Several clinical studies demonstrate reduced serum concentrations of renally excreted drugs in patients with cystic fibrosis (CF). To explain this phenomenon, we propose a model supporting increased ...proximal tubular secretion of certain drugs in individuals with CF. We hypothesize that the chloride channel located on the apical surface of renal proximal tubular cells and controlled by the cystic fibrosis transmembrane conductance regulator (CFTR) operates suboptimally in CF patients, and that the abnormal CFTR decreases Cl
− reabsorption, resulting in an increased concentration of CI
− in the tubular lumen. We postulate that, in an effort to maintain homeostasis, luminal CI
− moves intracellularly in exchange for organic anions. The result of stimulating this anion exchanger is an increased rate of organic anion secretion by the renal tubule. Hence, due to enhanced tubular secretion, individuals with CF demonstrate increased tubular clearance of organic anion drugs, resulting in lower steady state serum concentrations.
Theophylline disposition (5.5 mg/kg administered intravenously) was studied in 12 patients with cystic fibrosis (CF) and 16 healthy control volunteers. Dietary controls and logs were used to minimize ...the influence of food on theophylline metabolism. Control subjects were restudied in random order on two subsequent occasions after 2 weeks of either pancreatic enzymes or placebo. Theophylline and its three main metabolites, 1‐methyluric acid, 3‐methylxanthine, and 1,3‐dimethyluric acid, were analyzed in serum and urine by HPLC. The total body clearance, renal clearance, nonrenal clearance, and volume of distribution of theophylline were significantly greater (p < 0.05) in patients with CF than in control subjects. The increased nonrenal clearance was the result of increased biotransformation to each of the three main metabolites. Patients with CF exhibited enhanced N‐demethylation and 8‐hydroxylation of theophylline, pathways that appear to be mediated by two different families of P‐450 enzymes. Theophylline clearance after 2 weeks of pancreatic enzyme administration in the control subjects was the same as with placebo. Possible reasons for enhanced theophylline biotransformation in CF are discussed.
Clinical Pharmacology and Therapeutics (1988) 44, 254–264; doi:10.1038/clpt.1988.147
Recent studies in adults have suggested that parenteral 1,25-dihydroxyvitamin D3 (1,25OH2D3) may have advantages over oral therapy in the management of renal osteodystrophy. The purpose of this study ...was to determine whether there were clear differences between oral and IP 1,25(OH)2D3 treatments in children who did not pose a treatment problem. Seven children (5 males, 2 females, aged 1.8 to 16 years, median 4.8 years) undergoing peritoneal dialysis were initially treated with oral 1,25(OH)2D3 for a one month equilibration period They were randomly assigned to 3 months of either oral or intraperitoneal (IP) therapy with 1,25(OH)2D3 followed by 3-months-treatment using the alternative route. No significant differences in serum creatinine, phosphate, or parathyroid hormone concentrations were found between the different routes of administration in the patients. No significant differences in height standard deviation scores or renal osteodystrophy scores were found over the six-month study. Paired oral and IP pharmacokinetic studies were performed on these 7 patients and 2 other children who had been treated for at least 2 months using either oral or IP 1,25(OH)2D3. Serum was taken prior to one of the usual 1,25(OH)2D3 doses and 0.5, 1.5, 3, 6, and 24 h afterward. The highest measured concentrations of 1,25(OH)2D3 were found at 1.5 h for both oral and IP treatments (mean Cmax SD: oral 116 23 pmol/l, IP 121 24 pmol/l, p > 0.05). The AUC's for oral and IP therapy were similar (1701 276 and 1645 301 pmol/h/l, respectively). In the paired pharmacokinetic studies no significant differences were found between oral and IP treatments for the serum half life (27.4 11.6 h and 19.2 8.1 h, respectively) and total body clearance (15.3 2.1 h and 18.4 3.3 h, respectively) of 1,25(OH)2D3. In children who respond appropriately to oral 1,25(OH)2D3 there is no biological advantage to the use of IP 1,25(OH)2D3.
Immune responses provoked by human immunodeficiency virus (HIV) infection ultimately are insufficient to control the disease and do not include strong lymphocyte-proliferative responses to HIV ...antigens or antibodies to many viral epitopes. A randomized double-blind, placebo-controlled trial evaluated the immunogenicity of recombinant HIV envelope vaccine (rgpl60) in HIV-infected subjects with ⩾$400/mm^3$CD4 T cells. Controls received hepatitis B vaccine. Of subjects receiving rgpl60, 98% developed lymphocyte-proliferative responses to the immunogen, 33% to a different envelope protein, and 56% and 60% to p24 and p66, respectively. All doses of vaccine (20, 80, 320, 1280 /μg) induced new responses. New antibodies to epitopes on rgpl60 developed only in recipients of higher doses of rgpl60. CD4 T cell percentages declined less rapidly in recipients of rgpl60 than in controls. Vaccination of HIV-infected subjects with rgpl60 results in cellular and humoral immune responses to HIV that infection itself had not stimulated.
Clean indoor air (CIA) ordinances in Toledo, Ohio, and Bowling Green, Ohio, regulate smoking in restaurants to protect patrons and employees. Yet complete protection is questionable because the ...ordinances allow for smoking in certain dining sections. Two restaurants were studied in each city, one smoking and one nonsmoking. Levels of contaminants related to environmental tobacco smoke (ETS)-determined by personal and area air monitoring-in the nonsmoking restaurants were comparable to levels in a control environment. However, levels of ETS-related contaminants in the smoking restaurants, including designated nonsmoking sections, were significantly higher than levels in the control environment. ETS-related contamination of the nonsmoking sections in the smoking restaurants is attributable to direct openings between the smoking and nonsmoking sections. Reasonable protection of employees and patrons against ETS-related contaminants requires strict enforcement of CIA ordinances. Full protection is achievable only with 100% smoke-free policies.
A report is given on the use of fungi as a biosynthetic agent to produce high-quality protein from cellulose wastes such as kraft paper, agricultural waste, and urban refuse after a process such as ...hydro-pulping first separates the cellulose fibres in the refuse from non-cellulose materials. Several processes for increasing the biodegradability of cellulose were tested, but only nitrite photochemical treatment proved efficient and economically feasible.
Nurse monitors collected clinical and laboratory data from 204 hospitalized patients receiving furosemide (122 men and 82 women; mean age 69.6 years). Biochemical abnormalities and clinical problems ...definitely or probably induced by any drug occurred in 70.6% and 49.0% respectively of the patients, and were attributed to furosemide in 81.3% and 13.0% respectively of these patients. The most important clinical events were dehydration and hypotension. Furosemide-induced hypochloremia, hypokalemia and hyponatremia occurred in 35.8%, 25.0% and 24.5% of the patients respectively. Most of the biochemical changes were slight, and only 3.9% of the patients had a furosemide-induced decrease in the serum potassium concentration to less than 3.0 mmol/L. Surprisingly, 24.5% of the patients also manifested drug-induced hyperkalemia. Administration potassium supplements or spironolactone, or both, concurrently with furosemide was responsible in most cases for the development of hyperkalemia. The occurrence of drug-induced adverse effects after 2 weeks of hospitalization was significantly associated (P less than 0.05) with subsequent prolongation of hospitalization. The high frequency of drug-induced events warrants careful monitoring of all patients receiving furosemide in spite of the low frequency of serious toxic effects produced by the drug.
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