Health care and philanthropy: where are we headed?

Peering into health-care's future means examining social, economic and political issues. Knowing what's coming will help development professionals deal with this new world.

Effects of cimetidine and ranitidine on the pharmacokinetics of a chronotherapeutically formulated once-daily theophylline preparation (Uniphyl).

The effects of cimetidine and ranitidine on the steady-state pharmacokinetics, safety, and efficacy of a chronotherapeutically formulated (CTF), once-daily theophylline preparation (Uniphyl) were evaluated in 12 adult patients with asthma. In this randomized, double-blind, three-way crossover study, patients received a fixed dose of CTF-theophylline and concurrent cimetidine, ranitidine, or placebo for a period of 7 days each. Asthma symptoms, drug side effects, and beta 2-agonist inhaler use were recorded daily. Venous blood sampling for pharmacokinetic assessment was done over a complete dosing interval on day 7 of each phase. Coadministration of cimetidine, but not ranitidine, was associated with a significant decrease in the apparent oral clearance of theophylline (2.47 +/- 0.91 vs 1.85 +/- 0.63 L/hr; P = 0.004) and increases in the theophylline area under the curve (233.48 +/- 58.99 vs 307.43 +/- 79.07 mg/L/hr; P = 0.003), peak concentration (13.2 +/- 2.8 vs 16.7 +/- 3.7 mg/L; P = 0.002), and trough concentration (6.4 +/- 2.5 vs 9.0 +/- 3.0 mg/L; P = 0.008). Despite the changes in theophylline pharmacokinetic parameters during cimetidine treatment, no significant differences in asthma symptom scores or side effects were seen when once-daily CTF-theophylline was administered concomitantly with cimetidine, ranitidine, or placebo.

Dietary lipids modify receptor- and non-receptor-dependent components of alpha 1-adrenoceptor-mediated contraction.

Dietary lipid modulation of alpha-adrenoceptor (adrenergic receptor)- and non-adrenoceptor-mediated contractile properties of isolated rat abdominal aortic segments were assessed during the early developmental period. Rats were raised from conception to 90 days of age on semisynthetic diets containing various types and amounts of lipids. Aortic segments from three groups of rats fed high-fat diets (15% wt/wt) consisting of olive oil, corn oil, or lard as the sole lipid sources were compared with those from rats fed a low-fat control diet containing corn oil (5% wt/wt). alpha-Adrenoceptor activities were assessed by measuring the norepinephrine dose response of the tissue rings with and without partial inactivation of alpha-receptors by benextramine. alpha-Adrenoceptor sensitivity to norepinephrine increased, whereas receptor affinity decreased significantly in rats raised on high-fat diets. Qualitative features of dietary lipids influenced non-adrenoceptor-dependent aspects of vascular contractility. Diets rich in polyunsaturated fatty acids (high- and low-fat corn oil) raised the maximum response to norepinephrine and the contractile response to 60 mM potassium compared with more-saturated diets (olive oil and lard). These results demonstrate an effect of chronic feeding of high dietary fat on alpha-adrenoceptor-mediated contractility of abdominal aortic rings from young Sprague-Dawley rats. Qualitative features of dietary lipids also appear to modify receptor-independent parameters of the contractile response of the arterial tissue rings in these animals.

Inspiratory flow limitation in divers.

Inspiratory dyspnea becomes an important factor in reducing a diver's ability to carry out physical work at depths in excess of 300 m. It is possible that dynamic compression of the trachea occurs when the intratracheal pressure drops below environmental pressure, thereby causing transient reduction in inspiratory flow. Vocal cords form an orifice of variable diameter, and orifice flow is predicted to occur at flow rates as low as 22 liter/min when gas density is 5 kg/m3 or more. Pressure drop across the vocal cords is calculated to range from 70 N/m2 at flow rate 1 liter/sec to 2.8 kN/m2 flow rate 4 liter/sec, aperture of the vocal cords 1.2 X 10(-2) m, gas density range 5-10 kg/m3. A smaller aperture, 0.6 X 10(-2) m, results in a pressure drop range 1.29-41.15 kN/m2 for the same flow rates and density range. Thus the transmural pressures that can occur are high enough to cause tracheal compression. At 300 m, gas density 5.9 kg/m3, 3 of 4 divers showed evidence of sudden inspiratory flow limitation.

Effect of glucose administration on various rat hepatic constituents and on the spectral binding of hexobarbital and methadone to rat hepatic cytochrome P450.

The administration of glucose to rats for 48 h resulted in an increase in the duration of anesthesia produced by intraperitoneal injection of pentobarbital. The effect of this glucose treatment on hepatic glycogen and on microsomal protein, cytochrome P450 (P450), cholesterol, lipid and phospholipid content, as well as on the spectral binding of hexobarbital and methadone to microsomal P450, was examined. The glucose treatment appeared to have no effect on microsomal protein or P450 content. The binding of hexobarbital and methadone by P450 produced a type 1 spectrum in both control and glucose-treated animals. The glucose treatment resulted in a decrease in the spectral dissociation constant (Ks) and in the maximal spectral binding (delta Amax) of hexobarbital to P450 while with methadone there was an increase in Ks and a decrease in delta Amax. Total lipid, phosphatidylcholine and phosphatidylethanolamine were increased in the microsomal fractions from glucose-treated animals. The changes in the parameters for drug binding to microsomal P450 probably relate to the increased lipid content of the microsomes although changes in the proportion of P450 isoenzymes could be involved. The previously observed decrease in the microsomal metabolism of hexobarbital and methadone following glucose treatment may be due to decreased binding of these compounds to microsomal P450.

Change of deformability and Heinz body formation in G6PD-deficient erythrocytes treated with 5-hydroxy-6-desmethylprimaquine.

Glucose-6-phosphate deficient human erythrocytes were incubated with low concentrations of 5-hydroxy-6-desmethylprimaquine, a metabolite of primaquine in animals, for up to 18 hours under sterile conditions. These erythrocytes became less deformable than untreated erythrocytes. This decrease in deformability was closely associated with the extent and time course of formation of Heinz bodies in the G6PD-deficient erythrocytes. These results support the hypothesis that the in vivo formation of low concentrations of 5H6DPQ by metabolism of primaquine could be the cause of Heinz body formation and the hemolytic anemia seen when primaquine is administered to G6PD-deficient individuals.

Effects of an NADPH-generating system on primaquine degradation by hamster liver fractions.

1. Primaquine (PQ) often causes severe anaemia in individuals with glucose 6-phosphate dehydrogenase (G6PD) deficient erythrocytes, and metabolites have been implicated as the toxic substance. These studies present data identifying additional metabolites of PQ. 2. Two metabolites of primaquine (PQ) previously identified in human studies, namely, 6-methoxy-8-aminoquinoline (MAQ) and 8-(3-carboxy-1-methylpropylamino)-6-methoxyquinoline (PQC) were also formed on incubation of PQ with hamster liver fractions for up to 24 h without an NADPH-generating system. 3. The alcohol (PQAOH) and lactam (PQLT) derivatives of PQ were also formed on incubation with hamster liver fraction used in these studies. 4. The microsomal metabolism of PQ was decreased in presence of an NADPH-generating system, but not by SKF-525A or glutathione (GSH) indicating that the oxidative reactions were probably not due to the cytochrome P-450 system or free radical mechanisms.

Small-airways disease in recipients of allogeneic bone marrow transplants. An analysis of 11 cases and a review of the literature.

In a retrospective review of 116 consecutive allogeneic bone marrow transplants (BMT), severe obstructive airways disease was identified in 11 patients. Lung pathology demonstrated bronchiolitis in 9 patients and physiologic studies showed small-airways disease consistent with bronchiolitis in the other 2. None of the 5 patients with associated infection survived, while 3 of the 6 patients without an identified pathogen stabilized or improved. Analysis of the 11 cases presented and all 25 cases reported in the literature (1982 to 1985) supports the conclusion that graft-versus-host disease is a major risk factor for bronchiolitis in BMT recipients. Among the proposed mechanisms for the development of bronchiolitis after allogeneic BMT, the 2 most likely are graft-versus-host disease directly causing bronchiolitis, and increased immunosuppressive therapy given for graft-versus-host disease predisposing to viral bronchiolitis. The available evidence would suggest that it is prudent to obtain serial pulmonary function tests even in asymptomatic patients post-BMT, and particularly in those with chronic graft-versus-host disease, in the hope that early detection will allow for early intervention that will arrest or reverse the progression of the obstructive airways disease.

Prevention of acute pulmonary edema after bone marrow transplantation.

In a retrospective review of 21 bone marrow transplantation procedures (BMT), we identified ten episodes of acute pulmonary edema coinciding with significant weight gain in the second week after BMT. When we prospectively observed nine consecutive BMT recipients, six patients developed acute pulmonary edema associated with significant (p less than 0.05) weight gain and an increase in echocardiographically determined left ventricular end diastolic diameter. These findings led to a prospective prophylactic intervention study of 30 consecutive BMT patients. Prophylactic intervention consisting of reduced fluid volume of parenteral alimentation, and diuretic therapy was instituted at any clinical sign of fluid overload. No episode of pulmonary edema occurred. The dramatic difference--acute pulmonary edema occurred in 16/30 untreated vs 0/30 treated cases--suggests that this post-BMT complication is critically related to fluid balance and can be prevented by careful clinical examination, close monitoring of weight change, avoidance of fluid overload and the appropriate use of diuretic therapy.

Delayed digoxin toxicity following discontinuance in acute renal failure.

A digitalized 75-year-old patient with postoperative renal failure demonstrated a progressive rise in serum digoxin concentration, peaking at 3.4 nmol X L-1 three days following discontinuance of the drug. This was accompanied by cardiac bradyarrhythmias. Although the serum digoxin concentration had already started to climb from a therapeutic level prior to the discontinuance of the drug, the unabated and substantial rise was consistent with a dramatic decrease in the apparent volume of distribution of digoxin accompanying acute renal failure. Serum digoxin levels were determined with fluorescence polarization immunoassay, which has an improved specificity when compared to the commonly used radioimmunoassays for digoxin.

Ciguatera poisoning: a report of three cases.

Confirmed ciguatera poisoning is reported in three Canadian adults who ingested grouper imported from Florida. Two required hospitalization for management of marked gastrointestinal, neurological, and cardiovascular disturbances. Outside of endemic areas, the recognition of this type of fish poisoning may be inadequate. The pathogenesis, diagnosis, and therapy of the disease are outlined.

Effects of refeeding on respiration and skeletal muscle function.

This article discusses refeeding in relation to respiratory skeletal muscle function and the subsequent function of the respiratory system as a whole. The characteristic alterations in malnourished skeletal muscle and the response to refeeding are outlined. Following this, a simple energetic model is used to explore future areas of therapeutic research and practical recommendations.

Maximal inspiratory and expiratory pressures are reduced in hyperinflated, malnourished, young adult male patients with cystic fibrosis.

We measured maximal inspiratory and expiratory pressures (MIP and MEP, respectively) in 23 male patients with cystic fibrosis (CF), 16 to 35 yr of age (22.1 +/- 3.7), and in a control group of 33 male volunteers, 17 to 39 yr of age (22.5 +/- 6.8), to evaluate the effects of chronic hyperinflation and malnutrition on MIP and MEP in the patients with CF. Routine pulmonary function tests and skeletal muscle indexes, such as the force generated by the adductor pollicis muscle with supramaximal ulnar nerve stimulation at a frequency of 10 Hz as percentage of force at 100 Hz (F10/100) and midarm muscle circumference as a percentage of predicted (MAMC), were also measured in the patients with CF. Severe hyperinflation in this study was defined as a ratio of residual volume to total lung capacity above 50% and malnutrition as a ratio of actual weight to the ideal weight for the patient's age and height of 90% or less. The severely hyperinflated subgroup of patients with CF had significantly reduced MIP values in comparison with those in the other patients with CF. The malnourished subgroup, which was also severely hyperinflated, differed from the well-nourished one in both skeletal muscle indexes; MAMC was reduced, whereas F10/100 was elevated, and respiratory muscle pressure generation, MIP, and MEP were reduced. We conclude that patients with CF who are malnourished and/or severely hyperinflated have reduced maximal respiratory pressures.

Synthesis of certain hydroxy analogues of the antimalarial drug primaquine and their in vitro methemoglobin-producing and glutathione-depleting activity in human erythrocytes.

A number of hydroxy analogues of the antimalarial drug primaquine [8-[(4-amino-1-methylbutyl)amino]-6-methoxyquinoline] were synthesized and characterized by 1H NMR and mass spectra. Several of the compounds were found to be active in forming methemoglobin in human erythrocytes, particularly in those from glucose-6-phosphate dehydrogenase (G6PD) deficient subjects. Decreased levels of glutathione (GSH) in G6PD-deficient erythrocytes were also found with compounds that were active methemoglobin formers.

In vitro metabolism of the antimalarial agent primaquine by mouse liver enzymes and identification of a methemoglobin-forming metabolite.

From a mouse liver microsomal system, we have isolated and identified a methemoglobin-forming metabolite of primaquine (PQ). Evidence has been found for both O-dealkylation and hydroxylation of PQ to form a metabolite, 5,6-dihydroxy-8-(4-amino-1-methylbutylamino)quinoline, which is highly active in forming methemoglobin in both normal and glucose-6-phosphate dehydrogenase-deficient erythrocytes. It also actively decreases glutathione levels in glucose-6-phosphate dehydrogenase-deficient erythrocytes. The inhibitor SKF 525-A prevented metabolite formation while iproniazid and carbon monoxide did not inhibit metabolism completely but may have resulted in formation of a different unidentified metabolite. Mass spectrometry, HPLC, NMR, and other more indirect methods were used to help identify the metabolite. It was identified indirectly via a blue compound which results from extracting the actual metabolite from the incubation mixture with organic solvents under alkaline conditions in the presence of light. The blue compound was identified as a quinonimine in which the 8-amino side chain of PQ cyclizes to produce a third ring system.

Metabolism of 8-aminoquinoline antimalarial agents.

Some of the most effective antimalarial agents are derivatives of 8-aminoquinoline. The metabolic products of many of these compounds appear to be toxic to the erythrocytes of certain human subjects, especially those deficient in glucose-6-phosphate dehydrogenase. Although a number of studies have been conducted over many years, the metabolism of most of these compounds has not been determined. These studies are reviewed.Adult dogs dosed with tritium-labelled primaquine were observed to excrete approximately 16% of the injected radioactivity in the urine within 8 hours. Organic extracts of the urine were fractionated by thin-layer chromatography and the metabolic pattern obtained. Some primaquine was excreted along with at least five metabolites including 5-hydroxy-6-methoxy-8-(4-amino-1-methylbutylamino)quinoline (5HPQ) and a small amount of 6-hydroxy-8-(4-amino-1-methylbutylamino)quinoline (6HPQ). The 5HPQ could form a quinoneimine-type compound which may be a methaemoglobin-forming compound. This and other metabolites isolated from urine were found to be active methaemoglobin formers in in vitro studies. In vitro metabolism of primaquine by mouse liver enzymes also produced compounds capable of methaemoglobin formation. One of these had a blue colour when exposed to alkaline conditions, air, and light, and mass spectral data and nuclear magnetic resonance analysis indicated a structure similar to a 5,6-dihydroxy derivative of primaquine. However, the chemical structure of the metabolite was not identified in these studies.