High-performance liquid chromatographic analyses of porphyrins in hamster Harderian glands.

Porphyrin content and 5-aminolaevulinate synthase activity of the Harderian gland were measured in intact and gonadectomized male and female hamsters; porphyrin profiles were analysed by high-pressure liquid chromatography. The total porphyrin content of the two female groups was similar, but enzyme activity in females ovariectomised for 20 weeks significantly decreased. Intact males have low porphyrin content and enzyme activity, while in castrates (6 weeks) both increased to female levels. Protoporphyrin IX formed 93% of total porphyrins in intact females, compared with 70% of total porphyrins in intact males. The remainder in both sexes was chiefly penta- and hexacarboxylic porphyrins and coproporphyrin and (in females) Harderoporphyrin. Gonadectomy in either sex resulted in protoporphyrin levels intermediate between male and female values.

Who still prefers aggressive surgery for breast cancer? Implications for the clinical applications of clinical trials.

Conservative breast surgery and modified radical mastectomy may, according to recent reports, yield equivalent survival. Analysis of a 1985 Canada-wide study (N = 228) compared surgeons and oncologists still recommending modified radical mastectomy (30%) with those recommending less aggressive surgery (69%) for a hypothetical stage I patient. The groups did not differ significantly in most physician characteristics, estimated survival and cure probabilities, importance of most treatment goals, uncertainty about treatment choice, or most attitudinal responses. Although equally involved with and cognizant of the value of clinical trials, the modified radical group expressed more skepticism about the ability of trial results to be transferred to practice and to take sufficient account of patient uniqueness, indicating greater focus on variation than mean results. Trial results might be more readily adopted if they are reported in accessible data-bases, incorporating patient characteristics potentially relevant to treatment choice. This would allow clinicians to individualize treatment by analyzing patient subsets of their own choosing.

Neurochemical actions of the desglycinyl metabolite of remacemide hydrochloride (ARL 12495AA) in mouse brain.

1. Remacemide hydrochloride, a recently developed antiepileptic drug, is believed to exert its effects, at least in part, via its desglycinyl metabolite, ARL 12495AA. 2. We have investigated the effects of ARL 12495AA on several neurochemical parameters in mouse brain. Adult male ICR mice were randomized into two groups and administered ARL 12495AA (0-75 mg kg-1) intraperitoneally, either as a single dose or once daily for 5 days. 3. Six hours after the final dose, animals were killed and their brains removed. Brain tissues were analysed for concentrations of gamma-aminobutyric acid (GABA), glutamine and glutamate and for the activities of GABA-transaminase (GABA-T) and glutamic acid decarboxylase (GAD). 4. Single dose ARL 12495AA was without effect on any of the parameters investigated. 5. Repeated ARL 12495AA treatment did not alter brain concentrations of GABA and glutamine, but at a high dose there was a trend toward reduced brain glutamate concentrations (P = 0.10). 6. Repeated administration of ARL 12495AA at a high dose significantly increased GABA-T activity (P < 0.05) and decreased that of GAD (P < 0.05). 7. These findings may have relevance to the clinical use of remacemide hydrochloride in human epilepsy.

Effects of anti-epileptic drugs on glutamine synthetase activity in mouse brain.

1. Glutamine synthetase (GS) is a key enzyme in the regulation of glutamate neurotransmission in the central nervous system. It is responsible for the conversion of glutamate to glutamine, and for the detoxification of ammonia. 2. We have investigated the effects of single and repeated intraperitoneal administration of a range of established and new anti-epileptic drugs on GS activity in mouse brain. 3. Four hours after the final dose, animals were sacrificed and the brains removed for analysis of GS activity. 4. Both single and repeated doses of phenytoin and carbamazepine were found to reduce enzyme activity (P<0.05). 5. Single doses of phenobarbitone, felbamate and topiramate were without effect, however repeated administration of these drugs dose-dependently reduced GS activity (P<0.05). 6. Single and repeated doses of sodium valproate, vigabatrin, lamotrigine, gabapentin, tiagabine, levetiracetam and desglycinyl-remacemide were found to have no effect on GS activity. 7. The reduction in enzyme activity demonstrated is unlikely to be related to the anti-epileptic actions of these drugs, but may contribute to their toxicity.

Hepatic drug metabolism and haem biosynthesis in lead-poisoned rats.

1 Pretreatment of rats with intraperitoneal injections of lead was shown to result in a depression of the microsomal mixed function oxidase system, as assessed by a decrease in hepatic microsomal P-450 and b5 content and by a decrease in the activity of the enzymes aniline hydroxylase and aminopyrine demethylase. Lead had a more marked effect on cytochrome P-450 than b5. 2 The activity of the rate-limiting enzyme of haem biosynthesis, delta-aminolaevulinic acid synthase, was inversely correlated with the microsomal cytochrome P-450 content. 3 The activity of the haem biosynthetic enzymes delta-aminolaevulinic acid dehydratase, coproporphyrinogen oxidase and ferrochelatase were decreased by increasing lead pretreatment. 4 The activity of the haem catabolic enzyme, haem oxygenase, was increased by lead pretreatment.

Hormones and the control of porphyrin biosynthesis and structure in the hamster harderian gland.

The hamster Harderian gland seems to present both an excellent model for the control of porphyrin biosynthesis and an unusually robust example of the interrelationship between structure and function. It has been known for some time that 1) the capacity for manufacturing and storing porphyrins and 2) gland histology and ultrastructure are controlled by androgens. Thus, in intact males as well as in gonadectomised animals of either sex treated with androgens, porphyrin synthesis by the Harderian gland is suppressed and the gland tubules characteristically possess two cell types, the cytoplasm of both containing polytubular complexes. By contrast, the Harderian glands of intact females and castrated males synthesise and store large amounts of protoporphyrin, while their tubules possess only one cell type which lacks a polytubular complexes. So overarching is the effect of androgens that they have been described as a "coarse tuning" effect on the gland. By contrast, the role of the ovary is both less dramatic and less well understood. In female hamsters, ovariectomy leads to degenerative changes in Harderian gland tubules and (probably) a release of stored porphyrin; at the same time there is a reduction in enzyme levels and new synthesis. The causative hormone in this "fine tuning" is unclear at present. There is now clear evidence that the Harderian gland is also controlled directly by pituitary hormones. In particular, the use of continuous infusion osmotic minipumps has allowed us to demonstrate not only 1) that the expected rise in porphyrins and feminisation of gland morphology does not occur in castrated males receiving the dopamine agonist bromocriptine, but that 2) the simultaneous administration of prolactin does permit these changes; furthermore, 3) the administration of prolactin alone increases porphyrin synthesis above the levels found in untreated castrates. Similarly, bromocriptine administration to ovariectomised females markedly reduces porphyrin synthesis and masculinises gland structure; again, this is reversed by the simultaneous administration of prolactin. Prolactin must therefore be seen as equipotent with androgens in determining gland structure and activity.

The effect of verapamil on the pharmacokinetics of adriamycin.

The concurrent administration of adriamycin (intravenous) and verapamil (oral) is of considerable interest because of experimental data suggesting that resistance to adriamycin may be overcome by this means. The potential for a pharmacokinetic interaction between the two drugs has therefore been investigated in five patients with small cell lung cancer treated with combination chemotherapy comprising adriamycin, VP16, vincristine and cyclophosphamide. The data indicate that a significant interaction takes place. Adriamycin peak levels, terminal half-life and the volume of distribution at steady state are higher, whereas plasma drug clearance and the volume of the central compartment are lower with co-administration of verapamil. There was no evidence of enhanced drug toxicity in this study; however, the data should be considered in the interpretation of clinical trials in which adriamycin and verapamil are used together, both in terms of toxicity and tumour response.

Neurochemical actions of gabapentin in mouse brain.

Gabapentin (GBP) is a recently licensed antiepileptic, drug whose mode of action remains to be fully elucidated. The following studies were designed to investigate the effects of GBP on several gamma-aminobutyric acid (GABA) related neurochemical parameters in mouse brain. GBP (0-75 mg/kg) was administered by intraperitoneal injection either as a single dose or twice daily for 8 days. Animals were sacrificed 4 h after the final administration and their brains removed and analysed for concentrations of GABA, glutamate and glutamine and the activities of GABA-transaminase (GABA-T) and glutamic acid decarboxylase (GAD). Single dose GBP increased brain GABA-T activity and glutamine concentration but was without effect on GAD activity or the concentrations of GABA and glutamate. Following repeated treatment with GBP, brain GABA-T activity was consistently decreased and there was also a decrease in brain glutamate concentration. Repeated drug treatment was without effect on the activity of GAD or on the concentrations of GABA and glutamine. These results suggest that GBP has effects on the GABAergic system which may contribute to its antiepileptic and/or neuroprotective actions.

Nimodipine in refractory epilepsy: a placebo-controlled, add-on study.

Twenty-two patients (8 male, 14 female) with refractory epilepsy entered a balanced, double-blind, placebo-controlled crossover trial of nimodipine as adjunctive therapy. Treatment periods of 12 weeks (nimodipine 30 mg tds, 60 mg tds, 90 mg tds each for 4 weeks and matched placebo) were followed by wash-out intervals of 4 weeks. Five patients withdrew (2 side-effects, 1 intercurrent illness, 2 non-compliance). Median values (placebo vs. nimodipine) did not vary for total (17 vs. 18), partial (14 vs. 18) and generalised tonic-clonic seizures (2 vs. 5) or seizure days (13 vs. 13). Monthly analysis also failed to uncover any benefit for nimodipine. Side-effects were reported no more frequently with nimodipine than with placebo and pulse and blood pressure did not alter significantly. Antiepileptic drug levels were not affected by nimodipine treatment but circulating nimodipine concentrations were low. In this trial, nimodipine did not fulfil the promise of its success in animal models of epilepsy. Enzyme induction by concurrent antiepileptic therapy may provide an explanation.

Delta-aminolaevulinic acid metabolism in normal and lead-exposed humans.

The activity of the haem biosynthetic enzymes delta-aminolaevulinic acid synthetase (ALA.S) and delta-aminolaevulinic acid dehydratase (ALA.D) were measured in the peripheral blood of a group of lead workers and control subjects. The haem precursor delta-aminolaevulinic acid (ALA) was measured in blood and urine, whilst lead levels were measured in whole blood. The inter-relationships between all these parameters were examined and quantified. The results demonstrate that above a blood lead concentration of 2 mumole/l and below an erythrocyte ALA.D activity of 18 nmole ALA utlized/min/ml red blood cells (R.B.C.), Haem synthesis is depressed to such an extent that the activity of leucocyte ALA.S, the rate-limiting enzyme of haem biosynthesis, is increased by negative feedback.

Overconfidence among physicians and nurses: the 'micro-certainty, macro-uncertainty' phenomenon.

Overconfidence in clinicians was examined in two independently designed studies, each using a different research approach. The first study examined treatment choices of physicians in treating breast cancer, and the second rapid decision making among nurses working in Intensive Care Units. In both studies, individual respondents were highly confident they had made the right choice ('micro-certainty'), although there was no consensus across respondents as to what the optimal treatment would be ('macro-uncertainty'). The difference between micro-certainty of individuals and macro-uncertainty within the clinical community may cast some light on the persistence of practice variation. The implications of overconfidence in clinical treatment for patients, practitioners, and professional regulation are discussed.

Health care in Canada: current trends and issues.

Canada's universal health care system is perceived as threatened by rising costs, an aging population, and technological growth. This popular and successful program has largely kept costs under control while maintaining quality and ensuring equity. However, its success demonstrates the limits of medical care; remaining health problems are less amenable to improvement by merely improving access to traditional services. A widening view of health implies a larger health role in other policy arenas, and a larger group of legitimate participants; coordinating an evolving and expanding system becomes increasingly difficult. Policy options include some combination of laissez faire, business as usual, managed care, manpower regulation, and system change. Change implies controversy and conflict. Hard decisions are clearly ahead.

Planning for cardiac surgical services: advice from an Ontario consensus panel. For the Consensus Panel on Cardiac Surgical Services in Ontario and the Steering Committee of the Cardiac Care Network of Ontario.

The Cardiac Care Network of Ontario (CCN) Consensus Panel on Cardiac Surgical Services drew on the literature and its own expertise to recommend guidelines for expanding services. This report, which is not an official position paper of the Canadian Cardiovascular Society, presents these recommendations. Rates of surgery are linked to diagnostic capacity, requiring increases in interventional therapies to match increases in invasive diagnostic activity. For quality and efficiency, panel members recommend an annual minimum of 150 procedures per surgeon and 500 per centre; a centre should serve a minimum population of 500,000. Services should be as close to patients' homes as possible while maintaining recommended volumes. Expanding the CCN's cardiac surgery database to include other cardiac modalities will yield a more accurate assessment of waiting times. The panel recommends collaborative regional planning associations, mentorship arrangements between new and existing centres, prompt action on human resource shortages and exploration of alternative funding models.

Central and peripheral benzodiazepine receptors in rat brain and platelets: effects of treatment with diazepam and clobazam.

Tolerance to the effects of benzodiazepines (BZ) may be mediated by changes in benzodiazepine receptors (BZRs). Peripheral BZRs (in brain and platelets) and central BZRs (in brain) were measured in rats following intraperitoneal administration of diazepam and clobazam each for 4 and 12 days. BZRs were measured by binding assays using [3H] PK 11195 (peripheral) and [3H] flunitrazepam (central) as radioligands. Diazepam, but not clobazam, increased peripheral BZR numbers in platelets (both P < 0.005), but not in brain, after 4 and 12 days' treatment compared with appropriate controls. Neither drug altered central BZR affinities or numbers in rat brain. BZ effects on peripheral BZRs in platelets cannot be extrapolated to predict changes in brain receptors, either peripheral or central.

Vigabatrin and tiagabine are pharmacologically different drugs. A pre-clinical study.

In light of theirclosely related mechanisms of action, and preliminary clinical evidence suggesting that they possess similar efficacies, it has been anecdotally suggested that vigabatrin and tiagabine may prove to be therapeutically indistinguishable. As a result, we have conducted a preclinical comparison of their anticonvulsant profile and mechanism of action. Pentylenetetrazol and maximal electroshock seizures were employed to determine the experimental anticonvulsant profile. Mechanisms of action were investigated using assays of gamma -aminobutyric acid (GABA), GABA-transaminase and glutamic acid decarboxylase in mouse brain and GABA uptake and GABA-transaminase in rat astrocyte cultures. Vigabatrin was without effect on either pentylenetetrazol- or maximal electroshock-induced seizures, whereas tiagabine increased the latency to pentylenetetrazol seizures and reduced the incidence of maximal electroshock seizures. In mouse brain assays, tiagabine was without effect, while vigabatrin increased GABA concentrations and reduced GABA-transaminase and glutamic acid decarboxylase activities. In cortical astrocyte cultures, vigabatrin reduced the activities of both GABA uptake and GABA-transaminase, whereas tiagabine blocked GABA uptake alone. These results suggest that vigabatrin and tiagabine have differing efficacy in experimental seizure models and distinct neurochemical effects. It is possible, then, that these drugs will have different spectra of activity and toxicity profiles in human epilepsy.

Effects of tiagabine and vigabatrin on GABA uptake into primary cultures of rat cortical astrocytes.

Tiagabine (TGB) and vigabatrin (VGB) are two novel anticonvulsant compounds reported to exert their pharmacological effects via an action on the gamma-aminobutyric acid (GABA) system. We have investigated the effects of acute exposure of these drugs on the uptake of GABA into rat cortical astrocytes in primary culture. Astrocytes were prepared from the cerebral cortices of one day-old rat pups by a mechanical dissociation technique and were assayed for GABA uptake activity after 21 days in culture. Tiagabine (100-300 nM) and VGB (100 microM) reduced GABA uptake when compared to control at four hours post-exposure. GABA uptake was also reduced following eight and 24 hour exposures to 200 nM TGB. A combination of TGB (200 nM) and VGB (100 microM) treatments reduced GABA uptake when compared to both control and VGB treated cultures. These results support the efficacy of TGB as a GABA uptake inhibitor and suggest that VGB may also exert an effect by this mechanism.

Effects of valproate, vigabatrin and tiagabine on GABA uptake into human astrocytes cultured from foetal and adult brain tissue.

The antiepileptic agents sodium valproate (VPA), vigabatrin (VGB) and tiagabine (TGB) have been proposed to exert their effects, at least in part, by an action on the transport of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). This information has, however, been gleaned from studies employing experimental systems derived from animal tissues. We have conducted preliminary studies of the effects of VPA, VGB and TGB on the transport of GABA into primary cultures of human astrocytes, derived from both adult and foetal tissues. Astrocytes were prepared from cerebral cortical tissue obtained from patients undergoing surgery for intractable epilepsy, and from spontaneously aborted foetuses (16-24 weeks gestation). The cells were isolated via a series of enzymatic digestions, grown under standard culture conditions for around 21 days and then assayed for GABA uptake activity. VPA (1,000 microM), VGB (100 microM) and TGB (200 nM) all significantly (p < 0.05) reduced the uptake of GABA into primary cultures of human adult astrocytes following a one hour exposure. VPA (1,000 microM) and VGB (100 microM) similarly reduced GABA uptake into astrocytes derived from human foetal tissue, while TGB (200 and 500 nM) was without effect. The results of these preliminary studies suggest that VPA and VGB reduce GABA transport into both adult- and foetally-derived human astrocytes, whereas TGB appears active only in cells cultured from adult brain. Delayed development of the GAT-1 transporter in foetal tissue could explain this observation.

Analytic solution of a dynamic pool model incorporating constant marginal cost and discount rates.

A simple dynamic pool model is extended to describe the economics of a single-species fishery by incorporating constant marginal cost and discount rates. Assuming that the population has already come to equilibrium under an initial fishing mortality rate and that any change in that rate is to be sustained indefinitely, the model can be solved analytically to yield the optimal fishing mortality rate. When this rate is expressed as a proportion of the natural mortality rate, the solution takes the form of a third-degree polynomial whose coefficients are simple functions of four other parameters. The solution exhibits positive conservation effects as long as all four parameters are sufficiently high. These conservation effects may be great enough to warrant closing the fishery when the marginal cost rate exceeds a well-defined limit.

Redesigning services to meet client needs: the Gage Transition to Independent Living.

The Gage Transition to Independent Living, offered by Toronto's West Park Hospital, helps physically disabled adults acquire the skills necessary for living independently in the community. Although the program's goal has remained constant, its structure has changed considerably. In response to client feedback and community trends, the program has replaced its original institutional framework with a community-based one. This article traces how those involved changed the program to meet client needs, and describes what they learned in the process.