. The changes remained during the 3 h of observation. Foetal heart rate was not affected. No side‐effects were encountered. 3 Plasma noradrenaline increased significantly from 1.54 +/‐ 0.16 to a peak value of 2.37 +/‐ 0.41 nmol/l suggesting sympathetic activation following labetalol. Plasma adrenaline levels were essentially unchanged. Plasma glucose, insulin and C‐peptide showed only minor changes. No major effects on lipid metabolism were seen except a significant fall of nonesterified fatty acids at 60 min. Plasma cyclic AMP increased significantly throughout the observation period, perhaps indicating beta‐adrenoceptor agonist activity of labetalol. 4 The effectiveness of labetalol as an acute hypertensive agent together with apparent absence of metabolic disturbances and other side‐effects makes it an interesting drug for the treatment of hypertension during pregnancy.
Prazosin disposition in young and elderly subjects.
Authors: Rubin PC , Scott PJ , Reid JL
Published: July 2012

1 The disposition of prazosin following oral and intravenous administration has been studied in seven young and seven elderly men, all of whom were in good health and living independently in the community. 2 The elimination half‐life (min) of prazosin was 123 +/‐ 19.4 (s.d.) in the young and 194 +/‐ 36 in the elderly (P less than 0.01). 3 Clearance (ml min‐1 kg‐1) was 3.94 +/‐ 0.73 in the young and 3.53 +/‐ 1 in the elderly (P greater than 0.1). Volume of distribution at steady state (1 kg‐1) was 0.63 +/‐ 0.14 in the young and 0.89 +/‐ 0.26 in the elderly (P less than 0.05). 4 The absolute bioavailability of orally administered prazosin was 0.68 +/‐ 0.17 in the young and 0.48 +/‐ 0.16 in the elderly (P less than 0.05). 5 The significant increase in prazosin half‐life in the elderly results from an increased volume of distribution, not from decreased clearance. 6 Gastrointestinal absorption of prazosin decreases in old age.
A study of conjugation and drug elimination in the human neonate.
Authors: Cummings AJ , Whitelaw AG
Published: July 2012

1 An investigation has been made of the excretion of alpha‐methyldopa, alpha‐methyldopa sulphate, lorazepam and lorazepam glucuronide in the urine of neonates. 2 The rate of elimination of both the drugs in the newborn is slow compared with the adult rate, and apparent half‐life being 3 to 4 times longer than the reported adult values. 3 The newborn appear able to readily metabolise alpha‐methyldopa to alpha‐methyldopa sulphate and to slowly conjugate lorazepam with glucuronic acid. alpha‐ Methyldopa tends to be conjugated to a greater extent and lorazepam to about the same or slightly lesser extent in the newborn than in adults. 4 It is postulated that elimination in the neonate is mainly controlled by the rate of renal excretion in the case of alpha‐methyldopa and by the rate of conjugation in the case of lorazepam.
Epoxide hydrolase activity in human skin.
Authors: O'Neill VA , Rawlins MD , Chapman PH
Published: July 2012

1 Epoxide hydrolase (EH) activity was measured in biopsied skin (n = 42) using 7‐[H3]‐styrene oxide as substrate, and separation of the products by high performance liquid chromatography. 2 EH activity (mean +/‐ s.d.) was present in separated epidermis (139 +/‐ 105 pmol glycol formed mg‐1 min‐1) and dermis (165 +/‐ 120 pmol glycol formed mg‐1 microsomal protein min‐1). 3 Whole skin EH activity (mean +/‐ s.d.) varied widely (433 +/‐ 254 pmol glycol formed mg‐1 microsomal protein min‐1) 4 No significant difference in EH activity was observed in skin from breast, penis and leg. 5 Skin EH activity does not appear to contribute significantly to the systemic metabolism of epoxide, but may be important in determining the effects of epoxides formed within the epidermis.
Theophylline pharmacokinetics in advanced age.
Authors: Antal EJ , Kramer PA , Mercik SA , Chapron DJ , Lawson IR
Published: July 2012

1 Theophylline kinetics following a single oral dose were characterized and compared in non‐institutionalized ambulatory elderly and young gender‐matched control subjects. Study design stressed stringent, yet realistic, control of several external factors known to influence theophylline metabolism. 2 Plasma levels of total drug were significantly higher in the elderly only at early sampling times (0.5 and 1 h) and at 36 h, while unbound theophylline levels were significantly higher (P less than 0.05) at all sampling times resulting in a 45% greater AUC for unbound drug. 3 While no significant differences in volume of distribution (Vd) or overall plasma clearance were observed when calculations were based on total plasma theophylline, a 37% reduction in Vd (P less than 0.005) and a 30% reduction in overall plasma clearance (P less than 0.02) in the elderly became apparent when plasma protein binding was taken into account. 4 When urinary excretion patterns were compared, the elderly were found to have excreted a significantly higher fraction of the recovered dose as 1‐methyluric acid (P less than 0.01) and a lower fraction as unchanged theophylline (P less than 0.02). A 47% reduction in the renal clearance of unbound theophylline (P less than 0.005) was also observed in the elderly. 5 Results were consistent with less viable metabolism and renal excretion pathways for theophylline elimination in the elderly and serve to reemphasize the importance of including an assessment of plasma protein binding in studies of drug disposition in the elderly.
Clonidine kinetics in man‐evidence for dose dependency and changed pharmacokinetics during chronic therapy.
Authors: Frisk‐Holmberg M , Paalzow L , Edlund PO
Published: July 2012

1 Clonidine kinetics were studied in 21 patients with essential hypertension. All received two bolus i.v. injections in the mean dose range of (0.78–3.36 micrograms kg‐1) and one single oral dose (mean dose 1.7–2.3 micrograms kg‐1) on separate occasions. The kinetics were also studied in some of these patients after multiple therapeutic oral dose (mean dose 1.1 or 1.9 micrograms kg‐1) twice daily during a dosage interval after 6–12 months monotherapy with clonidine. The multiple oral dosage was based on the therapeutic response. 2 With increasing i.v. doses the rate constants (alpha, beta) decreased and the plasma clearance was reduced by 74% (9.94–2.61 ml min‐1 kg‐1) indicating dose‐ dependent kinetics. The volume of distribution (Vd beta) did not change with dose in contrast to the volume of the plasma compartment (Vc) which was increased at the highest doses. 3 The single oral dose kinetics agreed with the i.v. kinetics at comparable dose. The bioavailability was 90%. 4 During multiple oral dosing the elimination rate constants decreased compared to the single dose. The plasma clearance increased (7.18 ml min‐1 kg‐1) compared to the corresponding single dose (4.17 ml min‐1 kg‐1). The latter change was probably caused by the decrease in bioavailability to about 65%. 5 The pharmacodynamic properties of the drug could explain the changes in pharmacokinetics with increased dose and during multiple doses.
Correlation between antithyroid effect and serum concentrations of propylthiouracil in patients with hyperthyroidism.
Authors: Kampmann JP , Hansen Molholm JE
Published: July 2012

1 Correlation between the kinetics of propylthiouracil and its antithyroid effect was studied in 17 hyperthyroid patients. The serum concentration of propylthiouracil 1 h after an oral dose of 400 mg of hyperthyroid patients. The serum concentration of propylthiouracil 1 h after an oral dose of 400 mg of the drug was used as kinetic parameter as this concentration from the previous study was found to correlate significantly (r = 0.84, P less than 0.01) with the area under the serum concentration‐time curve. 2 After 3 weeks of treatment with 200 mg propylthiouracil three times daily the serum concentration of propylthiouracil was correlated to the decrease in various thyroid parameters such as total and free indexes of serum thyroxine, triiodothyronine and reverse triiodothyronine. 3 Significant correlations were found between the serum concentration of propylthiouracil and all the measured thyroid variables except reverse triiodothyronine. The highest degree of correlation was obtained between serum propylthiouracil and the percentage decrease in total and free indexes of triiodothyronine (r = 0.63 and 0.70, respectively, P less than 0.01). 4 It is suggested that a serum concentration of propylthiouracil above 4 to 5 micrograms/ml 1 h after an oral dose of 400 mg of the drug will secure a sufficient and rapid antithyroid effect during continuous therapy.
Acceptable sampling times at plateau for drug analysis.
Authors: Rowland M , Unadkat JD
Published: July 2012

1 Two methods of estimating the average plasma drug concentration at plateau Cav are considered. 2 Given an acceptable error in the estimate of Cav, a range of sampling times, rather than a single time, during the dosing interval, can be calculated. This range depends on the variability of the half‐life within the patient population, the dosing interval, the error in assay measurement and the therapeutic index of the drug. 3 When the minimum plasma drug concentration is monitored, an estimate of the individual's half‐life is needed, unless the dosing interval is short. Then the population half‐life may be used to obtain a reasonable estimate of Cav.
The effect of co‐trimoxazole on serum creatinine.
Authors: Dijkmans BA , Van Hooff JP , de Wolff FA , Mattie H
Published: July 2012

1 Co‐trimoxazole induces a highly significant and reversible elevation of the serum creatinine level. 2 In renal‐allograft patients the degree of this elevation is significantly correlated with the concentration of serum creatinine before administration of co‐trimoxazole and with the concentration of non‐protein‐bound trimethoprim.
Speed of onset of pharmacodynamic activity of propranolol, practolol, oxprenolol and metoprolol after intravenous infection in man.
Authors: Lochan R , Silke B , Taylor SH
Published: July 2012

1 The speed of onset of the pharmacodynamic activity of intravenous propranolol, practolol, oxprenolol and metoprolol was determined, using attenuation of isoprenaline‐induced tachycardia as the end‐point, in 16 patients with clinically coronary heart disease. 2 Antagonism was evident within 15 s of injection into the central circulation of all four drugs. The time to maximum attenuation of isoprenaline tachycardia was significantly more rapid with propranolol and oxprenolol than with practolol and metoprolol.
Atenolol in the treatment of pregnancy‐induced hypertension.
Authors: Thorley KJ , McAinsh J , Cruickshank JM
Published: July 2012

1 The pharmacological properties of atenolol suggest its possible usefulness in pregnancy‐induced hypertension. The pharmacokinetics of atenolol in the pregnant woman, concentrations in cord blood, and its effects on maternal blood pressure and the foetus, are evaluated. 2 We studied 13 pregnant women with hypertension, most of them uncontrolled on methyldopa. Whole blood concentrations and urinary excretion of the drug were measured over 24 h following a 100 mg dose. Effects on maternal blood pressure, pulse rate and foetal heart rate and cardiotocograph were compared for the 4 days before treatment and the first 4 days of treatment. The birth weights and Apgar scores of the babies were recorded. 2 The pharmacokinetics of atenolol (plasma half‐ life of about 8 h) in pregnant women do not differ from the findings in the non‐pregnant. The levels of atenolol in the cord blood were confirmed as approximately equal to those in the maternal blood. 4 In the ten women in whom blood pressure was assessed a small significant fall in blood pressure was observed. 5 A 5% mean fall in foetal heart rate resulted but in one case was a rate below 120 beats/min recorded. There was no evidence of depression of the stress response of the foetal heart. Apgar scores 5 min post partum were satisfactory. 6 Atenolol appears to be safe for use in hypertensive pregnancies. Its effectiveness as an antihypertensive agent in pregnancy requires further controlled evaluation.
Diazepam kinetics in patients with renal insufficiency or hyperthyroidism.
Authors: Ochs HR , Greenblatt DJ , Kaschell HJ , Klehr U , Divoll M , Abernethy DR
Published: July 2012

1 Eight patients with end‐stage renal insufficiency on maintenance haemodialysis, and seven patients with newly diagnosed hyperthyroidism, received a single intravenous dose of diazepam, followed by blood sampling over the next 7 days. Fifteen healthy volunteer controls, matched with patients for age and sex, were similarly studied. 2 Diazepam half‐life in renal failure patients (mean 37 h) was greatly reduced compared to controls (mean 92 h, P less than 0.05) and clearance of total (free plus bound) diazepam correspondingly increased (0.94 v 0.34 ml min‐1 kg‐1, P less than 0.01). 3 However, differences were largely related to disease‐related changes in drug binding and distribution. Mean unbound fraction of diazepam in plasma of renal patients (7.0%) was greatly increased over controls (1.4%, P less than 0.01) and Vd of unbound diazepam greatly reduced (57 v 157 l/kg, P less than 0.01). 4 Clearance of pharmacologically active unbound diazepam (intrinsic clearance) was not significantly different between renal patients and controls (23 vs 30 ml min‐1 kg‐1). 5 None of the kinetic variables for total or unbound diazepam in thyrotoxic patients differed significantly from those in controls matched for age and sex. 6 End‐ stage renal failure (or its associated drug therapy) alters diazepam protein binding and distribution, but does not significantly change clearance of unbound drug. Thyrotoxicosis does not influence diazepam kinetics.
The effect of chronic propranolol treatment on overnight plasma levels of anterior pituitary and related hormones.
Authors: Dart AM , Lewis MJ , Groom GV , Meek EM , Henderson AH
Published: July 2012

1 Treatment of eight healthy males with propranolol (80 mg twice daily) for 6 weeks resulted in a significant reduction in overnight plasma levels of prolactin and LH. 2 Plasma testosterone levels were elevated whilst GH and cortisol were unchanged by such treatment. 3 Measurement of overnight hormone levels 48 h after discontinuing treatment showed no evidence of a ‘rebound’ phenomenon. 4 Cortisol, GH, prolactin, and testosterone plasma levels all showed time dependent changes: propranolol treatment significantly altered the time course of cortisol but not of the other hormones. 5 The effects of chronic propranolol treatment are discussed in terms of a probable direct central action of the drug. In addition the lowered plasma prolactin levels may directly contribute to the hypotensive action of propranolol.
The pharmacokinetics of nortriptyline in patients with chronic renal failure.
Authors: Dawlilng S , Lynn K , Rosser R , Braithwaite R
Published: July 2012

1 The pharmacokinetics of single oral doses of nortriptyline were studied in twenty patients with chronic renal failure, eight of whom were receiving treatment with haemodialysis. 2 The median nortriptyline half‐life was 25.2 h (range 14.5‐140.0 h) and the median nortriptyline clearance was 32.3 l/h (range 8.1‐122.0 l/h). 3 No differences were observed between the dialysed and non‐dialysed groups. 4 Comparisons of nortriptyline half‐life and clearance between the patients and groups of physically healthy subjects revealed no significant differences. 5 There was no significant linear correlation between age and either of these measurements. In the twelve patients not receiving haemodialysis there was no correlation between nortriptyline clearance and glomerular filtration rate. 6 Chronic renal failure is not associated with a significant alteration in nortriptyline metabolism as measured by its half‐life or clearance, but the drug should nonetheless be used with caution, and monitored whenever possible. However, the marked inter‐ individual differences observed in nortriptyline half‐life and clearance in patients with chronic renal failure may not be solely responsible for their unpredictable response to tricyclic antidepressant therapy, and other possible contributory factors are discussed.
Effect of cimetidine on renal function in man.
Authors: Dutt MK , Moody P , Northfield TC
Published: July 2012

1 Renal function was studied in nine patients with chronic peptic ulcer before and at repeated intervals during treatment with cimetidine (1.6g daily). 2 Plasma creatinine concentration was significantly increased on the first day after starting cimetidine, and at 3 weeks, but not at 12 weeks. Blood urea concentration was unchanged. 3. Clearances of creatinine 51Cr EDTA and 125I‐hippuran were significantly reduced within 6 h of starting cimetidine. Clearances of 51Cr EDTA and 125I‐ hippuran returned to baseline within 3 weeks, and creatinine clearance within 12 weeks. 4 Urinary creatine excretion was significantly increased at 3 weeks, but there was no significant change in urinary creatinine excretion, or in serum creatine phosphokinase concentration. 5. These observations suggest that cimetidine causes an early but short‐ lived fall in glomerular filtration rate (GFR) and effective renal plasma flow. The later rise in plasma creatinine was unaccompanied by any change in GFR, and may have been due to competition by cimetidine for renal tubular handling. 6 Caution should be exercised when administering cimetidine to patients with pre‐existing renal failure.
Kinetics of prostacyclin synthetase in umbilical artery microsomes from normal and pre‐eclamptic pregnancies.
Authors: Downing I , Shepherd GL , Lewis PJ
Published: July 2012

1 Prostacyclin synthetase in umbilical artery microsomes obeys Michaelis‐Menten kinetics. 2 The maximum velocity (Vmax) of prostacyclin synthetase prepared from normal umbilical arteries was significantly higher than the Vmax of prostacyclin synthetase in umbilical arteries taken from pre‐eclamptic pregnancies. 3 The Michaelis‐Menten constant (Km) of the two prostacyclin synthetase preparations was significantly different with the synthetase from pre‐ eclamptic arteries have a higher affinity for substrate. 4 The limiting factor for prostacyclin synthesis is Vmax at high substrate concentrations which appears to be the case in umbilical arteries. However, at low substrate concentration there would be no difference in prostacyclin synthesis by the two forms of prostacyclin synthetase.
Influence of sex, menstrual cycle and oral contraception on the disposition of nitrazepam.
Authors: Jochemsen R , Van der Graaff M , Boeijinga JK , Breimer DD
Published: July 2012

1 The effects of sex and oral contraceptives (OC) on the disposition of oral nitrazepam were studied in six healthy young males, in six healthy young females in the follicular and luteal phase of the menstrual cycle and in six healthy young females using OC‐steroids in two stages of the pill cycle. 2 There was no influence of the menstrual cycle on the pharmacokinetic parameters of nitrazepam, nor was there a significant difference between these parameters in males and females in either phase of the cycle. The elimination half‐life was 27.3 +/‐ 1.3 h in males, 27.7 +/‐ 1.5 h in females in the follicular phase and 29.6 +/‐ 1.4 h in the luteal phase of the menstrual cycle. Total plasma clearance was 59.3 +/‐ 2.7 ml/min, 58.2 +/‐ 3.3 and 55.8 +/‐ 5.0 ml/min respectively. 3 The use of OC‐steroids did not significantly alter the elimination half‐life of nitrazepam: 30.6 +/‐ 2.3 and 31.2 +/‐ 2.2 h in the first and second half of the pill cycle. The total nitrazepam clearance in these females (46.6 +/‐ 4.6 and 45.6 +/‐ 4.1 ml/min) was significantly lower than in males (P less than 0.05). 4 The protein unbound fraction of nitrazepam was progressively higher going from males (11.4 +/‐ 0.1%) to females in the luteal phase of the cycle (12.4 +/‐ 0.5%) to females using OC‐steroids (13.5 +/‐ 0.4%). Only the difference between males and females using OC‐steroids was statistically significant. 5 The clearance calculated relative to the unbound drug (intrinsic clearance) was significantly decreased in females taking OC‐steroids as compared to males and females not taking them (Cli = 323 +/‐ 30 ml/min in females using OC‐steroids, 530 +/‐ 37 ml/min in males and 459 +/‐ 40 ml/min in females). 6 The results of this study are not likely to have important consequences for dosage of nitrazepam as an hypnotic. The most pronounced effect observed was inhibition of nitrazepam clearance and especially intrinsic clearance by OC‐steroids. Females on OC‐steroids taking a nitrazepam tablet every evening, will have highly steady levels of nitrazepam (and certainly of unbound nitrazepam) than males or females not taking OC‐steroids.
Response of the renin‐angiotensin‐aldosterone system to upright tilting and to intravenous frusemide: effect of prior metoprolol and propranolol.
Authors: Sonkodi S , Agabiti‐Rosei E , Fraser R , Leckie BJ , Morton JJ , Cumming AM , Sood VP , Robertson JI
Published: July 2012

1 Upright tilting in normal volunteers caused increases in plasma active and total renin, angiotensin II and aldosterone; a slight but significant fall in inactive renin accompanied these changes. 2 The alterations in the renin‐angiotensin‐aldosterone system on tilting took up to 1 h upright to become fully established. 3 Large intravenous doses of propranolol or metoprolol attenuated, without abolishing, the rises in active renin, angiotensin II, and aldosterone; the attenuation was most evident soon after tilting and was largely overcome by 1 h upright. Inactive renin did not fall significantly after beta‐ adrenoceptor blockade. 4 Intravenous frusemide caused immediate rises in plasma active, total and inactive renin, angiotensin II, and aldosterone, which then declined over 2 h despite increasing cumulative sodium losses. 5 Intravenous propranolol or metoprolol attenuated, without abolishing, these early increases in the components of the renin‐angiotensin‐aldosterone system after frusemide. 6 Prior oral metoprolol or propranolol, while significantly slowing the heart, did not limit the early rise in plasma angiotensin II following intravenous frusemide. 7 Thus in contrast to previous workers, we did not find that propranolol eliminated the response of the renin‐angiotensin system to upright tilting; in part this difference appeared to be due to the longer tilt we employed. 8 Also in contrast to earlier work, we found attenuation by both intravenous propranolol and metoprolol of the immediate rise in renin after intravenous frusemide.
A simple pharmacokinetic method for separating the three acetylation phenotypes: a preliminary report.
Authors: Lee EJ , Lee LK
Published: July 2012

1 Until recently, phenotyping the N‐acetyltransferase enzyme had been restricted to distinguishing the slow acetylators from the rapid. Further separation of the heterozygous rapid phenotype from the homozygous rapid phenotype has only been possible by detailed pharmacokinetic studies using sulphadimidine and necessitating prolonged plasma sampling. 2 A simple method of deriving the basic pharmacokinetic parameters is presented. In this study of ten healthy volunteers, one urine sample and hourly plasma sampling over only 5 h enabled calculation of the total body (TBC) and metabolic clearances (MC) wih enough accuracy to distinguish the three (slow, intermediate and rapid) acetylator phenotypes. The spread of the distribution for the elimination rate constant was however too wide to enable their clear separation.
The use of buccal partitioning as a model to examine the effects of aluminium hydroxide gel on the absorption of propranolol.
Authors: McElnay JC , Temple DJ
Published: July 2012

1 A buccal partitioning model showed no absorption interaction between propranolol and aluminium hydroxide gel in three volunteer subjects. 2 The previously reported in vivo interaction is therefore not due to propranolol adsorption to, or complexation with the antacid but is more probably due to a decreased gastric emptying rate caused by the antacid. 2 Buccal partitioning has proved useful in the examination of the mechanism of the propranolol/aluminium hydroxide absorption interaction and may also be a suitable in vivo bioavailability screening model for other drugs which can be partitioned in the buccal membranes.
Plasma protein binding of phenytoin in the aged: in vivo studies.
Authors: Patterson M , Heazelwood R , Smithurst B , Eadie MJ
Published: July 2012

1 The relation between plasma water phenytoin content and whole plasma phenytoin content in vivo was studied in 22 elderly patients (age range 62 to 87 years) and in 22 young patients (age range 18 to 33 years), all of whom were taking the drug for epilepsy. 2 The percentage of the drug existing unbound in plasma was slightly, but statistically significantly, higher in the elderly (12.8 +/‐ 1.8%) than in the young (11.1 +/‐ 2.5%). Reduced plasma albumin levels in the elderly (33.0 +/‐ 2.0 gl‐1) as compared with the young (45.3 +/‐ 3.5 gl‐1) probably contributed to the reduced protein binding in the older subjects.
Hypnotic activity and effects on performance of lormetazepam and camazepam‐analogues of temazepam.
Authors: Nicholson AN , Stone BM
Published: July 2012

1 The effects of lormetazepam and camazepam on sleep electroencephalography, visuo‐motor coordination, digit symbol substitution and subjective assessments of mood and sleep quality were compared with placebo in six young adult males (18‐27 years). The study was double blind. 2 Over the dose range 0.5, 1.0 and 2.0 mg, lormetazepam increased total sleep time (P less than 0.05), reduced wakefulness (P less than 0.05) and drowsy sleep (linear effect P less than 0.05). With 2.0 mg there were increases in stage 3 (P less than 0.05) and reduction in rapid eye movement sleep (P less than 0.01). Overnight ingestion of 2.0 mg, was followed by impaired visuo‐motor coordination and fewer substitutions with the digit symbol test. 3 The hypnotic effect of 10‐20 mg camazepam was limited to reduced awake activity (P less than 0.05), and with 20 mg there were increased substitutions on the digit symbol test. After 40 mg overnight stage 4 sleep was reduced (P less than 0.001) and performance at the digit symbol test was impaired (P less than 0.05 at 9.75 h). Morning ingestion of 20 mg camazepam did not alter performance, and the subjects assessed themselves to be more relaxed. 4 Lormetazepam is not specially indicated for those involved in skilled activity, but may prove useful for patients with insomnia resistant to other drugs. Camazepam would appear to be a promising anxiolytic with minimal effects on performance.
Assay and characterisation of debrisoquine 4‐hydroxylase activity of microsomal fractions of human liver.
Authors: Kahn GC , Boobis AR , Murray S , Brodie MJ , Davies DS
Published: July 2012

1 A method for the assay of debrisoquine 4‐hydroxylase activity in vitro by microsomal fractions of human liver is described. The assay utilises gas chromatography‐mass spectrometry with d9‐4‐ hydroxydebrisoquine as internal standard. 2 The limit of detection of 4‐ hydroxydebrisoquine was 2 ng ml −1 and the coefficient of variation was 4.4%. 3 Debrisoquine 4‐hydroxylase activity was linear with protein to concentrations above 2.1 mg ml −1 and with incubation times of at least 15 min. 4 Debrisoquine 4‐hydroxylase is a microsomal enzyme with a requirement for NADPH. Activity was inhibited by carbon monoxide. It is concluded that the activity is catalysed by cytochrome P‐450. 5 In three samples of human liver the mean value for Vmax of debrisoquine 4‐ hydroxylase activity was 69.9 +/‐ 14.3 pmol mg −1 min −1 and for Km it was 130 +/‐ 24 microM. 6 The only variable from smoking status, alcohol ingestion, sex of the patients, source of liver sample and presence of liver disease that had a significant effect on 4‐hydroxylation of debrisoquine was the presence of liver disease. This was associated with a decrease in enzyme activity.
Saliva carbamazepine levels in children before and during multiple dosing.
Authors: Moreland TA , Priestman DA , Rylance GW
Published: July 2012

1 Saliva carbamazepine (CBZ) pharmacokinetics were determined in six children aged 7‐11 years at the start and after 5 weeks of CBZ therapy. 2 A single oral dose of CBZ, 14.7 +/‐ 2.3 mg kg −1, was administered and mixed saliva was collected at intervals during the next 36 h. CBZ therapy was then continued using the same total daily dose divided into two equal doses. After 5 weeks of therapy saliva samples were collected once more as on day 1. 3 The mean (+/‐ s.d.) saliva CBZ clearance increased over the study period from 142 +/‐ 28 to 402 +/‐ 79 ml h −1 kg −1 (P less than 0.001) and the mean half‐life decreased from 23.6 +/‐ 5.3 to 8.0 +/‐ 2.3 h (P less than 0.005). The mean apparent volume of distribution after the first dose, 4.72 +/‐ 0.84 1 kg −1, was similar to that after 5 weeks treatment, 4.66 +/‐ 1.68 1 kg −1. 4 The mean saliva steady‐state CBZ concentrations after 5 weeks therapy were less than 40% of those predicted from the single dose kinetic parameters.