[Cerebral protection following cardiopulmonary arrest: reality, pipe dream or utopia?].
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Acidosis, Lactic↗
Biomedical subjects
M G Bogaert
Publications and source records attributed to M G Bogaert.
The influence of aging on the stereoselective pharmacokinetics of propranolol in the rat.
The influence of aging on the pharmacokinetics and the tissue distribution of (R)- and of (S)-propranolol was studied in 3-, 12-, and 24-month-old rats. After both iv and oral administration of rac-propranolol, the plasma concentrations were higher for the (R)- than for the (S)-enantiomer. For the tissue concentrations, the reverse was true. The free fraction of (S)-propranolol in plasma was about 4 times larger than that of (R)-propranolol, and this is the main factor responsible for the differences in kinetics between the two enantiomers. There was a suggestion for a difference in tissue binding between the two enantiomers. With aging, the plasma and tissue concentrations of both enantiomers increase, probably due to a decrease in blood clearance. Tissue binding did not change much with aging. Notwithstanding the marked differences between the kinetics of the propranolol enantiomers, the changes which occur with aging affect both enantiomers to the same degree.
Administration, Oral↗
Medication utilization and patient information in homes for the aged.
A random cross-sectional sample of 198 residents was taken from a convenience sample of 20 Flemish, community-based nursing homes for the aged. Twenty trained interviewers reviewed the medication list of these residents and interviewed the nurses responsible for their daily care to assess their activities of daily living (ADL) and cognitive status. Direct interview was possible of 128 residents (65%); communication with the other 70 residents was impossible because of dementia (55 patients) or communication problems, such as aphasia and deafness (15 patients). An average of 4.5 different medicines was mentioned on the medication lists of the 198 residents. Drug use increases with age but stabilises after the age of 80 y. Medicines are ordered from local community pharmacies and are delivered to the ward rooms in original drug dispensing packs. The nursing staff is responsible for distribution inside the institution. Nursing personnel read the inserts of the medicines given to 98% of the residents and keep the inserts of 77% in the nursing office. Only 11% of the residents maintained some autonomy in ordering, keeping and taking their medication, although 42% were evaluated by the nurses as functionally and cognitively fit. Only 4% of the 128 residents able to respond to an interview had a notion of the potential adverse effects of their medication; the two most important sources of information about medicines mentioned by those residents were the general practitioner and the nursing personnel; 4% mentioned relatives and friends, or the pharmacist, as information sources.
Activities of Daily Living↗
Influence of age on stereoselective pharmacokinetics and metabolism of hexobarbital in the rat.
The influence of age on stereoselective pharmacokinetics and in vitro metabolism of R- and S-hexobarbital was studied in the rat. After intravenous administration of the racemate, the plasma concentrations of S-hexobarbital are markedly lower than those of R-hexobarbital. For S-hexobarbital the half-life is somewhat shorter and the volume of distribution and plasma clearance is higher than for its antipode. For both enantiomers an increase in AUC and half-life, and a decrease in clearance are observed with aging. These changes occur mainly between the 3rd and the 12th month and are slightly more pronounced for R- than for S-hexobarbital, as appears from the S/R ratios. The volume of distribution shows no changes with aging. In vitro disappearance rate in 3-month-old rats is significantly higher for S- than for R-hexobarbital. There is for both enantiomers an increase in disappearance rate in 12-month-old rats as compared to younger or older rats, but this is significant only for the R-enantiomer. There are pronounced differences in the kinetics and metabolism of both hexobarbital enantiomers; changes with aging occur, but are only slightly and not always significantly more important for R- than for S-hexobarbital.
Aging↗
Receptor function in heart failure.
In patients with congestive heart failure, down-regulation of beta-adrenoceptors is present, probably as a result of sympathetic overstimulation. In end-stage dilated cardiomyopathy, beta 1-adrenoceptor density is markedly reduced, while beta 2-adrenoceptor density is normal. This latter finding does not necessarily imply normal sensitivity to beta 2-stimulation, due to possible alterations in the beta-adrenoceptor/adenylate cyclase complex beyond the receptor. In some disease states, such as ischemic cardiomyopathy and mitral valve disease, there seems to be a concomitant reduction of the beta 1- and beta 2-adrenoceptor density. The finding of beta-adrenoceptor down-regulation has stimulated the search for novel therapeutic approaches in heart failure patients. Beta-agonists could even further down-regulate beta receptors, and this perhaps explains why they seem not to be useful in long-term use. Agents that directly stimulate adenylate cyclase activity, such as forskolin, or that increase cyclic adenosine monophosphate degradation, such as the phosphodiesterase inhibitors, are being tested. Beta-adrenoceptor blocking agents were used in treatment of heart failure before beta-adrenoceptor down-regulation was recognized in these patients. It is tempting to speculate that the beneficial clinical and hemodynamic effects seen in these patients treated with metoprolol is indeed due to an antagonism of the beta-adrenoceptor down-regulation. Studies testing whether beta-adrenoceptor blocking agents can improve survival in congestive heart failure patients are on-going.
Down-Regulation↗
Comparison of the bioavailability of two slow release preparations of disopyramide.
The bioavailability of two slow release preparations of disopyramide has been compared in a randomized cross-over trial of Rythmodan L.A. 250 mg b.d. and Dirytmin Durettes 300 mg b.d., given to 10 healthy volunteers. The plasma concentrations of disopyramide were measured on the 5th day of each treatment period. With both preparations, plasma concentrations were well sustained. The amount absorbed was slightly lower after Rythmodan L.A. than after Dirytmin Durettes, but the fluctuations over a dosing interval were significantly more pronounced for Dirytmin Durettes than for Rythmodan L.A.
Adult↗
Nimodipine decreases resuscitability in a cardiopulmonary arrest model in the rat.
Although calcium has been implicated in ischemia-induced brain death or dysfunction, many animal studies do not show a beneficial effect of calcium-entry blockers given after resuscitation from a cardiopulmonary arrest (CPA). This may be due to the fact that treatment was started too late; we, therefore, evaluated the effect of the calcium-entry blocker nimodipine administered at the earliest feasible postischemic moment, i.e. at the start of the resuscitation attempts. In anesthetized Wistar rats, CPA was induced by an intra-cardiac injection of KCl, and maintained for 7 min by chest restriction. At the start of the resuscitation attempts, 50 rats were blindly and randomly assigned to intravenous treatment with either nimodipine (10 micrograms/kg over 2 min, followed by 1 micrograms/kg per min for 60 min; n = 25) or saline (n = 25). In the nimodipine group, significantly less rats could be resuscitated (11/25 versus 20/25) and the survival rate at the end of the 7 days evaluation period tended to be lower (5/25 versus 11/25). In the rats surviving after 7 days, there was no difference between both groups in incidence of seizures, neurological status and histological lesions in the hippocampus. It is concluded that nimodipine, in the dose tested and given during resuscitation in this rat model, has a detrimental effect on resuscitability and no beneficial effect on the neurological outcome in the surviving animals.
Animals↗
Plasma norepinephrine concentrations during resuscitation in the dog.
The objective of this study was to evaluate whether the adrenal glands contribute to the increase in plasma norepinephrine concentrations during cardiopulmonary resuscitation, by releasing norepinephrine and/or by secreting epinephrine that facilitates the release of norepinephrine from sympathetic nerve endings via stimulation of presynaptic beta receptors. The experiments were performed in adrenalectomized and in sham-operated dogs. In adrenalectomized dogs the increase in plasma norepinephrine concentrations during cardiopulmonary arrest and basic life support (BLS) was markedly smaller than in sham-operated dogs. Intravenous infusion of physiologic doses of epinephrine during BLS in adrenalectomized animals did not influence the plasma norepinephrine concentrations. These data indicate that, as suggested by others, the marked increase in plasma norepinephrine concentrations during BLS in dogs is mainly of adrenomedullary origin. They also suggest that presynaptic facilitation of norepinephrine release by epinephrine is not important, but further experiments using higher doses of epinephrine are necessary.
Adrenal Glands↗
Plasma concentrations of epinephrine during CPR in the dog.
STUDY OBJECTIVE: The purpose of this study was to evaluate whether the marked increase in the plasma concentrations of epinephrine during cardiopulmonary arrest and basic life support (BLS) could be due in part to decreased distribution and/or elimination. DESIGN AND INTERVENTIONS: Dogs were randomly assigned to undergo adrenalectomy or sham-operation. Some adrenalectomized animals received an epinephrine infusion. MEASUREMENTS AND MAIN RESULTS: In the seven sham-operated dogs, the plasma epinephrine concentrations increased markedly during BLS as expected. In the seven adrenalectomized dogs receiving a constant infusion of epinephrine, cardiopulmonary arrest and BLS induced a three to sixfold increase in plasma epinephrine concentrations, with an increase in the mean plasma epinephrine concentrations (calculated from the area under the curve) of 1.21 +/- 0.12 ng/mL (P less than .05). In the seven adrenalectomized dogs receiving a constant epinephrine infusion but not subjected to cardiopulmonary arrest, the plasma epinephrine concentrations remained stable. Finally, in the seven adrenalectomized dogs not receiving an epinephrine infusion, the mean plasma epinephrine concentrations during BLS (calculated from the area under the curve) increased only by 0.05 +/- 0.04 ng/mL, significantly less than in adrenalectomized dogs receiving an epinephrine infusion (P less than .01). CONCLUSION: The increase in plasma epinephrine concentrations during cardiopulmonary arrest and BLS is due in part to an altered disposition of epinephrine.
Adrenalectomy↗
The enantiomeric distribution of propranolol is not influenced by its beta-blocking activity.
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Animals↗
Attitude of the public toward technical package inserts for medication information in Belgium.
We designed an 84-item questionnaire to determine the attitude of the Belgian public toward package inserts (PI) for medication information, written in technical language and intended for health professionals, within an original drug-dispensing distribution system. There were 398 respondents to this general public survey, based on a 0.05 percent selection from election registers of the districts of Gent and Liège. Eighty-nine percent of the respondents read the PI, focusing their attention principally on adverse effects (88 percent), dosage and dosing guidelines (85 percent), contraindications (82 percent), indications (79 percent), and medication shelf-life (76 percent). Compliance (83 percent), reassurance (57 percent), increased knowledge about the medication (50 percent), and decision to take the medicine (31 percent) were among the respondents' motives for reading the PI. Most respondents considered the PI information useful and complete, but difficult to remember and understand. Readers further criticized its legibility and poor graphic illustration. The PI was seen as a supplementary source of information, instrumental to the physician-pharmacist-patient relationship, without the power to overrule the physician's or pharmacist's instructions. Some respondents reported that the PI made them afraid to use the medication. Expectations for the ideal PI were contradictory and can only be met with a never-optimal compromise between comprehensiveness and conciseness.
Adolescent↗
Binding of alfentanil to human alpha 1-acid glycoprotein, albumin and serum.
The variability of the serum binding of the short-acting narcotic analgesic alfentanil was studied. Binding of alfentanil was measured in human alpha 1-acid glycoprotein (AAG) and human albumin solutions, and in serum from 6 groups of individuals: control subjects, patients with renal failure, cirrhosis, rheumatoid arthritis and myocardial infarction, and intensive care patients. Alfentanil is mainly bound to AAG and the influence of a change of the AAG concentration on its binding is much more marked than that of a change of the albumin concentration. In patients with renal failure, myocardial infarction and rheumatoid arthritis and in intensive care patients, AAG concentrations are increased, but alfentanil binding is significantly increased only in patients with myocardial infarction. In patients with cirrhosis, AAG, albumin concentrations, and alfentanil binding are decreased. In vitro addition of lidocaine, disopyramide, bupivacaine and quinidine, in concentrations that are observed clinically, lead only with disopyramide to an important increase in free fraction of alfentanil (from 7 to 19%). This latter finding was confirmed in 2 volunteers, treated chronically with disopyramide.
Adult↗
Determination of the calcium antagonist nimodipine in plasma by capillary gas chromatography and nitrogen detection.
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Animals↗
Binding of diltiazem to albumin, alpha 1-acid glycoprotein and to serum in man.
Binding of drugs can vary considerably. Therefore, binding of the calcium antagonist diltiazem was studied in protein solutions and in serum of healthy persons, patients with renal failure, patients with cirrhosis, patients with rheumatoid arthritis, patients with myocardial infarction, and intensive care patients. The effect of in vitro addition of some cardiovascular drugs (lidocaine, disopyramide, quinidine, and bupivacaine) on the binding of diltiazem in serum of healthy volunteers was also investigated. Diltiazem is bound as well to alpha 1-acid glycoprotein (AAG) as to albumin. In patients with renal failure, myocardial infarction, and rheumatoid arthritis and in intensive care patients, AAG concentrations are increased, and in the patients with myocardial infarction an increased binding of diltiazem is found. In patients with cirrhosis, AAG concentrations and diltiazem binding are decreased. In vitro addition of lidocaine, disopyramide, bupivacaine, or quinidine in concentrations between 5 and 100 micrograms/mL, before dialysis, decreases the binding of diltiazem; the displacing effect is most pronounced with bupivacaine.
Adult↗
Nimodipine has no beneficial effect on neurological outcome in a cardiopulmonary arrest model in the rat.
Brain damage after resuscitation from cardiac arrest is believed to be related to calcium influx in ischaemic neurons and to postischaemic calcium-dependent vasospasm. We therefore evaluated the potentially protective effects of the calcium-entry blocker nimodipine in a cardiopulmonary arrest model in the rat. Male Wistar rats were anaesthetized with ketamine (group I) or hexobarbital (group II) and subjected to a KCl-induced cardiac arrest during 7 min (group I) or 12 min (group II). Five minutes after resuscitation, the rats were treated intravenously in a randomized and blind fashion. Group I received either saline or 1 microgram.kg-1.min-1 or 5 micrograms.kg-1.min-1 of nimodipine and group II either saline or 1 microgram.kg-1.min-1 of nimodipine. Survival, occurrence of seizures and neurological status were assessed daily during 7 days after resuscitation. On day 7, the brains of the surviving rats were perfusion-fixed and a histopathological evaluation of the hippocampus was performed. Nimodipine, in the doses tested, had no beneficial influence on the 7 day survival rate, nor on the occurrence of seizures and the neurological and histopathological scores in the rats surviving after 7 days. With the highest dose of nimodipine, there was even a trend towards a decrease of the survival rate, probably related to the drug's hypotensive effect. Therefore, our data do not show a protective effect of nimodipine after cardiac arrest.
Animals↗
Placing obsolete hypnotics on prescription and the admission rate for acute poisoning with these drugs.
Since January 1 1988, certain older hypnotics have no longer been available over the counter in Belgium, but can still be dispensed on prescription. The influence of this measure on admission to our Emergency Department for acute poisoning with these hypnotics has been examined. From 1983 to 1987, a mean of 93 patients (range 87 to 99) per year were admitted as compared to 15 and 5 in 1988 and 1989, respectively. For older hypnotics that were on prescription before and after 1st January 1988, there was no decrease in 1988, and a reduction was observed in 1989. There was no change in the number of patients with benzodiazepine poisoning. The data indicate that moving these older hypnotics onto the prescription-only list resulted in a decrease in acute poisoning with them. The reduction observed in 1989 for the older hypnotics that were on prescription before as well as after 1988 may have been due to an influence of the measure on the prescribing habits of physicians.
Acute Disease↗
Package inserts for antihypertensive drugs: use by the patients and impact on adverse drug reactions.
In Belgium, all dispensed drugs are provided with package inserts. Traditional physician-orientated inserts are gradually being replaced by patient package inserts (PPIs). The present survey is focused on the use of inserts for antihypertensive drugs and their impact on the reported occurrence and attribution of adverse drug reactions (ADRs). A group of 28 general practitioners (GPs) from the Flemish part of Belgium collected data from 702 hypertensive patients. Each participating GP submitted a consecutive sample of his patients to an interview in the Spring 1989, when 25% of the antihypertensive specialties carried a PPI-version. 1049 prescriptions for antihypertensive drugs had been dispensed. Two thirds of the patients, mostly those with a higher educational level, had read the package inserts. PPIs accounted for 16% of the inserts, and they had not been read significantly more than the traditional inserts. Reporting by the patients of possible drug-related health problems (spontaneously + after having heard the items on a check-list) was not affected by reading the insert or by the type of insert. However, the PPI did bring about spontaneous reporting, especially by patients with a low educational level. Attribution of at least one health problem to the medication was not affected by reading in itself but by the type of insert. Attribution was higher when the patient had received a PPI, except in the case of highly educated patients. Spontaneous reporting and attribution of health problems to the medications prescribed was found more frequently among patients with higher education, who did not seem to need a PPI to recognize problems as being drug-related.
Antihypertensive Agents↗
Investigation of possible pharmacokinetic and pharmacodynamic interactions between epanolol and digoxin.
The possibility of a pharmacokinetic and/or pharmacodynamic interaction between epanolol and digoxin has been investigated in 10 healthy male subjects taking digoxin 0.375 mg daily for 14 days. During that period epanolol 200 mg daily or matching placebo was also given, each for 7 days, according to a double-blind, randomized cross-over plan. The plasma digoxin concentration-time profiles after 7 days of concomitant placebo or epanolol were comparable. Trough and peak plasma digoxin levels were similar (placebo: 0.84 and 2.62 ng.ml-1; epanolol: 0.87 and 2.46 ng.ml-1). The renal clearances of digoxin and creatinine were lower during treatment with epanolol, but the differences were not significant (placebo 142.0 and 126.5 ml.min-1; epanolol 105.7 and 109.3 ml.min-1). STI indexes were lower during treatment with digoxin plus epanolol, than after digoxin alone. The difference was significant for QS2I (513 versus 503 ms), PEPI (119 versus 112 ms) and PEP/LVET (0.286 versus 0.304). The observations suggest that in healthy volunteers there is no pharmacokinetic interaction between epanolol and digoxin, and that epanolol does not interfere with the positive inotropic action of digoxin.
Adrenergic beta-Antagonists↗