Iron chelation with oral deferiprone in patients with thalassemia.
Explore the source record for details and available documents.
Biopsy↗
Biomedical subjects
M Spino
Publications and source records attributed to M Spino.
Hypothetical framework for enhanced renal tubular secretion of drugs in cystic fibrosis.
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 Cl- in the tubular lumen. We postulate that, in an effort to maintain homeostasis, luminal Cl- 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.
Chlorides↗
High variability in drug pharmacokinetics complicates determination of bioequivalence: experience with verapamil.
PURPOSE: For the assessment of bioequivalence it is assumed that drug clearance in each subject on each of the study days is the same and any observed differences in AUC and/or Cmax between a brand and generic formulation are due to differences in bioavailability. We hypothesized that this assumption was invalid for highly variable drugs such as verapamil and tested it by comparing bioavailability for the brand vs itself. METHODS: To avoid any contribution from potential formulation differences, we evaluated bioavailability for isoptin SR 240 mg tablets in 9 healthy volunteers on 2 occasions separated by 1 week as part of a larger study. A validated HPLC assay was used to measure serial blood samples over 36 hours. RESULTS: The AUC0-1 varied 3.8 fold among subjects and 5/9 subjects had > 30% difference in AUC0-1 on the 2 days. After log transformation, the mean AUC0-1 +/- %cv (ng.h/mL) on Occasion 1 (878 +/- 38) was 23% greater (p = 0.031) than on Occasion 2 (713 +/- 41). The 90% confidence interval of Occasion 1/Occasion 2 was 106-143%. The Cmax varied > 9 fold (30-278 ng/mL) among subjects. The intrasubject difference between days ranged from -46% to +298%. The 90% confidence interval was 72-152% for Cmax. Since the same lot of Isoptin was used in the same subjects on 2 occasions, the observed differences must be due to biological variability in verapamil pharmacokinetics, not formulation differences. CONCLUSIONS: The intra-subject biological variability complicates bio-equivalence assessment and can lead to an erroneous assumption of bioinequivalence.
Adult↗
Comparisons between oral and intraperitoneal 1,25-dihydroxyvitamin D3 therapy in children treated with peritoneal dialysis.
Recent studies in adults have suggested that parenteral 1,25-dihydroxyvitamin D3 (1,25[OH]2D3) 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.
Administration, Oral↗
Are current pediatric dose recommendations for intravenous theophylline appropriate?
Theophylline, a first-line antiasthma drug, is often associated with severe toxicity even when taken in the recommended schedule. Theophylline toxicity has been associated with upper respiratory tract infections (URTI) due to reduced total-body clearance of theophylline. Some researchers believe this inhibition stems from a direct effect of viruses, but others postulate it is a result of the fever. We examined whether current theophylline dose recommendations are appropriate for children with acute asthma with a concurrent URTI. We also wished to elucidate whether the viral infection or the fever inhibits theophylline clearance. A total of 2254 medical records of asthmatic children admitted to The Hospital for Sick Children in Toronto were reviewed between 1987 and 1990. Clearance rate was calculated as the ratio between the infused dose rate and measured steady-state concentrations. Subsequently, these clearance rates were used to calculate steady-state concentrations that would be achieved by the recommended dose rates of theophylline. Reduced theophylline clearance was associated with the presence of URTI (p = 0.029) but not fever. Age correlated significantly with theophylline clearance (p = 0.027). If these children were to receive the recommended intravenous dose rate of theophylline, two-thirds of them would achieve steady-state serum concentrations above 15 mg/L, and one-third would achieve concentrations above 20 mg/L. Reevaluation of the present recommended theophylline dose rate is needed, as the majority of children requiring intravenous theophylline have a concurrent URTI with compromised total-body clearance. A correction factor of 60% is recommended to adjust the dose rate during an URTI. If utilized by prescribing physicians, it may reduce theophylline toxicity during an URTI episode.
Adolescent↗
Ciprofloxacin in patients with mycobacterial infections: experience in 15 patients.
In vitro and animal investigations have demonstrated the antimycobacterial activity of some fluoroquinolones, including ciprofloxacin, but information regarding their clinical usefulness in mycobacterial infections is sparse. This article presents treatment results of 11 patients with tuberculosis and 4 with atypical mycobacterial infections. They were treated with combinations of ciprofloxacin and one or two other antituberculosis agents. Susceptibility of the infecting organisms to ciprofloxacin was determined in 14 of the 15 patients: in 12 of them, minimum inhibitory concentrations ranged between 0.31 and 1.25 micrograms/mL, suggesting a good level of activity. Serum concentrations of ciprofloxacin, sampled one hour after dosing and measured by a specific HPLC assay, revealed considerable variability (range 0.22-8.41 micrograms/mL). Serial plasma samples taken under controlled conditions suggested that a decreased rate of absorption was responsible for low one-hour concentrations in one of the subjects. Adverse reactions to ciprofloxacin were few and included nausea in four patients, crystalluria in one, and febrile reaction in another. A satisfactory response in terms of clinical and radiologic improvement, bacteriologic conversion, and absence of relapse was seen in 13 of the 14 patients who completed an adequate course of therapy. A controlled clinical trial of this promising antimycobacterial agent is needed.
Adult↗
Use of an isolated in situ canine lung perfusion model to evaluate dopamine clearance by the lung.
An isolated in situ lung perfusion model was used to assess dopamine clearance by the lungs in 12 dogs. The preparation consisted of a closed perfusion system in situ, in which systemic arterial blood supply was interrupted. Blood flow to the lungs was maintained at presurgery flow rates. The inflow was restricted to the lungs by the pulmonary arteries and outflow was limited to the pulmonary veins. Pulmonary artery pressure, temperature and pO2 were maintained at physiological levels. After confirmation of a stable base line, one of 3 doses (1, 2, or 5 micrograms/kg/min) of dopamine was infused over 30 min to achieve steady-state blood concentrations, then blood samples were drawn at specified times during and after the infusion. Dopamine plasma concentrations were analyzed by high performance liquid chromatography with electrochemical detection. Dose-dependent disposition of dopamine was observed in both plasma concentration-time profiles and in clearance (20.3 +/- 9.6 ml/min/kg at 5 micrograms/kg/min vs. 41.6 +/- 19.1 ml/min/kg at 1 micrograms/kg/min, P = 0.038). A sham experiment revealed that the blood in this experimental preparation contributed less than 10% to the total clearance of dopamine. This study revealed that our isolated in situ model is an excellent method to evaluate the role of the lungs in drug removal. Furthermore, it confirmed that the lungs contribute to the clearance of dopamine from the body.
Animals↗
Colchicine: a state-of-the-art review.
Colchicine is an ancient drug that is attracting renewed interest because of its actions at a subcellular level. Specifically, it interferes with microtubule growth and therefore affects mitosis and other microtubule-dependent functions. Various mechanisms have been proposed to account for the action of colchicine in acute gouty arthritis, its interaction with cellular membrane and cyclic 3',5'-adenosine monophosphate, and its action in amyloidosis. Pharmacokinetic studies have been relatively limited and their results somewhat contradictory, with mean terminal elimination half-lives of 19 minutes to 9 hours being reported. Some of these differences may be attributed to assay difficulties. Colchicine can cause gastrointestinal side effects and should be used with care to protect patients from toxic doses. Colchicine-induced myopathy and neuropathy may be more frequent than previously recognized, and therefore patients receiving long-term therapy should be monitored carefully. Bone marrow depression has been reported, primarily in cases of acute colchicine intoxication, and intravenous administration of the drug has been associated with severe pancytopenia and death. Colchicine intoxication causes multiple organ failure. Because of its cytogenic effects and reported association with Down's syndrome, the agent should not be used by pregnant women.
Amyloidosis↗
Angiotensin converting enzyme inhibitor therapy to decrease microalbuminuria in normotensive children with insulin-dependent diabetes mellitus.
It has been proposed that lowering glomerular pressure in children with insulin-dependent diabetes mellitus will reduce microalbuminuria and that this reduction may preserve renal function. We therefore conducted a double-blind, placebo-controlled, crossover trial to compare 3 months of treatment with the angiotensin converting enzyme inhibitor captopril (0.9 mg/kg/day), and 3 months of placebo administration to 12 normotensive adolescents with insulin-dependent diabetes mellitus, 11 with microalbuminuria (albumin excretion rate of 15 to 200 micrograms/min) and one with early overt nephropathy. Mean age (+/- SD) was 14.4 +/- 1.7 years, and disease duration was 5.1 +/- 2.5 years. Albumin excretion rate decreased significantly during captopril therapy (baseline 78 +/- 114 micrograms/min; mean of monthly measurements 38 +/- 55 micrograms/min vs placebo 78 +/- 140 micrograms/min; p less than 0.001). During captopril therapy, albumin excretion was reduced by 41 +/- 44% and decreased in 10 of 12 subjects, but was unchanged in two, one with a borderline albumin excretion rate (16.3 micrograms/min) and one with diabetes of short duration (2.9 years). Plasma renin activity rose significantly during captopril therapy, and mean arterial pressure decreased slightly (placebo 81 +/- 7 mm Hg; captopril 76 +/- 5 mm Hg; p = 0.004). After 3 months of captopril treatment, glomerular filtration rate and renal plasma flow did not change significantly. Hemoglobin Alc values remained stable during the study. The only side effect of captopril was diarrhea in one patient. We conclude that, in the short term, captopril is effective in decreasing albumin excretion rate in normotensive children with insulin-dependent diabetes mellitus and microalbuminuria, without significant side effects. Longer trials are indicated in an attempt to delay or prevent overt nephropathy.
Adolescent↗
Effects of cisapride in patients with cystic fibrosis and distal intestinal obstruction syndrome.
In a double-blind, placebo-controlled, crossover trial, we investigated the effects of the prokinetic drug cisapride in patients with cystic fibrosis and chronic recurrent distal intestinal obstruction syndrome (DIOS). After a baseline period, 17 patients (12.9 to 34.9 years; 12 boys) received, in random order, cisapride (7.5 to 10 mg) and placebo three times daily by mouth, each for 6 months. Gastrointestinal symptoms (flatulence, abdominal pain, fullness, abdominal distension, nausea, anorexia, heartburn, diarrhea, vomiting and regurgitation) were scored three times monthly and physical examinations assessed. At baseline and at each 6-month period, assessment included food intake for 7 days, 3-day stool collection, pulmonary function tests, and abdominal radiographs. During cisapride therapy compared with placebo, there were significant reductions in flatulence (p less than 0.005), fullness, and nausea (p less than 0.05). Patients with the worst symptom scores benefited most from cisapride. With cisapride, 12 patients felt better and three worse (p less than 0.05); physicians judged 11 patients improved and two worse (p less than 0.05). No side effects were noted. There were no significant differences between cisapride and placebo periods in nutritional status, x-ray scores, pulmonary function, food intake (fat, protein, calories), stool size and consistency, and fecal losses of fat, bile acids, chymotrypsin, and calories. For acute episodes of DIOS, intestinal lavage was needed 6 times in 4 patients during treatment with cisapride, and 11 times in 6 patients receiving placebo. In comparison with unselected patients with cystic fibrosis and pancreatic insufficiency who were receiving enzyme supplements and who had no distal intestinal obstruction, fecal fat losses (percentage of intake) were almost twice as high in the study group with DIOS (31.2 +/- 20.6% vs 16.2 +/- 17.6%; p less than 0.01). We conclude that in the dosage used, long-term treatment with cisapride appears to improve chronic abdominal symptoms in patients with cystic fibrosis and DIOS, but fails to abolish the need for intestinal lavage. Cisapride treatment had no effect on digestion and nutritional status of cystic fibrosis patients with pancreatic insufficiency.
Adolescent↗
Pharmacokinetic analysis of cloxacillin loss in children undergoing major surgery with massive bleeding.
To determine the magnitude of cloxacillin loss during surgical procedures involving significant blood loss and high fluid replacement, we compared the pharmacokinetics of cloxacillin in children during craniomaxillofacial surgery with the disposition of the drug in healthy young adult volunteers with intact circulation. Blood loss during craniofacial operations may exceed blood volume, in some cases by as much as three times. Hemodynamic replacement with electrolyte solutions and blood products, which do not contain the drug, further dilute cloxacillin concentrations. In the patients that we studied, mean drug loss was estimated at 71%. Cloxacillin concentrations in serum fell below the lower range of the MIC for Staphylococcus aureus during significant portions of the surgical procedures. Thus, the traditional dosing of cloxacillin during prolonged operations with massive blood loss is inadequate. A more frequent dosing interval or priming of all replacement fluids with the drug may be required to maintain therapeutic levels. Our findings suggest that massive blood loss is likely to have a dramatic effect on the level of any drug with a small distribution volume. If such a drug is essential to the patient's well-being (e.g., antibiotics, antiarrhythmics, and anticonvulsants), it must be replaced promptly.
Adolescent↗
Bioequivalence of generic aerosol bronchodilators: what are the issues?
I have attempted to address some critical issues relating to the introduction of generic aerosol bronchodilators in Canada. I approached Genpharm to obtain information on the data submitted to the HPB, including the number of subjects involved, but the company refused to divulge this information because it was concerned about the use of such information by its competitors. In addition to the in-vitro testing conducted by the HPB, should a single pharmacodynamic study be sufficient to demonstrate the safety and efficacy of a drug that serves such a critical role in the prevention of serious illness and possibly death? If so, what will constitute the minimum requirements for the design of such a study? In general, what should be the minimum standards required for safety, efficacy and bioequivalence of aerosol bronchodilators? The next phase rests with the provincial governments. What criteria will they use to determine whether a generic aerosol bronchodilator will be considered bioequivalent? It is essential that the criteria for bioequivalence be developed by experts, and ideally those criteria should be agreed upon and accepted by federal and provincial regulatory bodies before a product is given the status of bioequivalence. Unless such a step is taken it will be difficult to have confidence that products can be considered interchangeable. The issue of interchangeability of aerosol bronchodilators demands immediate attention. Regulatory agencies are caught between those groups with vested interests on both sides. Since patients will either benefit or suffer as a consequence of regulatory decisions, action must be taken to ensure that the best decisions are made. Scientists, clinicians and government officials should convene as soon as possible to formulate a satisfactory approach to this problem of interchangeability. The medical and pharmaceutical professions need reliable information, and patients should not be denied less expensive generic drugs if it can be determined that they are comparable to the innovator's product.
Aerosols↗
Cystic fibrosis: enhanced theophylline metabolism may be linked to the disease.
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 less than 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.
Adolescent↗
Pulse dosing versus continuous infusion of antibiotics. Pharmacokinetic-pharmacodynamic considerations.
The issue of whether it is better to administer antibiotics as an intermittent bolus dose or a continuous intravenous infusion has been debated for several decades. This paper reviews the extensive literature on the topic, considering both the pharmacokinetic and pharmacodynamic aspects of antibacterials as well as experimental results from studies conducted in vitro, in animals and in humans. It is evident from reviewing the literature that neither mode of administration is clearly superior to the other. The decision regarding the mode of administration must take into account the antibiotic being used, the bacteria, the patient and the infection, as well as the pharmacokinetics of the particular drug in the individual patient. The minimum inhibitory concentration (MIC) and the minimum bactericidal concentration (MBC) are useful indicators of the relative in vitro effectiveness of antibiotics, but it is not clear what relevance these parameters have to the desired antibiotic concentrations in vivo. Furthermore, questions of serum vs tissue fluid concentrations, peak concentrations vs AUC, and free vs total concentration are all important issues to consider in assessing the optimal mode of administration. The importance of newer indices such as the post-antibiotic effect are now beginning to be recognised. A number of scientists are actively engaged in developing a system to identify the most appropriate mode of administration based upon the integration of an antibiotic's pharmacodynamics and pharmacokinetics. Within the next few years we anticipate that appropriate guidelines should have been developed to aid the optimisation of parenteral administration, at least for some antibiotics.
Anti-Bacterial Agents↗
The theophylline-erythromycin interaction.
Since its publication in 1976, the original report of an interaction between erythromycin and theophylline by Cummin, Kozak, and Gillman has generated considerable interest and controversy. Many studies with considerably different designs have been performed to address this question. Those studies that most closely simulate the clinical setting suggest that a 7- to 10-day course of concurrent theophylline and erythromycin therapy will result in variable changes in theophylline clearance. It may be that as many as 25% of patients, especially when maintained with serum theophylline concentrations at the upper portion of the therapeutic range, display elevations in serum theophylline concentrations that might lead to clinical symptoms of theophylline toxicity. There has been a suggestion, based on the mean changes in several studies, that the interaction may lead to a 25% increase in serum theophylline concentrations; however, it is clear that there may be a much larger increase in some patients. This toxicity can be anticipated and avoided if careful attention is paid to monitoring the serum theophylline concentrations of such high-risk patients when erythromycin therapy is contemplated as an addition to theophylline therapy. Other macrolide antibiotics may display interactions with theophylline, which may be due in part to the ability of the various antibiotics to form complexes with isoenzymes of the cytochromes P-450. The growing impression of the importance of mycoplasma in asthmatics and the introduction of new macrolides onto the market make the appreciation of this possible interaction of extreme importance to primary care and chest physicians.
Drug Interactions↗
Highly sensitive determination of cimetidine and its metabolites in serum and urine by high-performance liquid chromatography.
Explore the source record for details and available documents.
Animals↗
Pharmacokinetics of cimetidine after subchronic administration.
The influence of cimetidine on its own pharmacokinetics after subchronic administration was assessed in 8 healthy volunteers, aged 26-29 years. On control Day 1, each subject received cimetidine 300 mg i.v., and serum and urine samples were obtained. Each subject was initiated on cimetidine 600 mg b.i.d. orally for 2 weeks. There were 3 further study days repeated after 1 and 2 weeks of cimetidine dosing and 1 week after stopping cimetidine. There was no significant difference in the mean total body clearance of cimetidine among the 4 study days. Mean elimination t1/2 beta and V beta were similarly unchanged. However mean renal clearance (CLR) and fe were significantly increased following 2 weeks of drug dosing (CLR 5.41 ml X min-1 X kg-1; fe 0.61) compared to control (CLR 4.00 ml X min-1 X kg-1; fe 0.48). Although the non renal clearance was reduced from control values of 4.29 to 3.51 ml X min-1 X kg-1 following 2 weeks of dosing the difference was not significant. Dosage adjustment of cimetidine appears unnecessary after short-term dosing in the presence of normal renal function.
Administration, Oral↗
Assessment of glomerular filtration rate and effective renal plasma flow in cystic fibrosis.
A study was conducted to examine renal function in 10 healthy control subjects and eight patients with cystic fibrosis in stable condition. Sequential bolus injections of 99mTc-DTPA and 125I-OIH were administered to assess glomerular filtration rate and effective renal plasma flow, respectively. Blood was subsequently collected for 3 hours, and urine for 24 hours. Renal clearances of both radioisotope markers were virtually identical in patients and controls. Inasmuch as neither glomerular filtration rate nor effective renal plasma flow was enhanced in patients with cystic fibrosis, increased clearance of drugs in these patients is unlikely to be the result of enhanced glomerular filtration or tubular secretion.
Adolescent↗