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Biomedical subjects

C M Kaye

Publications and source records attributed to C M Kaye.

At least 19 recordsLinked to original sources
PubMed1989

Timing of prophylactic antibiotics in abdominal surgery: trial of a pre-operative versus an intra-operative first dose.

When prophylactic antibiotics are used in abdominal surgery it is customary to give the first dose before the operation. Whilst intra-operative antibiotics may be effective in elective surgery, there may be an advantage to starting pre-operatively when there is already an infective focus such as appendicitis. Antibiotics started pre-operatively (group P) have been compared with antibiotics started after initial abdominal exploration (group T). Three intravenous doses of 500 mg metronidazole plus 1 g cephazolin were given in a randomized, double-blind study of 700 emergency and elective high-risk abdominal operations. Antibiotic plasma concentrations at the end of the operation were significantly lower in group P but lay well within the therapeutic range. Wound infection rates, which included minor and delayed infections, were similar in both groups (group P, 57 of 342, 16.7 per cent; group T, 55 of 358, 15.4 per cent; 95 per cent confidence intervals for the difference being -4.1 to +6.7 per cent. In appendicitis, wound infection rates were 12.1 and 13.9 per cent for groups P and T respectively. However, non-fatal deep sepsis was more common in group P (nine cases) than in group T (two cases) (chi 2 = 4.9, P less than 0.05). Postoperative infection was twice as common in obese patients whose body mass index (BMI) was greater than or equal to 26 (39 of 132, 30 per cent) than in thin patients whose BMI was less than 24 (41 of 288, 14 per cent; chi 2 = 13.8, P less than 0.001). This study failed to show any advantage to starting antibiotics pre-operatively, even in appendicitis.

Abdomen↗
PubMed1989

A review of the metabolism and pharmacokinetics of paroxetine in man.

Paroxetine is well absorbed from the gastrointestinal tract, and appears to undergo first-pass metabolism which is partially saturable. Consistent with its lipophilic amine character, paroxetine is extensively distributed into tissues. Its plasma protein binding at therapeutically relevant concentrations is about 95%. Paroxetine is eliminated by metabolism involving oxidation, methylation, and conjugation. All of these factors lead to wide interindividual variation in the pharmacokinetics of paroxetine. Renal clearance of the compound is negligible. The major metabolites of paroxetine are conjugates which do not compromise its selectivity nor contribute to the clinical response. Ascending single-dose studies reveal that the pharmacokinetics of paroxetine are non-linear to a limited extent in most subjects and to a marked degree in only a few. Also, steady-state pharmacokinetic parameters are not predictable from single-dose data. In many subjects, daily administration of 20-50 mg of paroxetine leads to little or no disproportionality in plasma levels with dose, although in a few subjects this phenomenon is evident. Steady-state plasma concentrations are generally achieved within 7 to 14 days. The terminal half-life is about one day, although there is a wide intersubject variability (e.g. with 30 mg, a range of 7-65 hours was observed in a group of 28 healthy young subjects). In elderly subjects there is wide interindividual variation in steady-state pharmacokinetic parameters, with statistically significantly higher plasma concentrations and slower elimination than in younger subjects, although there is a large degree of overlap in the ranges of corresponding parameters. In severe renal impairment higher plasma levels of paroxetine are achieved than in healthy individuals after single dose. In moderate hepatic impairment the pharmacokinetics after single doses are similar to those of normal subjects. Paroxetine is not a general inducer or inhibitor of hepatic oxidation processes, and has little or no effect on the pharmacokinetics of other drugs examined. Its metabolism and pharmacokinetics are to some degree affected by the induction or inhibition of drug metabolizing enzyme(s). From a pharmacokinetic standpoint, drug interactions involving paroxetine are considered unlikely to be a frequent occurrence. Data available have failed to reveal any correlation between plasma concentrations of paroxetine and its clinical effects (either efficacy or adverse events).

Antidepressive Agents↗
PubMed1985

Acebutolol: ten years of experience.

During 10 years of clinical use involving almost 3 million patient-years, acebutolol has become established as a remarkably safe and well-tolerated beta-blocking agent, effective in treating essential hypertension and cardiac arrhythmias. The existence of a long-lived active metabolite (diacetolol) confers a 24-hour duration of action, which permits effective use of a once-daily regimen, particularly for hypertension. Acebutolol has low lipid solubility and low protein binding; the former property reduces the risk of central side effects, and the latter means that displacement interactions with other drugs are unlikely. Because acebutolol and its metabolite normally have both renal and hepatic excretion pathways, an alternative pathway is available should either be compromised through disease. Acebutolol is cardioselective, and clinical use has borne out the low incidence of bronchospasm in patients with impaired lung function. The possession of intrinsic sympathomimetic activity (ISA) leads to only modest reductions in cardiac output, which in turn reduces the chance of excessive bradycardia and the likelihood of precipitating heart failure. A combination of selectivity and ISA may be responsible for the low incidence of tiredness and cold extremities observed with acebutolol compared with other beta blockers. The unique pharmacologic and pharmacokinetic profile of acebutolol confers several therapeutic advantages and may be responsible for the generally low level of side effects experienced in clinical use.

Acebutolol↗
PubMed1978

Studies of cardioselectivity and partial agonist activity in beta-adrenoceptor blockade comparing effects on heart rate and peak expiratory flow rate during exercise.

1 The effects of beta-adrenoceptor antagonists given in single doses by oral or intravenous routes were examined in two double-blind controlled studies performed in healthy volunteers. Heart rate and peak expiratory flow rate (PEFR) were measured at rest and during standardized exercise. 2 Propranolol 80 mg and metoprolol 100 mg orally tended to reduce, and propranolol and metoprolol 0.2 mg/kg intravenously did reduce the physiological increase in PEFR during exercise; oxprenolol 80 mg orally and 0.2 mg/kg intravenously did not. Practolol 200 mg orally reduced this increase, but practolol 1 mg/kg intravenously did not. 3 In a third study of similar design, pindolol 0.05 mg/kg intravenously did not affect exercise-induced increase in PEFR. 4 Heart rate during exercise was reduced to a comparable extent at different times by all the active treatments. 5 Oxprenolol and pindolol share with practolol the property of partial agonist activity, which might contribute to their apparent lack of effect on airways resistance. A further possibility is that alpha-adrenoceptor blockade helps to maintain exercise-induced increase in PEFR.

Adrenergic beta-Antagonists↗
PubMed1977

An investigation of "absolute plasma level effect relationships" and "absolute cardioselectivity" with respect to beta-adrenoceptor blockade.

In a group of 6 healthy (but physically unfit) volunteers an investigation was made of whether there was a true plasma level effect relationship and absolute "cardioselectivity" with respect to beta-adrenoceptor blockade due to practolol. To this end three treatments were given orally, namely placebo, practolol 100 mg and practolol 400 mg. Cardiac beta-adrenoceptor blockade was assessed by measuring the inhibition of exercise heart rate and pulmonary beta-adrenoceptor blockade was assessed by measuring the reduction in exercise peak flow rate, up to 24 h after each dose. Plasma practolol levels were determined spectrophotometrically. From the results obtained there was no reason to doubt the existence of a valid relationship between cardiac beta-adrenoceptor blocking activity and the plasma concentration of practolol. It was also concluded that even in non-asthmatics, practolol does not possess absolute "cardioselectivity" since significant reductions in peak flow rate were discernible during vigorous exercise, particularly when the large dose had been given.

Adult↗
PubMed1977

Pharmacokinetics of salicylate and indomethacin in coeliac disease.

The plasma concentrations of salicylate and indomethacin were measured after a single oral dose of aspirin (600 mg) and indomethacin (50 mg) in twelve starved normal subjects and twelve adult patients with coeliac disease. The absorption of salicylate in the coeliac patients was faster than in the normal subjects. The plasma concentration/time curve of indomethacin in both groups was similar during the absorption phase, but there were significant differences between the groups in its elimination. The abnormal absorption pattern of salicylate in coeliac disease does not appear to be related to its pKa. Possible causes of the difference in salicylate absorption include changes in gastric emptying or altered small intestinal permeability.

Adult↗
PubMed1977

The different effects of sodium bicarbonate and aluminium hydroxide on the absorption of indomethacin in man.

The influence of oral sodium bicarbonate and aluminium hydroxide on the absorption of indomethacin has been studied in normal volunteers. While sodium bicarbonate appeared to increase indomethacin absorption, aluminium hydroxide markedly reduced both the rate and extent of absorption. The buccal absorption of indomethacin over the pH range 5-9 was also studied in normal volunteers, and showed that the percentage absorption increased markedly as the pH was reduced. The clinical importance both of pH-partition and of adsorption are discussed in the context of antacid interactions. It is concluded that caution must be exercised when prescribing an antacid with other orally-administered drugs.

Absorption↗
PubMed1976

Observations on the pharmacokinetics of acebutolol.

Using a balance, randomized, crossover design, single intravenous (1 mg/kg) or oral (3 X 100 mg) doses of acebutolol were administered at weekly intervals to 6 healthy volunteers. For each subject venous blood samples and timed urine collections were obtained after each treatment. Plasma and urinary acebutolol levels were measured by a spectrophotometric method that measures acebutolol and its N-acetyl metabolite (which has equivalent cardiac activity). Using a computer program, various pharmacokinetic parameters were estimated from the date of each subject. From the intravenous data (obtained up to 6 hr after dosing), the following mean (+/-SD) values were found: distribution half-life (T 1/2D), 0.60 (+/-0.43) hr, plasma elimination half-life (T 1/2El), 3.2 (+/-1.1) hr, apparent volume of distribution (VD), 224 (+/-69) L, and apparent VD/kg, 3.0 (+/-0.8) L/kg. Using the oral data (obtained up to 10 hr after dosing), the value for T 1/2El was 3.2 (+/-0.9) hr. The mean cumulative urinary recovery (expressed as % dose) after the intravenous route was about 60%, while that after the oral route was of the order of 35%, suggesting that about half of the oral dose reached the systemic circulation. The mean creatinine clearance of the 6 subjects was 103 (+/-7) ml/min, while the value (obtained between 2 and 4 hr after intravenous dosing) for renal clearance of acebutolol as measured was 298 (+/-68) ml/min and the corresponding plasma clearance was 818 (+/-64) ml/min. These results support the occurrence of substantial nonrenal elimination and renal tubular secretion.

Acebutolol↗
PubMed1976

Absorption of propranolol and practolol in Coeliac disease.

Plasma concentrations of propranolol and practolol were measured in patients with coeliac disease and normal subjects. The mean plasma propranolol concentration in the coeliac patients was higher throughout the period of study, the differences being significant at one, six, and eight hours. The plasma concentration profile of practolol in the coeliacs followed a similar pattern but lagged behind that of the normal subjects. A possible reason for these differences is an alteration in the rate of drug diffusion across the atrophic mucosa of the upper jejunum in coeliac disease. Analysis of the results of the propranolol study suggests that an increase in the rate of absorption combined with saturation of first pass extraction may account for the increased plasma concentrations of unchanged propranolol found in coeliac disease. These abnormalities of drug absorption do not appear to be related to the duration of treatment with a gluten free diet.

Adult↗
PubMed1975

Cardiac and pulmonary effects of acebutolol.

In a double-blind randomised study, single intravenous doses of propranolol (0-1 mg. per kg.), practolol (1 mg. per kg.), acebutolol (1 mg. per kg.), or placebo were each administered at weekly intervals to six healthy volunteers. Forced expiratory volume in 1 second (F.E.V.1), resting and exercise heart-rate, and resting and exercise peak flow-rate (P.F.R.) were determined before and at 2, 3, 4, and 6 hours after each treatment. Venous blood-samples were also obtained at these times. Compared with placebo, resting heart-rate was reduced after all three drugs, but the corresponding differences in exercise heart-rate were much greater, more consistent, and of greater statistical significance. At 2, 3, and 4 hours when acebutolol and propranolol produced equivalent cardiac beta-blocking activity (judged by reductions in exercise heart-rate), their mean plasma concentratios were in the ratio of about 8/1; and at 2 hours when practolol and acebutolol gave rise to almost equivalent cardiac beta blockade, their mean plasma concentratio ration was 3/1. At times, reductions in F.E.V.1 and resting P.F.R. after propranolol (but not after practolol or acebutolol) were significantly greater than the corresponding changes after placebo. The reductions in exercies P.F.R. after propranolol (6 hours) and acebutolol (4 hours) (but not after practolol) were significantly greater than the changes after placebo. Changes in F.E.V.1, resting and exercise P.F.R. after propranolol, and the corresponding changes after practolol, were significantly different, all of which confirmed that practolol was more cardioselective than propranolo. In general, the reductions in F.E.V.1 and resting P.F.R. after acebutolol were slightly smaller than after propranolol, excepting at 6 hours when the difference between them was significant. The reductions in exercise P;F.R. after acebutolol and propranolol were of the same order, there being no significant differences between the two, whereas the reductions after acebutolol were clearly greater than the corresponding changes after practolol, the differences being significant at 2, 3, and 4 hours.

Acebutolol↗