Factors associated with rerupture of intracranial aneurysms after endovascular treatment: A retrospective review of 11years experience at a single institution and review of the literature.

Aneurysm rebleeding following initial endovascular management is uncommon, and the factors associated with its occurrence are poorly defined. We retrospectively analyzed a consecutive series of patients presenting with aneurysmal subarachnoid hemorrhage who underwent endovascular management to determine factors associated with rebleeding. Rebleeding occurred in 7/183 (3.8%) patients, 6 of which had an adjacent hematoma on initial neuroimaging. Aneurysms were located on the ACoA (n=5), PCoA (n=1), and MCA (n=1). Sizes ranged from 3.5 to 13.0mm (mean 8.0), with neck sizes ranging from 1.8 to 4.6mm (mean 3.2). Time-to-rerupture ranged from hours to years, with 3/7 cases rebleeding within 30days and 4/7 cases rebleeding later than 30days. Initial incomplete angiographic occlusion occurred in 2/3 cases of early rebleeding. The presence of adjacent intracerebral hematoma (ɸ=0.354, p<0.005), increasing Fisher Grade (t(9.4)=7.72, p<0.005), and aneurysmal outpouching (ɸ=0.265, p<0.005) were found to be the only factors associated with rerupture status. Recurrent hemorrhage following endovascular management of ruptured intracranial aneurysms is an uncommon but important source of morbidity, particularly in the early post-embolization period. The presence of high-risk features, such as an adjacent intracerebral hematoma or aneurysm outpouching, warrant early and frequent angiographic follow up to document stability and mitigate rupture risk.

The clinical pharmacology of lisinopril.

Structurally, lisinopril differs from captopril in that it does not contain a sulphydryl group and it differs from enalapril and related compounds in that it is not an ester prodrug. Published data on the clinical pharmacology of lisinopril are reviewed and data from new studies are presented. A radioimmunoassay has been used to study the clinical pharmacokinetics of lisinopril and 14C-lisinopril has been used in metabolism studies in man. Following oral administration, lisinopril is absorbed slowly but the absorbed drug is immediately available without any requirement for biotransformation by the liver. The plasma half-life controlling accumulation during chronic administration is 12-13 h and the absorbed drug is eliminated via glomerular filtration. These properties are consistent with once-daily dosing and uncomplicated clinical use in the treatment of hypertension and congestive heart failure.

The validity of lecturer ratings by students and trained observers.

This study sought to determine to what degree student ratings of specific lecturer characteristics relate to trained observer ratings of such characteristics and to identify the distinguishing delivery characteristics of highly rated lecturers. The 15 lowest-rated lecturers and the 15 highest-rated lecturers, based on the mean ratings of students from two consecutive years (1982 and 1983) in a large multi-instructor course, served as the target group. Blinded non-student raters observed the lectures in 1984 (two per lecture) and completed quantitative and qualitative forms. For all six subscores from the quantitative form, statistically significant differences between the lecturers given the highest and lowest ratings were obtained. It is concluded that the students' ratings were stable across the three years; the independent observers discriminated between the lecturers the students rated the highest and the lowest; voice presentation characteristics discriminated the most effectively; and nonmedical non-student observers are potentially a useful source of information regarding faculty teaching skills.

A survey to identify deficiencies in transfusion medicine education.

Medical faculty, blood center directors, and technologists were surveyed to assess current opinions of knowledge deficiencies in transfusion medicine among medical school graduates, housestaff, and practicing physicians. Over 90% of those responding believed additional training in transfusion medicine was needed. Nine categories of deficiencies were identified, with more than 40% of respondents' comments reflecting concern about the lack of knowledge of the use of blood and blood components. Clinical faculty and blood bankers differed in their assessments of the knowledge deficiencies in two of the nine categories. Information obtained in this survey is relevant to educational development in transfusion medicine.

Incorporation into endogenous metabolic pathways of small fragments derived from I.C.I, 58,834(vioxazine).

1. Metabolic degradation of the tetrahydro-oxazine ring of 2-(2-ethoxyphenoxymethyl)-2,3,5,6-tetrahydro-1,4-oxazine (I.C.I. 58,834) gives rise to one- or two-carbon fragments which are utilized by endogenous metabolic pathways. 2. Evidence of this in dogs is shown by the 14C-labelled residues in tissues, 14C-labelled material in blood which has a half-life of three weeks, and elimination of [14C]urea in urine. 3. The same phenomenon occurs in rat, mouse and man, but to a smaller extent than in the dog. 4. Intravenous administration of [14C]ethanolamine to a dog gave rise to residual 14C blood levels with a half-life comparable to that produced by metabolic incorporation of 14C from 14C-I.C.I. 58,834.

The state of the art: a commentary on the current practice of metabolism and pharmacokinetic studies in the pharmaceutical industry.

1. The role of those studying metabolism and pharmacokinetics within the safety evaluation process is discussed. 2. Current technology to undertake "classical" drugs disposition studies is adequate but some of the classical concepts may require modification in the future. 3. Problems of study design in the context of the broad objectives of regulatory requirements are reviewed. 4. The implications of new proposals which may affect the future design of metabolic and pharmacokinetic programmes are considered.

Safety of Hibitane. I. Laboratory experiments.

The safety evaluation of chlorhexidine (Hibitane) in animal species will be briefly reviewed. The relevance of these studies to human use will be discussed, and species comparisons made where possible. Animal studies with chlorhexidine were begun more than two decades ago and the evaluation of its safety has been under continual review ever since. Chlorhexidine is poorly absorbed after oral administration, well tolerated after parenteral administration and its percutaneous absorption is abolutely minimal. No clinical or histological effects have been obtained in any animal study to cause hesitation in the light of proliferating applications of chlorhexidine in human use. The various toxicological studies in animals will be described and in particular the results of a 2-year study in rats will be outlined. In this, as an in earlier long-term study, there were no effects whatsoever to suggest that chlorhexidine treatment could give rise to any kind of tumourigenic effect or any other toxic sign.

Activity of the natural algicide, cyanobacterin, on angiosperms.

Cyanobacterin is a secondary metabolite produced by the cyanobacterium (blue-green alga) Scytonema hofmanni. The compound had previously been isolated and chemically characterized. It was shown to inhibit the growth of algae at a concentration of approximately 5 micromolar. Cyanobacterin also inhibited the growth of angiosperms, including the aquatic, Lemna, and terrestrial species such as corn and peas. In isolated pea chloroplasts, cyanobacterin inhibited the Hill reaction when p-benzoquinone, K(3)Fe(CN)(6), dichlorophenolindophenol, or silicomolybdate were used as electron acceptors. The concentration needed to inhibit the Hill reaction in photosystem II was generally lower than the concentration of the known photosystem II inhibitor 3-(3,4-dichlorophenyl)-1,1-dimethyl urea. Cyanobacterin had no effect on electron transport in photosystem I. The data indicate that cyanobacterin inhibits O(2) evolving photosynthetic electron transport in all plants and that the most probable site of action is in photosystem II.

Blood level studies with viloxazine hydrochloride in man.

1 The pharmacokinetic characteristics of a new antidepressant, viloxazine hydrochloride, (ICI 58,834, Vivalan), have been investigated in four separate studies. 2 In Study 1, blood levels were measured over a period of 24 h after single doses of viloxazine hydrochloride from 10-100 mg (expressed as base). In Study 2, blood levels were measured over 24 h, during which three single doses of viloxazine hydrochloride (80 mg, expressed as base) were given 4 h apart. In Study 3, blood samples and urine and faeces were collected for 96 h after doses of 40 and 100 mg of [14C] viloxazine hydrochloride (40 muCi). In Study 4, 1 h blood levels were measured at weekly intervals during a comparative clinical trial in which viloxazine was given at a dose of 100 mg four times a day. 3 The half-life of the drug is in the range 2-5 h with maximum blood levels occurring in 1-4 h of the oral dose. Maximum blood levels are proportional to the oral dose given over the range studied (0.76(mug/ml)/(mg/kg)). The drug is very well absorbed orally, only 2% being found in faeces. Repeated dosing at 4 hourly intervals leads to slightly higher blood levels after the second, but not subsequent, doses. No accumulation was seen from week to week in depressed patients. No regular sex difference was seen in the pharmacokinetic characteristics of viloxazine hydrochloride but two females in one study did show a markedly higher maximum blood level and apparently longer half-life than the males. 4 It is concluded that viloxazine is rapidly and almost totally absorbed after an oral dose, and has a shorter half-life than the tricyclic antidepressants; therapy with it should be easily controllable.

The disposition and metabolism of I.C.I. 58,834 (viloxazine) in humans.

1. 2-(2-Ethoxyphenoxymethyl)-2,3,5,6-tetrahydro-1,4-oxazine (I.C.I. 58,834) in three 14C-labelled forms, given orally to two male volunteers, was completely absorbed, extensively metabolized and rapidly eliminated via the kidney. 2. O-Dealkylation, the major metabolic pathway in the rat, was not significant in man. 3. The major component in blood at all times was I.C.I. 58,834, which had a blood half-life of 4 h. The level of 14C in blood at 31 h was near the limit of detection. 4. The observed activity of the drug appears to be due to the parent compound alone.

The disposition and metabolism of I.C.I. 58,834 (viloxazine) in animals.

1. 2-(2-Ethoxyphenoxymethyl-2,3,5,6-tetrahydro-1,4-oxazine (I.C.I. 58,834) has been prepared in three different 14C-labelled forms and its absorption, distribution, metabolism and elimination studied in six animals species. 2. In all species I.C.I. 58,834 was well absorbed after oral administration and extensively metabolized. Excretion via the kidney was the main route of elimination. 3. In the rat the major metabolic pathway is o-dealkylation and sulphate conjugation; the dealkylated metabolite was detected in brain extracts. A novel type of polar metabolite was isolated from rat urine, apparently a conjugate with sulphate and hippurate. 4. The metabolic pathways in beagle dogs include hydroxylation of the phenyl ring (and subsequent conjugation), N-methylation, formation of the N-methyl-N-oxide, and oxidation of the oxazine ring. 5. Maximum blood levels of I.C.I. 58,834 in dogs were unchanged during eight weeks daily administration and the half-life was 2.5-3 h. I.C.I. 58,834 is the main component in dog blood. Rat serum contains mainly conjugates of dealkylated I.C.I. 58,834 and the parent compound is a minor component. 6. None of the metabolites has significant CNS activity and activity observed following administration of I.C.I. 58,834 is due primarily to the parent compound.

The disposition and metabolism of meropenem in laboratory animals and man.

The disposition and metabolism of meropenem were studied in rats, dogs and cynomolgus monkeys following intravenous administration of [14C]-meropenem, and also in man following intravenous infusion of meropenem. Following intravenous administration to rats and dogs, radioactive material was very rapidly and widely distributed in the tissues, with highest levels detected in the kidney and other highly perfused organs. Concentrations in all tissues decreased rapidly with time. The plasma elimination half-life of meropenem was approximately 6 min in rats, 30 min in monkeys, 45 min in dogs and 1h in man. In all species 90-100% of the dose was excreted via the urine within 24 h. Analysis of the radioactive material in urine from animal studies showed that the major components were unchanged compound (36-43%) and a metabolite corresponding to a beta-lactam ring-opened form (34-51%). In man, approximately 65% of the dose was excreted in urine as unchanged meropenem and most of the remainder as the ring-opened metabolite. As part of the preclinical safety evaluation programme of meropenem, the distribution, metabolism and excretion of [14C]-meropenem were studied in the rat, dog and cynomolgus monkey after single intravenous administration at dose levels corresponding to the lower doses used in toxicity studies. In addition, the metabolism and pharmacokinetics of meropenem in human volunteers were studied.