Cryptococcal Meningitis in Patients with the Acquired Immunodeficiency Syndrome

The optimum therapy for cryptococcal meningitis in patients with the acquired immunodeficiency syndrome (AIDS) remains unresolved. Traditional therapy consists of amphotericin B with or without flucytosine. Obstacles exist in administering these agents to patients with AIDS. Mortality rates during initial therapy are relatively high. Given the lack of proved benefit, we do not recommend adding flucytosine to amphotericin B routinely. The search for more efficacious and less toxic agents continues. The oral triazoles, especially fluconazole, have increased the options for treatment of this disease. New strategies and novel approaches in managing cryptococcal meningitis in patients with AIDS continue to be developed.     

FEASIBILITY OF CONDUCTING CARDIOVASCULAR OUTCOME RESEARCH IN AUSTRALIAN GENERAL PRACTICE: RESULTS FROM THE ANBP2 PILOT STUDY

1. The present study aimed to determine the feasibility of conducting a 5 year cardiovascular outcome trial of the treatment of 6000 elderly hypertensive patients in Australian general practices. 2. General practitioners (GPs) were invited to participate by mail and personal follow-up. Patient records were reviewed to identify subjects for a blood pressure (BP) screening programme. Blood pressure was measured on three occasions and eligible subjects were included if the average BP was 160 mmHg systolic or 90 mmHg diastolic if systolic BP was 140 mmHg. 3. Seven hundred and forty-one GPs were approached and 89 were enrolled in the study (12% of mail invites and 75% of those receiving a personal contact). In 16 practices where screening was completed, 82 000 records were reviewed to identify 4% patients eligible for screening. Twenty-two per cent of eligible subjects attended screening. Of 1938 subjects screened, 180 (9%) had BP 5=160/90 mmHg. Forty-seven percent of subjects (n = 916) were receiving antihypertensive therapy and 184 (20%) were withdrawn from therapy. One hundred and sixteen (63%) of these subjects had BP return to study entry levels within 6 weeks. Fifty-seven newly diagnosed and 81 previously treated subjects were randomized (7% of the screened population). 4. Based on the high participation rate of GPs, the response rate of patients to attend a BP screening programme and the 7% randomization to screening ratio for entry into the study, the ANBP2 pilot study has demonstrated that it is feasible to recruit subjects from Australian general practices to a cardiovascular outcome trial.     

Use of metoclopramide, domperidone, and cisapride in the management of diabetic gastroparesis

The pathophysiology, diagnosis, and treatment of diabetic gastroparesis are reviewed, and the mechanisms of action, pharmacokinetics, clinical efficacy, adverse effects, and dosage of metoclopramide, domperidone, and cisapride are described. Diabetic gastroparesis is a state of delayed gastric emptying that reportedly affects 20-30% of diabetic patients. Symptoms include nausea, early satiety, postprandial bloating and fullness, and vomiting. Diabetic gastroparesis has been managed most successfully with drugs that stimulate gastric emptying. Of the three agents studied--metoclopramide, domperidone, and cisapride--only metoclopramide is commercially available in the United States. The clinical efficacy of metoclopramide, domperidone, and cisapride has been well documented in several placebo-controlled trials. Metoclopramide effectively decreases mean gastric emptying time, although tolerance to this stimulation of gastric emptying may develop with long-term therapy. However, symptomatic relief persists with long-term therapy because of metoclopramide's antiemetic properties. Domperidone, which has also been shown to stimulate gastric motility and to possess antiemetic properties, improves symptoms in patients suffering from diabetic gastroparesis. Cisapride appears to have continued beneficial effects on gastric motility with long-term therapy. All three agents have favorable adverse-effect profiles. Although metoclopramide is currently the first-line agent for the management of gastroparesis, domperidone and cisapride both possess properties that may make them useful alternatives in patients who are unresponsive to or cannot tolerate metoclopramide therapy.     

Evidence for the presence of a non-catecholamine, clonidine-displacing substance in crude, methanolic extracts of bovine brain and lung

In the present study we have prepared crude, methanolic extracts of bovine lung and bovine brain and, using radioligand binding assays in conjunction with a number of simple chromatographic techniques, provided evidence for the presence of a non-catecholamine ’clonidine-displacing substance‘ (CDS). The level of CDS in lung extracts (9?units/g wet weight n=11) is approximately 3 times that in the brain extracts. Furthermore, the effect of the crude, methanolic extracts are selective for non-adrenoceptor, imidazoline (labelled by [ ³H]-idazoxan) and a ₂-adrenoceptor binding sites (labelled by [ ³H]-clonidine); both extracts are 5–10-fold more potent displacers of ligand binding to a ₂-adrenoceptors compared with binding to opiate receptors (labelled by [ ³H]-etorphine) and practically inactive against a ₁-adrenoceptor and muscarinic binding sites (labelled by [ ³H]- prazosin and [ ³H]-quinuclidinyl benzilate, respectively). With the exception of the non-adrenoceptor, imidazoline binding assay, which used rat kidney membranes labelled by [ ³H]-idazoxan in the presence of the a ₂-adrenoceptor antagonist RS-15385-197, all radioreceptor assays involved bovine cerebral cortex membranes. Although the extracts contain catecholamines (brain only), histamine (lung only) and monovalent cations (both), which have the potential to interfere with the radioligand binding assays, their concentrations were too low to account for the effects observed. Preliminary attempts at purification of the extracts revealed that CDS activities from the two tissues are similar, i.e., practically insoluble in organic solvents at room temperature, not affected by either Sep-Pak C ₁₈ column or anion exchange resins but retained (along with the monovalent cations) by cation exchange resin. However, following chromatographic separation on a Biogel P2 column, the CDS-containing eluates are cation-free and exhibit qualitatively similar elution profiles. Future experiments will involve further purification of ’clonidine-displacing substance‘ to characterize its interaction with a ₂-adrenoceptor binding sites in greater detail and establish whether it has biological activity consistent with the properties implied by its effects in radioligand binding assays.     

The bioavailability and nonlinear pharmacokinetics of MK-679 in humans

MK-679 (R(?)-3-((3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)(3-(dimethylamino)-3-oxopropyl)thio)methyl)thio(propanoic acid) is a potent and specific LTD₄-receptor antagonist. The disposition of MK-679 was investigated in a three-way crossover study in 12 healthy males receiving single intravenous doses of 75, 250, and 500 mg of MK-679. A greater than proportional increase in the area under the plasma concentration—time curve of MK-679 was observed with increase in dose. The plasma concentration data for each subject fitted well to the differential equations for a two-compartment model with linear tissue distribution and Michaelis-Menten elimination from the central compartment, indicating that the elimination of MK-679 in humans is saturable. In a previous study, the disposition of MK-679 in humans was also dose-dependent when given together with its S(+)-isomer, L-668,018. Thus, the disposition of MK-679 in humans is dose-dependent regardless of the presence of its stereoisomer. Also, the bioavailability of MK-679 was determined in six healthy males receiving simultaneously an oral dose of 250 mg of MK-679 and intravenous infusion of 1 mg ¹⁴C-MK-679. Results of this study indicate that the oral bioavailability of MK-679 is nearly quantitative.     

Inter- and intra-individual variability of non-invasive tear break-up time in Hong Kong Chinese

Non-invasive tear break-up time (NITBUT) has been proposed as a measure of tear film integrity which is superior to the more commonly used tear break-up time (TBUT), since it does not alter the volume or the physicochemical properties of the tear layer by the addition of fluorescein. We measured NITBUT by measuring the time taken for distortions or discontinuities to appear in the reflected image of a grid pattern which covered about 80 per cent of the corneal surface. NITBUT measures were made 100 times on seven Hong Kong Chinese subjects with up to 20 consecutive measures being made on a single day. We also measured NITBUT on one occasion on an unselected population of 52 Hong Kong Chinese subjects. NITBUT shows a skewed distribution in all subjects, with many shorter values and some extremely long values. There are statistically significant variations in NITBUT from day to day, and from subject to subject. The group of 52 subjects also had a skewed NITBUT distribution with many short values and some very long values. The arithmetic mean does not adequately represent NITBUT data, either for individual subjects or for this group of subjects. As many as five to eight measures may be necessary to gain a stable estimate of the NITBUT and stability of the measure is improved if extreme values are omitted. We recommend the use of nonparametric statistics to compare NITBUT values from day to day in or between subjects.     

Therapeutic progress I: Current treatment of rheumatoid arthritis

Over recent years the pharmacological treatment strategy for rheumatoid arthritis (RA) has changed. An early, aggressive approach has been adopted with a view to maintaining functional capacity. The changing role of nonsteroidal antiinflammatory agents is discussed in the light of the potential toxicity of this class of drugs. The current use of second-line agents is dealt with in depth and includes guidelines to patient monitoring. Particular attention has been paid to the growing use of cyclosporin A in the treatment of RA as this drug represents the newest, most potent, nonexperimental form of treatment. The questions of when to introduce second-line agents, who should receive treatment and how many drugs should be prescribed are all addressed in this review. The relative efficacy and toxicity of these agents is discussed and a treatment protocol is proposed.     

1/T1 rho and low-field 1/T1 of tissue water protons arise from magnetization transfer to macromolecular solid-state broadened lines.

We argue that, for solutions of immobilized protein and for tissue, the dependence of 1/T1 of solvent protons on B(0) at low fields and 1/T1 rho on B1 for all B(0) are both manifestations of the same underlying phenomena: magnetization transfer between mobile water protons and solid-state broadened protein proton levels. Broadening causes rapid mixing of spin orientation within the transverse plane, at all B(0), unless B1 is greater than the protein internal field; this affects 1/T1 rho of solvent protons by magnetization transfer. Similarly, decreasing B(0) below the internal field mixes all orientations of magnetization, which affects the solvent proton low-field 1/T1 and high-field 1/T2.     

PSEUDOHYPERPHOSPHATAEMIA AND MONOCLONAL GAMMOPATHY

SUMMARY A case is reported of pseudohyperphosphataemia in association with a monoclonal gammopathy of undetermined significance.     

DNA probe technology: implications for service planning in Britain

For certain genetic conditions DNA testing identifies carriers and determines the risk status of foetuses, thus helping parents to make more informed prenatal decisions. Data, collected from three genetic centres in England and Wales from August 1986 to July 1990, are used to describe trends in demand for DNA testing, the impact of DNA tests on carrier risk assessment, and the use of DNA tests in relation to pregnancy outcome. Altogether the data include 23,388 subjects and 681 pregnancies in 8738 families divided into five cohorts by year of entry and referral. The most frequent gene disorders referred to the genetic centres are currently being tested or will soon be tested. For these disorders the initial high level of activity has declined and may have reached steady state. Demand for DNA services is high for cystic fibrosis and Duchenne muscular dystrophy, intermediate for Huntington's disease, and low for adult polycystic kidney disease, phenylketonuria and tuberous sclerosis. Based on these findings we suggest that demand for DNA tests will be high in serious, untreatable and slow progressing conditions with early onset; intermediate for conditions affecting intellect and neurological integrity with later onset; and low for treatable, late-onset conditions, or those for which there is evidence of heterogeneity, and variable penetrance. It would be helpful to assess the extent to which this view of demand is confirmed when the new disorders being DNA tested are considered and for the pattern of activity of DNA testing for some types of cancer. Since no DNA centre could offer a fully comprehensive testing service, it is recommended that a structure is created to audit overall activity, assist in policy formulation, and influence supraregional service organisation, in order that the spread of DNA services be planned as effectively as possible. This structure would facilitate monitoring of the evolution of contract specifications agreed by commissioners and providers on a regional basis.