bluuebunny/crossref_metadata_2025 huggingface dataset:
Peripheral analgesia: mechanism of the analgesic action of aspirin‐like drugs and opiate‐antagonists.
Authors: Ferreira SH
Published: July 2012

1 Prostaglandins released by tissue injury sensitize nociceptors and produce hyperalgesia. 2 Aspirin‐like drugs inhibit prostaglandins I2 and E2, synthesis, which explains their anti‐algic effect. 3 The anti‐ algic effect of aspirin‐like drugs in carrageenin‐induced rat paw inflammation may involve a central component. 4 Prostaglandin E2‐ induced hyperalgesia, once established, is not relieved by systemically administered drugs. 5 Prostaglandin‐induced hyperalgesia is possibly a cyclic adenosine, 3′,5′‐monophosphate C2+ dependent process. 6 Morphine, enkephalins, opiate antagonists and cyclic guanosine 3′,5′‐ monophosphate have a peripheral analgesic effect in the prostaglandin hyperalgesia test. 7 Morphine may produce peripheral analgesia by inhibiting adenylatecyclase activity at the nociceptors.
Pharmacological evaluation of mild analgesics.
Authors: Romer D
Published: July 2012

1 The analgesic, anti‐inflammatory, antipyretic and ulcerogenic properties of the non‐steroidal agents, acetylsalicylic acid, paracetamol, ibuprofen, propyphenazone and aminophenazone are compared. 2 The results show that ibuprofen has the most potent effect on all four parameters followed in descending order of potency by aminophenazone, propyphenazone, paracetamol and acetylsalicylic acid. 3 The inflamed paw technique and the adjuvant arthritis model, both in the rat and involving pathological (chronic) pain, are the most successful methods of predicting analgesic activity in man. The short‐ lasting oedema caused by injecting naphthoylheparamine into the rat paw is the most useful method of predicting clinical anti‐inflammatory activity.
Biodistribution of mild analgesics.
Authors: Brune K , Rainsford KD , Schweitzer A
Published: July 2012

1 Macro‐autoradiographic methods were used to assess the biodistribution of [3H]‐, or [14C]‐acidic (aspirin, indomethacin, phenylbutazone) and non‐acidic (antipyrine, aminopyrine, paracetamol) mild analgesics in rats with carrageenan‐induced inflammation. 2 At anti‐inflammatory doses all the acidic drugs (and/or their metabolites) were found to reach high concentrations in the stomach wall, liver, blood and bone marrow, kidney cortex and the inflamed tissue, that is, the tissues in which these drugs exert their therapeutic or side‐ effects. 3 In contrast, at analgesic doses, the non‐acidic mild analgesics (and/or their metabolites) are equally distributed throughout the body with the exception of the gastro‐intestinal lumen and the liver. This distribution pattern correlates well with the lack of acute side‐effects and anti‐inflammatory action of these drugs at therapeutic doses.
Kinetics and metabolism of paracetamol and phenacetin.
Authors: Prescott LF
Published: July 2012

1 The rate of absorption of oral paracetamol depends on the rate of gastric emptying and is usually rapid and complete. The mean systemic availability is about 75%. 2 Paracetamol is extensively metabolized and the plasma half‐life is 1.5‐2.5 hours. About 55% and 30% of a therapeutic dose is excreted in the urine as glucuronide and sulphate conjugates, respectively, whereas mercapturic acid and cysteine conjugates (representing conversion to a potentially toxic intermediate metabolite) each account for some 4% of the dose. Paracetamol metabolism is age‐ and dose‐dependent. 3 With hepatotoxic doses, paracetamol metabolism is impaired and the half‐life prolonged. Sulphate conjugation is saturated and the proportion excreted as mercapturic acid and cysteine conjugates is increased. 4 The renal clearance of paracetamol depends on urine flow rate by not pH. The renal clearances of the glucuronide and sulphate conjugates often exceed the glomerular filtration rate and are independent of urine flow and pH. 5 Phenacetin absorption depends on formulation. It is extensively metabolized to paracetamol and minor metabolites are probably responsible for toxicity.
Kinetics and metabolism of pyrazolones (propyphenazone, aminopyrine and dipyrone).
Authors: Volz M , Kellner HM
Published: July 2012

1 Propyphenazone 220 mg was administered orally to volunteers. Maximum plasma concentrations between 1.5 microgram/ml and 3.5 micrograms/ml were found 30 min later. After comparable doses plasma concentrations in dog and rabbit were lower. The distribution volumes were 2 l/kg. 2 The major metabolic route of propyphenazone is demethylation. The main urinary metabolite is the enolglucuronide of N‐(2)‐ demethylpropyphenazone. 3 Aminopyrine is rapidly and almost completely absorbed after oral administration. Maximum plasma concentrations of 10 microgram/ml are reached 1.5 h after a 500 mg dose. The biological half‐ life is 2‐3 h, the relative distribution volume 60% on average, and binding to plasma proteins approximately 15%. 4 Unchanged aminopyrine is only excreted in small quantities. The major routes of metabolism are demethylation (4‐methylaminoantipyrine and 4‐aminoantipyrine) and acylation (4‐acetyl and 4‐formylaminoantipyrine). There are other biotransformation products. 5 After oral administration of [14C]‐ dipyrone 480 mg the maximum serum concentration of 13.4 +/‐ 0.8 microgram/ml occurred at 1‐1.5 hours. 6 Dipyrone was not detectable in serum or urine. Four of seven metabolites were identified, and were identical with the main metabolites of aminopyrine.
Intoxication with pyrazolones.
Authors: Okonek S
Published: July 2012

1 About 50 severe or fatal (mostly accidental) cases of intoxication in children by pyrazolones have been reported in the German literature of the past 59 years. 2 Characteristic symptoms are impaired consciousness progressing to coma and convulsions. In addition, sudden apnoea and cardiac arrest may occur. Hepatic lesions may develop after a latent period of 12‐24 hours. 3 Haemoperfusion seems to be the only therapeutic measure which is able to reduce the total body load of all pyrazolones to a toxicologically relevant extent. Actual clinico‐ toxicological data from poisoned patients are not available as yet; however, distribution volumes, plasma half‐lives and endogenous plasma clearances as well as removal kinetics in vitro of aminophenazone (aminopyrine), propyphenazone, metamizole (dipyrone), phenylbutazone and oxyphenbutazone as point to the efficacy of haemoperfusion with amberlite XAD‐4 resin.
Analgesics, allergy and asthma.
Authors: Szczeklik A
Published: July 2012

1 Recent studies of idiosyncratic reactions to analgesics have revealed several clinical patterns with a different pathogenesis. 2 In the pathogenesis of a common type of asthma precipitated by aspirin, inhibition of cyclooxygenase leading to disturbances in metabolism of arachidonic acid is of fundamental importance. 3 In some patients with urticaria/angioedema, symptoms are due to inhibition of cyclo‐oxygenase by analgesics; in others the cause might be impurities in commercial preparations of aspirin; and in others the mechanisms are still unknown. 4 There is a distinct group of patients who develop anaphylactic shock or urticaria following administration of pyrazolone drugs, but who tolerate aspirin and other cyclo‐oxygenase inhibitors. This type of hypersensitivity seems to have an immunological background.
Antipyrine elimination by patients under treatment with monoamine oxidase inhibitors.
Authors: Smith SE , Lambourn J , Tyrer PJ
Published: July 2012

1 Antipyrine elimination kinetics have been determined in fifteen patients before and after 4 weeks treatment with monoamine oxidase inhibitors and in five patients after treatment only. 2 Antipyrine elimination was slightly but significantly slowed by 28 days treatment with phenelzine but the degree of slowing was uninfluenced by acetylator phenotype or dosage of phenelzine administered. 3 The findings suggest that at the dosage used phenelzine is a weak inhibitor of hepatic microsomal mixed function oxidase in man and it is concluded that this is likely to provide an important source of drug interaction in some patients.
Factors determining the passage of drugs from blood into saliva.
Authors: Stephen KW , McCrossan J , Mackenzie D , Macfarlane CB , Speirs CF
Published: July 2012

1. Following single oral dosing of ampicillin, cephalexin, tetracycline, erythromycin estolate, clindamycin and rifampicin to six normal volunteers, antibacterial activity was measured at 1, 3 and 6 h in serum, gingival fluid and minor gland saliva from all subjects and in parotid and submandiabular saliva from three. 2. pH values of all gingival fluid and saliva specimens were noted. 3. Partition coefficients between n‐octanol and water were measured for erythromycin, clindamycin and rifampicin. Published data were used for ampicillin, cephalexin and tetracycline. 4. All antibiotics, but particularly rifampicin, were detected in gingival fluid. Only rifampicin and to a lesser degree, clindamycin were present in the other salivary constituents. 5. In studies of secretion of drugs in saliva, both the physico‐chemical characteristics of the drugs and the physiological differences between individual salivary components should be considered. 6. Parotid saliva samples are likely to be of greatest value.
A comparison of the pharmacodynamic profiles of nomifensine and amitriptyline in normal subjects.
Authors: Chan MY , Ehsanullah R , Wadsworth J , McEwen J
Published: July 2012

1 Six healthy male volunteers participated in a double‐blind placebo crossover comparison of the pharmacodynamic profiles of single oral doses of 75 mg nomifensine and 50 mg amitriptyline. 2 Nomifensine treatment did not influence salivary flow and did not significantly affect psychomotor performance (critical flicker fusion, pursuit rotor and reaction time): in addition nomifensine had no significant effect on subjective measurements of sedation and concentration. 3 By contrast, amitriptyline treatment significantly reduced salivary flow and was associated with significant sedation and reduced concentration: significant changes in psychomotor performance were also noted. 4 Plasma concentrations of amitriptyline and nomifensine were measured at 2 h. The respective median concentration values were 55.0 ng/ml and 52.0 ng/ml. 5 Ex vivo platelet amine uptake of dopamine (DA) and 5‐ hydroxytryptamine (5HT) was measured 2 h after each treatment. Both nomifensine and amitriptyline treatment significantly inhibited DA uptake to a similar extent. Amitriptyline treatment additionally inhibited 5‐HT uptake.
Pharmacology of centrally acting hypotensive drugs.
Authors: van Zwieten PA
Published: July 2012

1. A survey is given of the various aspects of centrally acting hypotensive drugs. The majority of centrally acting hypotensive agents act by way of central alpha‐adrenoceptors, probably located in the pontomedullary region of the brain. These central receptors are stimulated by clonidine, guanfacine and various related compounds, and also by alpha‐methylnoradrenaline, generated in vivo upon biotransformation of alpha‐methyldopa within the brain. The stimulation of the alpha‐adrenoceptors induces a decrease in peripheral sympathetic tone and thus a fall in arterial blood pressure and bradycardia. 2. The possibility that presynaptic alpha‐adrenoceptors in the brain are involved in the central hypotensive action of clonidine, guanfacine and related compounds is discussed. Also, the possible involvement of central histaminergic and cholinergic receptors in central hypotensive effects is reviewed. 3. Various experimental compounds with a central hypotensive effect different from that of clonidine and related drugs are mentioned. 4. Finally, it is pointed out that the hypotensive effects of various beta‐sympatholytic drugs and of prazosin are probably not of central origin.
Differences in psychic performance with guanfacine and clonidine in normotensive subjects.
Authors: Kugler J. , Seus R. , Krauskopf R. , Brecht HM , Raschig A.
Published: July 2012

1. Doses of clonidine 0.15 mg or guanfacine 1.0 mg, respectively, and 2 h later additional doses of clonidine 0.3 mg or guanfacine 2.0 mg, respectively, were given to 24 healthy students. 2. Blood pressure was reduced by the same amount by both drugs. 3. Plasma noradrenaline concentrations decreased with both drugs, but the reduction was significantly greater following the administration of clonidine. 4. Mental activity in the EEG was less suppressed in the guanfacine group than in the clonidine group. The differences were statistically significant. 5. Self‐estimations for well‐being and mood showed only small changes due to guanfacine but significant changes due to clonidine. 6. The decrease of information processing and the increase in reaction time, measured by performance in different psychometric tests, were significantly more pronounced after clonidine treatment than guanfacine. 7. A dose‐response relationship could only be observed in vigilosomnograms, in the tests of self‐estimation related to well‐ being and mood and in the decrease in plasma noradrenaline in the clonidine group. 8. It was concluded that guanfacine had a lesser CNS depressant action than clonidine, when administered in equipotent hypotensive doses.
Comparative study of two antihypertensive agents: guanfacine and guanethidine.
Authors: Szam I. , Kallay K.
Published: July 2012

1. The antihypertensive effect and side‐effects of the new centrally acting agent guanfacine (BS 100‐141, Estulic) and guanethidine (Ismelin) were compared in a single‐blind, cross‐over study. The study consisted of two active treatment periods of 6 weeks each, both preceded by a 1‐3 weeks placebo period. 2. Sixteen ambulant patients (six male, ten female) with mild or moderate hypertension were admitted to the study. The patients were also receiving diuretic therapy (clopamide 10‐20 mg daily). On average the optimal daily dose of guanfacine was 3 mg and of guanethidine 20 mg. 3. An equally large and significant decrease in blood pressure was produced by both drugs. Both guanfacine and guanethidine caused a very slight reduction in heart rate. Mild orthostatic hypotension occurred in 11 patients during guanethidine therapy. Dryness of the mouth occurred in 13 patients taking guanfacine.
Guanfacine and glucose metabolism.
Authors: Sailer S. , Lisch HJ , Patsch W.
Published: July 2012

1. The effect of a single dose of guanfacine 1.0 mg intravenously on glucose metabolism was compared with placebo. Six men participated in the cross‐over study. 2. An oral glucose tolerance test was performed 90 min after the administration of the medicaments. Guanfacine had no effect on blood glucose, insulin or the 'Insulinogenic index'.
Haemodynamic effects of guanfacine.
Authors: Magometschnigg D. , Hitzenberger G. , Bonelli J.
Published: July 2012

1. The haemodynamic mechanism of action of guanfacine 4 mg intravenously was investigated in resting conditions and during exercise for up to 20 h after administration of the drug. Cardiac output and pulmonary arterial pressure were determined by the Swan‐Ganz thermodilution method. Blood pressure was measured directly. 2. During and immediately after intravenous administration of guanfacine, blood pressure peripheral resistance and pulmonary arterial pressure increased (in keeping with an alpha‐sympathomimetic effect of the compound), whereas heart rate and cardiac output decreased. 3. Subsequently blood pressure fell as a result of a decrease in cardiac output. From the third hour peripheral resistance decreased, whereas cardiac output increased again, sometimes exceeding the control value. 4. During exercise blood pressure was reduced from the third hour after administration, as in resting conditions, as a result of the reduction in peripheral resistance. 5. In resting conditions guanfacine reduced heart rate at the beginning and during the whole course after administration of the drug. 6. Side‐effects noted included fatigue, drowsiness and bradycardia.
Alcohol absorption, gastric emptying and a breathalyser.
Authors: Holt S. , Stewart MJ , Adam RD , Heading RC
Published: July 2012

1 The value of a portable breathlyser (Alcometer AE‐M2) in the assessment of gastric emptying after alcohol ingestion was investigated by comparing breath and venous blood alcohol concentrations with simultaneous scintigraphic measurements of gastric emptying rate. 2 Alcohol absorption, as determined by the area under the venous blood alcohol concentration‐time curve during the first 30 min, correlated with gastric emptying during the same period, implying dependence of the rate of alcohol absorption on gastric emptying rate. 3 There was no correlation between breath and venous alcohol concentrations during the first 15 min after alcohol ingestion, but a significant correlation was observed thereafter. 4 Breath alcohol measurements may be sufficient to detect gross alterations in gastric emptying but measurements of venous blood alcohol are likely to be more reliable.
Tolerability of ibuprofen and flurbiprofen in G‐6‐PD deficient subjects: in vitro study.
Authors: Sheth UK , Valame SP , Gupta KC , Baxi AJ , Kulkarni VN , Pispati PK
Published: July 2012

1 A ‘GSH (reduced glutathione) stability test’ which consists of incubating blood samples with acetylphenylhydrazine and other test drugs and measuring GSH level before and after incubation, was carried out. 2 Application of this test to the blood of eight normal volunteers and twelve known G‐6‐PD deficient persons demonstrated that acetylphenylhydrazine and primaquine produced a significant decrease in GSH levels in G‐6‐PD deficient red cells compared to the reduction seen in normal red cells incubated with these drugs. No such change was observed with aspirin, ibuprofen and flurbiprofen. 3 The results of this in vitro study seem to indicate that ibuprofen and flurbiprofen are relatively innocuous in G‐6‐PD deficient individuals.
The effect of enzyme induction on the metabolism of disopyramide in man.
Authors: Aitio ML , Mansury L , Tala E , Haataja M , Aitio A
Published: July 2012

1 The effects of rifampicin, phenytoin, and disopyramide treatments on the metabolism of disopyramide were studied in patients and volunteers. 2 Rifampicin treatment markedly increased the metabolism of disopyramide. 3 Phenytoin had effects similar to those of rifampicin. The effect subsided in 2 weeks after stopping the treatment. 4 The metabolism of disopyramide seemed fastest in the patient group with the higher dose of disopyramide. Both in patients and volunteers a significant increase occurred in the urinary mono‐N‐ dealkyldisopyramide/disopyramide ratio during the first week of disopyramide therapy. This change can partly be due to pharmacokinetic differences between disopyramide and its metabolite. The inducing effect of disopyramide remained uncertain.
Pethidine clearance during continuous intravenous infusions in postoperative patients.
Authors: Austin KL , Stapleton JV , Mather LE
Published: July 2012

1 Pethidine pharmacokinetics in ten female patients during continuous i.v. infusion for 32 h post‐surgery have been determined. 2 The blood clearance of pethidine (mean +/− 2.d.) measured directly was 599 +/− 135 ml/min and is in marked contrast to some reported values. 3 Other model‐dependent pharmacokinetic parameters were consistent with previously reported values. 4 Pethidine and indocyanine green clearance were correlated but the correlation was mediated through body weight. 5 Pethidine clearance and steady state concentration were predictable retrospectively from linear multivariable equations involving simple physical characteristics of the patient.
The metabolic actions of intravenous salbutamol and aminophylline singly and in combination.
Authors: Jenkins CR , Marlin GE
Published: July 2012

1 The following four treatments were administered by constant intravenous infusion of four healthy volunteers in a balanced randomized study: 1) saline (30 min), salbutamol (0.15 micrograms kg‐1 min‐1 for 30 min) (sS), 2) saline, aminophylline (0.2 mg kg‐1 min‐1 for 30 min) (sA), 3) salbutamol, salbutamol (SS) and 4) aminophylline, salbutamol (AS). 2 Heart rate was recorded and venous blood taken for estimation of insulin, glucose, potassium and theophylline before and during the infusions (10, 20, 30, 40, 50 and 60 min). 3 The mean, peak heart rate increases from control, baseline values were 23.0 (sS), 3.5 (sA), 28.5 (SS) and 28.0 (AS) beats/min, the mean, peak insulin increases, 34.0 (sS), 0.5 (sA), 39.0 (SS) and 57.5 (AS) microU ml‐1, the mean, peak glucose increases, 1.4 (sS), 0.1 (sA), 2.6 (SS) and 2.0 (AS) mmol 1(‐1) and the mean, peak potassium changes, −0.45 (sS), 0.58 (sA), −0.78 (SS) and −0.68 (AS) mmol 1(‐1). 4 The mean, peak serum theophylline levels were 48.1 mumol 1(‐1) at 60 min in sA and 52.6 mumol 1(‐1) at 50 min in AS (39.1 mumol 1(‐1) at 30 min). 5 Salbutamol stimulated significant insulin release and produced hypokalaemia and glycogenolysis, whereas aminophylline induced no metabolic effect. 6 A comparison of sS and AS indicated a trend for aminophylline to potentiate the metabolic effects of salbutamol.
Theophylline‐salbutamol interaction: bronchodilator response to salbutamol at maximally effective plasma theophylline concentrations.
Authors: Barclay J , Whiting B , Meredith PA , Addis GJ
Published: July 2012

1 The effect of inhaled salbutamol following a maximally effective dose of theophylline given by intravenous infusion was determined in 12 patients with chronic bronchitis. 2 An initial single intravenous dose study was performed to estimate each patient's theophylline kinetics and to identify those patients who would respond to theophylline. 3 Pulmonary function was assessed at hourly intervals during four to five incremental steady state theophylline infusions over the concentration range 5‐25 mg/l. 4 Inhaled salbutamol (400 micrograms) was administered after the maximum effect from theophylline had been achieved or when theophylline concentrations reached 25 mg/l without maximum effect: pulmonary function was again assessed. 5 Ten patients achieved a further significant improvement in pulmonary function after salbutamol: in five, predicted values for FVC were exceeded. 6 Patients with chronic bronchitis may benefit from the combination of theophylline and salbutamol if steady state theophylline concentrations of 15‐20 mg/l are achieved.
Cimetidine‐a clinical and pharmacokinetic study.
Authors: Webster J , Barber HE , Hawksworth GM , Jeffers TA , Petersen J , Petrie JC , Brunt PW , Mowat NA , Griffiths R
Published: July 2012

1 The effect of six months therapy with cimetidine (800 mg or 1600 mg/day) and subsequent withdrawal was studied in 19 patients with duodenal ulceration. 2 The overall rates of healing were 63% and 79% of patients after 3 and after 6 months of treatment respectively. The longer course (6 months) or the higher dose (1600 mg) did not result in significantly increased rates of ulcer healing. 3 Abrupt withdrawal of cimetidine resulted in the recurrence of severe symptoms in 15 patients (79%). 4 Pharmacokinetic studies showed the mean elimination half‐life of cimetidine to be 100 +/− 25 min, the total body cimetidine clearance 652 +/− 223 ml/min, the mean volume of distribution at steady state 65 +/− 181 and the overall bioavailability 78%. 5 Long term cimetidine treatment does not result in drug accumulation or changes in its pharmacokinetic profile. 6 Inter‐individual differences in clinical and endoscopic response to cimetidine cannot be explained by pharmacokinetic differences.
The effect of probenecid on the pharmacokinetics and distribution of cefoxitin in healthy volunteers.
Authors: Reeves DS , Bullock DW , Bywater MJ , Holt HA , White LO , Thornhill DP
Published: July 2012

1 Cefoxitin was given by acute intravenous injection to six healthy volunteers, in a crossover study to investigate the effects of concurrent probenecid administration. 2 Serum antibiotic concentrations were determined by microbiological assay. Cefoxitin concentrations were simultaneously determined in the fluid of blisters produced by topical cantharides. All antibiotic was accounted for in the urine. 3 Cefoxitin was administered by intravenous infusion, subsequent to a loading dose, to produce steady state levels in the region of 10 microgram/ml, in one volunteer. The procedure was later repeated after prior administration of probenecid in the same subject. 4 Pharmacokinetic analyses indicated significant changes only in the parameters associated with renal excretion of drugs. Clearance was reduced by half. 5 The absolute and relative amounts of antibiotic in the central and peripheral compartments were calculated for both modes of administration. In the acute study probenecid produced a small change in distribution away from the peripheral or tissue compartment, towards the central compartment. 6 There was no elevation of initial serum concentrations and sustained levels of antibiotic could be accounted for principally by retarded excretion produced by probenecid, with little contribution by alteration in the disposition of antibiotic. 7 The sustained serum levels of cefoxitin that resulted from its decreased excretion were also reflected in blister fluid. It was concluded that the sustained cefoxitin levels produced by probenecid resulted in similar raised levels in the peripheral or “tissue” compartment, since the redistribution away from the peripheral compartment did not contribute materially to other changes in disposition of drug.
Control of essential hypertension with captopril, an angiotensin converting enzyme inhibitor.
Authors: El‐Mehairy MM , Shaker A , Ramadan M , Hamza S , Tadros SS
Published: July 2012

1 Captopril, an orally active angiotensin converting enzyme inhibitor, was compared with hydrochlorothiazide (HCT) in the treatment of mild and moderate essential hypertension. 2 Twenty outpatients received no antihypertensive therapy for 2 weeks, after which they were given placebo for 8 weeks. Since their diastolic blood pressure remained above 100 mm Hg, they were then randomized to receive either captopril (twelve patients) or HCT (eight patients) for a 4‐week titration period. If the supine diastolic blood pressure (SDBP) was normalized, (less than or equal to 90 mm Hg) by the end of titration period, the established regimen was continued for an 8‐week maintenance period; if not, the alternate drug was added in increasing doses for up to 4 weeks and the combined therapy was maintained for the remaining 4 weeks. 3 After the first 4 weeks of therapy, both groups showed a statistically significant decrease in both systolic and diastolic blood pressure. Normalization of SDBP occurred in 75% of patients treated with captopril alone, and the addition of HCT produced normalization in the remainder. HCT alone resulted in normalization of SDBP in 50% of patients and the blood pressure of the remaining patients was normalized after the addition of captopril. 4 Captopril given orally, either alone or in conjunction with HCT, is an effective agent for the control of mild and moderate essential hypertension. 5 In our series the main side effects encountered were vertigo and dizziness, transient eosinophilia, a rise of BUN and or/a rise of SGPT or SGOT.
A comparison of the effects of propranolol and oxprenolol on forearm blood flow and skin temperature.
Authors: Vandenburg MJ , Conlon C , Ledingham JM
Published: July 2012

1 The effects of oxprenolol 80 mg and propranolol 80 mg on resting forearm blood flow (RFBF) and skin temperature were compared in seven normotensive subjects, for 4 h after an oral dose. 2 There was a significant fall of RFBF after propranolol (mean +/‐ s.e. mean 0.74 +/‐ 0.24 ml 100 g‐1 min‐1) compared to a smaller non‐significant reduction after oxprenolol (0.35 +/‐ 0.19 ml 100 g‐1 min‐1). Propranolol produced a greater fall in heart rate than oxprenolol at all times except at 2.5 h. Three subjects experienced falls in skin temperature of over 4 degrees C with propranolol. There were no comparable falls after oxprenolol. 3 The results suggest that at the same dose oxprenolol has less effect on RFBF and skin temperature than propranolol.
Sulphinpyrazone metabolism during long‐term therapy
Authors: Pedersen AK , Jakobsen P
Published: July 2012

1 The plasma concentrations of sulphinpyrazone and four of its metabolites are reported together with the amounts excreted in urine. Eight insulin‐requiring diabetics were investigated, all treated with sulphinpyrazone 600‐800 mg day−1 for 2.5 years or more. 2 Blood samples were drawn before the first morning dose and 2 h later. The mean plasma concentrations were (t=0 h‐t=2 h): sulphinpyrazone 7.1‐16.0 μg ml−1; sulphide 2.8−4.3 μg ml−1; sulphone 1.7‐4.8 μg ml−1 p‐OH‐sulphide 0.67‐0.89 μg ml−1 p‐OH‐sulphinpyrazone 0.10‐0.16 μg ml−1. Statistically significant correlations were found between the plasma concentrations at t=0 of the sulphide and the p‐OH‐sulphide and that of sulphinpyrazone. 3 In urine, a very wide range in excretion of unconjugated compounds was observed. Sulphinpyrazone were excreted in amounts corresponding to 1‐30% of the daily dose. The metabolites were generally excreted in amounts corresponding to less than 1% of the daily dose; however, up to 3% was found as the sulphone. 4 Increases of the concentration of all compounds in urine were found after treatment with β‐glucuronidase indicating 0‐conjugation with glucuronic acid. 5 Since both the sulphide and the sulphone were found more active as inhibitors of platelet function in vitro than their parent compound, they may together constitute the major part of the platelet inhibitory drug activity in plasma during long‐term therapy with sulphinpyrazone.
Effects of caroxazone, a reversible monoamine oxidase inhibitor, on the pressor response to intravenous tyramine in man
Authors: Martini A , Bonollo L , Nicolis FB , Sega R , Palermo A , Braibanti E
Published: July 2012

1 Caroxazone is a new antidepressant drug with reversible MAO‐ inhibitory activity. 2 The pressor effect of intravenously injected tyramine has been evaluated in six male healthy volunteers before, during oral treatment with caroxazone 200 mg three times daily and at different time intervals after discontinuation of treatment. 3 Caroxazone produces a moderate tyramine supersensitivity. 4 The reversibility of MAO‐inhibition produced by caroxazone is clearly reflected by the time‐course of tyramine supersensitivity. In fact, tyramine potentiation does not accumulate with caroxazone cumulative dose, while it is correlated to drug plasma levels and disappears rapidly (half‐life 1.5 days) upon discontinuation of treatment. 5 Caroxazone seems to be safer and more manageable than all other clinically available MAO‐inhibitors which produce irreversible inactivation of MAO.
Blood pressure, body fluid volumes and glomerular filtration rate during treatment with labetalol in essential hypertension.
Authors: Rasmussen S , Nielsen PE
Published: July 2012

1 In a single blind study seventeen patients with mild or moderate essential hypertension and normal renal function were treated with labetalol alone in increasing doses from 300 via 600 to 1200 mg daily. 2 Average supine BP (systolic/diastolic) was reduced by 24/19 mm Hg. Seven patients attained a diastolic BP less than or equal to Hg. A significant postural fall in systolic BP was recorded, but no symptomatic orthostatic hypotension occurred. 3 In twelve patients measurements of plasma volume (125I‐albumin), extracellular volume (82Br‐space) and glomerular filtration rate (51Cr‐EDTA clearance) on placebo and subsequently labetalol showed no systemic changes. 4 Side effects were few causing two withdrawals because of impotence and arthralgia. 5 It is concluded that monotherapy with labetalol results in clinically relevant, persistent and dose dependent reduction in BP in patients with mild or moderate essential hypertension, apparently without concomitant expansion of body fluid volumes or influence on glomerular filtration rate.
The effects of oral acebutolol and propranolol on forearm blood flow in hypertensive patients.
Authors: Ireland MA , Littler WA
Published: July 2012

1 Nine hypertensive patients received by mouth daily doses of 400 mg of acebutolol and then, after a 2 week washout period, 80 mg of propranolol for 2 week periods in an open study. 2 Both treatments caused equivalent cardiac blockade as assessed by reduction in exercise tachycardia. 3 Both treatments lowered blood pressure, although this effect on pressure was better maintained in the case of acebutolol. 4 Forearm blood flow, at rest, was significantly reduced at 2 h after dosing with propranolol, but not after acebutolol. 5 This difference between the two drugs is probably due to the cardioselectivity of orally administered acebutolol in man.
Effect of propranolol on noradrenaline kinetics in patients with essential hypertension.
Authors: Esler M , Jackman G , Leonard P , Skews H , Bobik A , Jennings G
Published: July 2012

1 The rates of noradrenaline spillover to, and removal from, plasma were measured in ten patients with essential hypertension treated with propranolol, to ascertain if long‐term administration of this drug reduces sympathetic nervous system tone. 2 The plasma clearance of noradrenaline fell with propranolol, leading to a small rise in the mean plasma noradrenaline concentration. Sympathetic nervous activity in treated patients cannot be reliably gauged from plasma noradrenaline values because these are distorted by the reduction in noradrenaline clearance. 3 There was no consistent effect on noradrenaline spillover rates, which fell in six patients, but rose in the remaining four. The magnitude of the antihypertensive response was unrelated to these changes in noradrenaline release. During propranolol treatment, noradrenaline spillover rates were in every case within the normal range, much higher than in patients treated with the known sympathetic nervous systems suppressant, clonidine. 4 The principal mode of antihypertensive action of propranolol is something often than central suppression of sympathetic tone or pre‐synaptic inhibition of noradrenaline release.
Effect of chronic diuretic treatment on the plasma renin‐angiotensin‐ aldosterone system in essential hypertension.
Authors: Lijnen P , Fagard R , Staessen J , Amery A
Published: July 2012

1 Chronic treatment with a constant dose of hydrochlorothiazide or tienilic acid increases plasma renin activity (PRA) acutely to reach a maximum within the first week. 2 During chronic diuretic therapy from 1 month to 1 year, PRA remained elevated at a rather constant level, though this was somewhat lower than the maximum level reached after 1 week. 3 A significant (P less than 0.01) correlation (r = 0.74) between changes in plasma angiotensin II and renin activity provoked by chronic treatment for 3 months with hydrochlorothiazide and tienilic acid was found. 4 The increase in plasma aldosterone during chronic treatment with hydrochlorothiazide and tienilic acid (1000 mg) is related (r = 0.68; P less than 0.01) to the rise in plasma angiotensin II.
Pharmacokinetics of the H2‐ receptor antagonist ranitidine in man.
Authors: McNeil JJ , Mihaly GW , Anderson A , Marshall AW , Smallwood RA , Louis WJ
Published: July 2012

1 Ranitidine pharmacokinetics were studied in six healthy volunteers. Following an overnight fast, doses of 20 mg intravenously 20, 40 and 100 mg orally and 100 mg orally with a standard meal, were administered to each subject on separate occasions. 2 Following intravenous administration there was a bioexponential decline in plasma levels from 576 +/‐ 56 ng/ml at 4 min to 10 +/‐ 2 ng/ml at 8 h. The distribution half‐life (T 1/2 alpha) was 6.1 +/‐ 0.9 min, elimination half‐life (T 1/2 beta) was 1.9 +/‐ 0.1 h, the volume of distribution (Vd beta) was 115 +/‐ 7 l and systemic plasma clearance (Cltp) was 709 +/‐ 62 ml/min. 3 Following 20 mg oral doses, peak levels were reached at 1.6 +/‐ 0.2 h and the systemic availability was 88 +/‐ 10%. Elimination half‐life (T 1/2 beta) was unaffected by dose and the area under the curve increased linearly with dose and was unaffected by food. 4 Renal excretion (24 h) of unmetabolized ranitidine accounted for 50‐70% of the dose with a further 1‐3% appearing as desmethyl ranitidine.
Modelling theophylline response in individual patients with chronic bronchitis.
Authors: Whiting B , Kelman AW , Barclay J , Addis GJ
Published: July 2012

1 In six patients with chronic bronchitis, serial changes in both ventilatory function and plasma theophylline concentrations were measured simultaneously for 8 h following 500 mg aminophylline intravenously. 2 Using empirical mathematical models which can integrate this data, parameters were estimated which can express response as a linear function of steady state plasma theophylline levels. 3 Taking Forced Vital Capacity (FVC) as the target response, the mean (+/‐ s.d.) increase in FVC was 0.06 +/‐ 0.02 l/micrograms ml‐ 1, starting with pretreatment values in the range 1‐21. 4 This analytical approach could be used to determine whether or not a patient with chronic bronchitis could obtain a satisfactory response to theophylline at plasma levels normally encountered in clinical practice.
The pharmacokinetics of subcutaneous cytosine arabinoside in patients with acute myelogenous leukaemia.
Authors: Slevin ML , Piall EM , Aherne GW , Johnston A , Sweatman MC , Lister TA
Published: July 2012

1 The pharmacokinetics of subcutaneous cytosine arabinoside were compared with bolus intravenous injection and intravenous infusion in five patients with acute myelogenous leukaemia. 2 Subcutaneous cytosine arabinoside was rapidly absorbed and then declined biexponentially with initial and terminal half‐lives similar to intravenous bolus injection. 3 Cytosine arabinoside levels declined rapidly after intravenous bolus and subcutaneous bolus injection, and fell below steady state infusion levels after a mean time of 40 min (intravenous bolus) and 100 min (subcutaneous injection).
The relationship between peak velocity of saccadic eye movements and serum benzodiazepine concentration.
Authors: Bittencourt PR , Wade P , Smith AT , Richens A
Published: July 2012

1 Six healthy male volunteers received single oral doses of 10 mg diazepam, 20 mg temazepam, 15 mg flurazepam, 5 mg nitrazepam, 10 mg desmethyl‐diazepam and placebo in a double‐blind randomized fashion. 2 Peak velocity of saccadic eye movements, serum benzodiazepine concentration, and subjective ratings of wakefulness and co‐ordination were measured at intervals up to 12 h after drug administration. 3 All active treatments produced a statistically significant decrease in peak saccadic velocity. The effect of temazepam and diazepam was generally more pronounced than that of flurazepam, nitrazepam and desmethyl‐ diazepam. 4 There were log‐linear correlations between peak saccadic velocity and serum benzodiazepine concentration after ingestion of temazepam, diazepam and nitrazepam. 5 These results demonstrate a clear relationship between serum benzodiazepine concentration and its effect on a convenient measure of brainstem reticular formation function.
Cerebrospinal fluid concentrations of propranolol, pindolol and atenolol in man: evidence for central actions of beta‐adrenoceptor antagonists.
Authors: Taylor EA , Jefferson D , Carroll JD , Turner P
Published: July 2012

1 Single and multiple oral dose studies of the penetration into CSF of three beta‐adrenoceptor antagonists were performed in groups of patients needing lumbar puncture as part of their neurological investigation. Propranolol, pindolol and atenolol were chosen because of their differing physico‐chemical properties. 2 The CSF concentration of propranolol (lipid‐soluble) and pindolol (moderately lipid‐soluble) was proportional to the free plasma concentration and was similar to, although generally lower than, that theoretically predicted. 3 The CSF concentrations of the poorly lipid‐soluble atenolol were similar in different patients and were independent of plasma concentration. This may be due to the slow rate of diffusion of atenolol into CSF preventing the predicted concentrations being achieved.
Cardiovascular effects in man of intravenous prizidilol hydrochloride (SK&F 92657); a new antihypertensive agent.
Authors: Edmonstone WM , Manghani KK , Bell AJ , McLeod M , Milton‐Thompson GJ , Burland WL
Published: July 2012

1 Cardiovascular responses to intravenous prizidilol hydrochloride (SK&F 92657) 0.86 mg/kg were studied in eight supine resting healthy volunteers. Five subjects were slow and the remaining three were fast acetylators of sulphamethazine. Compared with pre‐infusion values, mean resting systolic and diastolic blood pressures were significantly reduced, while mean resting pulse rate was significantly increased at 30 min after the start of the twenty minute infusion. 2 During the 6 h study period the lowest mean +/‐ s.e. mean systolic blood pressure (108.8 +/‐ 1.7) was recorded 30 min after the start of the infusion. This represented a mean reduction of 5.2 mmHg. Reductions in mean diastolic blood pressure were greater and of longer duration, the lowest mean value (44.8 +/‐ 2.0 mmHg) being recorded 3.5 h after the start of the infusion and representing a reduction of 18.5 mmHg from the pre‐dosing value. At 6 h after the start of the infusion mean diastolic blood pressure was still significantly reduced (by 15.3 mmHg). 3 The maximum mean +/‐ s.e. mean resting pulse rate (79.3 +/‐ 4.4 beats/min) occurred 3 h after the start of the infusion, an increase of 23.0 beats/min over the pre‐infusion value. At the end of the study the pulse rate was still significantly raised (by 17.7 beats/min). 4 The left ventricular ejection fraction, evaluated in five subjects, 45 min after the start of the infusion, was not altered by prizidilol hydrochloride, but the left ventricular area decreased significantly. 5 Intravenous prizidilol hydrochloride decreases resting blood pressure and left ventricular area, increases pulse rate and has virtually no effect on left ventricular ejection fraction.
Lignocaine disposition in blood in epilepsy.
Authors: Routledge PA , Stargel WW , Finn AL , Barchowsky A , Shand DG
Published: July 2012

1 The plasma concentration of alpha 1‐acid glycoprotein (AAG) was significantly greater in 27 epileptic subjects receiving anticonvulsants compared with 27 age‐ and sex‐matched drug‐free control subjects. 2 Increased AAG concentration was associated with enhanced lignocaine binding in the plasma of epileptics. 3 Increased AAG concentration was also associated with a redistribution of lignocaine out of red cells and into plasma thus lowering the blood to plasma concentration ratio. 4 Enhanced lignocaine binding in epileptics receiving anticonvulsant therapy may result in lower free (unbound) plasma concentrations of the drug compared to normal subjects with equivalent total plasma lignocaine concentrations.
Peritoneal absorption of the antibacterial and antiendotoxin taurolin in peritonitis.
Authors: Knight BI , Skellern GG , Browne MK , Pfirrmann RW
Published: July 2012

1 Taurolin metabolite plasma concentrations were measured in two groups of patient undergoing abdominal surgery, one group with peritonitis and the other without peritonitis, each group receiving taurolin by intraperitoneal instillation. 2 There was no significant difference in the area under the curves, for the two groups, for one of the metabolites. This would suggest that the absorption of taurolin was not modified in inflammatory conditions such as bacterial peritonitis.
Pharmacokinetic study of cefuroxime in the elderly.
Authors: Broekhuysen J , Deger F , Douchamps J , Freschi E , Mal N , Neve P , Parfait R , Siska G , Winand M
Published: July 2012

1 The pharmacokinetics of cefuroxime have been investigated in 18 patients at least 70 years old. The drug was given either by continuous infusion (7 cases) or by multiple injections (11 cases) for 3 to 11 days (mean duration: 7 days). 2 The unchanged drug was assayed in blood plasma and in the urine by high performance liquid chromatography (h.p.l.c). 3 Cefuroxime was cleared, unchanged, almost exclusively by the kidneys, even when kidney function was impaired. Creatinine clearance ranged from 1.02 to 4.08 1/h (17 to 68 ml/min) in this group of patients and plasma clearance of cefuroxime varied from 1.02 to 8.16 1/h (17 to 136 ml/min) (r = 0.7 P less than 0.001 for linear correlation), but the apparent rate constant for nonrenal elimination remained quite small (average: 0.04 h‐1) and independent of creatinine clearance (r = 0.06, n = 17). 4 Since creatinine clearance decreases sharply with age, it might be suggested that cefuroxime dosage be related to creatinine clearance in the elderly, even when no renal impairment is suspected.
Comparison of the beta‐adrenoceptor blocking activity of oxprenolol, slow release oxprenolol and a combined oxprenolol diuretic preparation.
Authors: Kerr MJ , Harron DW , Kinney C , Shanks RG
Published: July 2012

1 Observations were made in five healthy subjects who exercised before and 2, 3, 6, 8 and 24 h after the oral administration on separate occasions of 160 mg oxprenolol, 160 mg slow release oxprenolol, 160 mg slow release oxprenolol with 0.25 mg cyclopenthiazide and placebo. Blood samples were obtained before and at 1, 2, 3, 6, 8, 12 and 24 h after drug administration and assayed for oxprenolol concentration. 2 The three formulations produced maximum reductions of 29% in the exercise tachycardia 3 to 6 h after drug administration. At 24 h the effects of the three preparations were not significantly different from placebo. 3 There were no significant differences in the plasma concentrations produced by the three formulations during the 24 h period. 4 These observations suggest that the slow release formulations of oxprenolol should be given twice daily to maintain cardiac beta‐ adrenoceptor blockade throughout a period of 24 h.
A comparative study of atenolol and metoprolol in the treatment of hypertension.
Authors: Rasmussen S , Arnung K , Eskildsen PC , Nielsen PE
Published: July 2012

1 In an open, randomized cross‐over investigation of thirteen patients (nine and four women, aged 37‐67 years) with mild or moderate essential hypertension a comparison between atenolol and metoprolol was carried out in order to study the effects of 50, 100 and 200 mg given once daily on blood pressure and heart rate at rest and during exercise. 2 Before one beta‐adrenoceptor blocking drug was replaced by the other in a patient an intervening drug‐free interval of sufficient length was secured to allow an increase in the blood pressure to pretreatment levels. 3 A maximal fall in blood pressure was achieve with 50 mg atenolol once daily, with no further reduction when the dose was increased to 100 mg or 200 mg. Maximal blood pressure reduction was achieved with 100 mg metoprolol daily, while the hypertensive effect of 50 mg once daily was not consistent. Significant reductions in heart rate in all test situations were observed with 50 mg atenolol, while 200 mg metoprolol 100 was necessary to reduce exercise‐induced tachycardia. 4 Atenolol 50 mg and metoprolol 100 mg once daily are efficient in treating mild or moderate hypertension and doses beyond these may not reduce the blood pressure further. On the contrary lower doses than generally recommended may be effective in the individual patient.
The prediction of individual systolic time interval v heart rate regression equations.
Authors: Kelman AW , Sumner DJ , Whiting B
Published: July 2012

1. Twenty‐eight sets of systolic time interval (STI) and heart rate (HR) data were available from studies in which small bolus doses of atropine had been given to alter heart rate. 2. Regression lines of the form LVET = A+B.HR and QS2 = C+D.HR were calculated. There was no significant relationship between PEP and HR. The values of the parameters A‐D were normally distributed. 3. The maximum likelihood Estimation was used to obtain the most likely values of the parameters A‐D for individual subjects. 4. The technique proved to be highly satisfactory and was subsequently validated with a further six sets of data.