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Biomedical subjects

D S Sitar

Publications and source records attributed to D S Sitar.

At least 37 records · Page 2Linked to original sources
PubMed1998

(-)Nicotine inhibits the activations of phospholipases A2 and D by amyloid beta peptide.

It has been established that amyloid beta peptide (AbetaP) activates phospholipase A2, phospholipase C and phospholipase D of LA-N-2 cells and other cell types. Nicotine in addition to being a cholinergic agonist, may be neuroprotective. We have investigated the ability of (-)nicotine to blunt the phospholipase activations by AbetaP in LA-N-2 cells. (-)Nicotine inhibits the AbetaP activation of phospholipase A2, with an IC50 of 76 microM and of phospholipase D with an IC50 of 252 microM. (-)Nicotine did not blunt the AbetaP activation of phospholipase C. These inhibitions of AbetaP activations were not observed with (+)nicotine or cotinine. The (-)nicotine inhibition of AbetaP activation of these two phospholipases was unaffected by hexamethonium and D-tubocurarine. There was no inhibition of the phospholipase A2 activity present in homogenates of LA-N-2 cells. Exposure of LA-N-2 cells to (-)nicotine for 2 h resulted in the blockade of phospholipase A2 activation by kainate and AbetaP but did not affect the ability of quisqualate and AbetaP to activate phospholipase D. These data suggest that if the nicotine inhibition of AbetaP activations is receptor occupancy mediated then it is by an atypical receptor type.

Acetophenones↗
PubMed1998

Treatment of acute otitis media with a shortened course of antibiotics: a meta-analysis.

OBJECTIVE: To conduct a meta-analysis of randomized controlled trials of antibiotic treatment of acute otitis media in children to determine whether outcomes were comparable in children treated with antibiotics for less than 7 days or at least 7 days or more. DATA SOURCES: MEDLINE (1966-1997), EMBASE (1974-1997), Current Contents, and Science Citation Index searches were conducted to identify randomized controlled trials of the treatment of acute otitis media in children with antibiotics of different durations. STUDY SELECTION: Studies were included if they met the following criteria: subjects aged 4 weeks to 18 years, clinical diagnosis of acute otitis media, no antimicrobial therapy at time of diagnosis, and randomization to less than 7 days of antibiotic treatment vs 7 days or more of antibiotic treatment. DATA EXTRACTION: Trial methodological quality was assessed independently by 7 reviewers; outcomes were extracted as the number of treatment failures, relapses, or reinfections. DATA SYNTHESIS: Included trials were grouped by antibiotic used in the short course: (1) 15 short-acting oral antibiotic trials (penicillin V potassium, amoxicillin [-clavulanate], cefaclor, cefixime, cefuroxime, cefpodoxime proxetil, cefprozil), (2) 4 intramuscularceftriaxone sodium trials, and (3) 11 oral azithromycin trials. The summary odds ratio for treatment outcomes at 8 to 19 days in children treated with short-acting antibiotics for 5 days vs 8 to 10 days was 1.52 (95% confidence interval [CI], 1.17-1.98) but by 20 to 30 days outcomes between treatment groups were comparable (odds ratio, 1.22; 95% CI, 0.98 to 1.54). The risk difference (2.3%; 95% CI,-0.2% to 4.9%) at 20 to 30 days suggests that 44 children would need to be treated with the long course of short-acting antibiotics to avoid 1 treatment failure. This similarity in later outcomes was observed for up to 3 months following therapy (odds ratio, 1.16; 95% CI, 0.90-1.50). Comparable outcomes were shown between treatment with ceftriaxone or azithromycin, and at least 7 days of other antibiotics. CONCLUSION: This meta-analysis suggests that 5 days of short-acting antibiotic use is effective treatment for uncomplicated acute otitis media in children.

Acute Disease↗
PubMed1997

Indomethacin and nordihydroguaiaretic acid inhibition of amyloid beta protein (25-35) activation of phospholipases A2 and D of LA-N-2 cells.

Amyloid beta protein (25-35) stimulates the phospholipase A2, C and D activation of LA-N-2 cells. Nordihydroguaiaretic acid reduced the phospholipase D activation by 30% (P < 0.008) and indomethacin reduced the phospholipase A2 activation by 58% (P < .001). There were no reductions of the amyloid beta protein activations by acetylsalicylic acid (ASA), gentisic acid, sulindac sulfone and acetaminophen. The activation of phospholipase C by amyloid beta protein was unaffected by these compounds.

Amyloid beta-Protein Precursor↗
PubMed1997

Pharmacokinetics of antimycobacterial drugs in patients with tuberculosis, AIDS, and diarrhea.

To test the hypothesis that antituberculous drug disposition is altered in patients with AIDS, we studied the steady-state pharmacokinetics of isoniazid (300 mg/d), rifampin (600 mg/d), and pyrazinamide (1,500 mg/d) in 29 adults (14 patients infected with human immunodeficiency virus [HIV] and 15 non-HIV-infected patients) with tuberculosis in Nairobi, Kenya. Intestinal integrity was assessed with xylose. Neither HIV infection nor diarrhea accounted for the interpatient variability in the area-under-the-plasma concentration vs. time curve (AUC), the maximum concentration, or the terminal half-life (t1/2) of isoniazid, rifampin, and pyrazinamide. No significant association between HIV infection or diarrhea and pharmacokinetics was seen for any of the compounds. In addition, neither the AUC nor the t1/2 of any of these drugs reflected interpatient differences in CD4 lymphocyte counts. Xylose absorption was uniformly low. We did not demonstrate that HIV infection, diarrhea, or CD4 lymphocyte counts contributed significantly to the variability in pharmacokinetics of isoniazid, rifampin, and pyrazinamide in TB patients in Nairobi.

AIDS-Related Opportunistic Infections↗
PubMed1997

Efficacy of ipecac during the first hour after drug ingestion in human volunteers.

OBJECTIVE: To determine the decrease of drug absorption when syrup of ipecac is administered at various times within one hour of drug ingestion. METHODS: Ten healthy human volunteers were recruited for a four-limbed randomized crossover study. The three experimental limbs consisted of administration of 30 mL syrup of ipecac, at 5, 30, or 60 minutes after ingestion of 3900 mg acetaminophen as 12 x 325 mg tablets with 250 mL room temperature water. The fourth limb served as control. Blood samples were drawn at 0, 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, and 8.0 hours after analgesic ingestion for serum acetaminophen concentration determination by high-performance liquid chromatography. Repeated measures ANOVA and Tukey's HSD tests were used for group comparisons. RESULTS: The area under the serum concentration vs time curve was (mean +/- SD) 206 +/- 48, 67 +/- 37, 183 +/- 78, and 162 +/- 47 mg/L for control, 5, 30, and 60 minutes, respectively. This corresponds to decreases in bioavailability of 67, 11, and 21%. Only the 5-minute group differed significantly from control (p < 0.05). Sedation was observed as a significant adverse effect of ipecac administration. CONCLUSIONS: Our data do not support benefit from ipecac administration at 30 minutes and beyond. Our data suggest that benefit is lost at some point between 5 and 30 minutes. The sedative effect of ipecac may confound the observation of patients who have ingested sedative hypnotic agents.

Acetaminophen↗
PubMed1996

Ability of nitrobenzylthioinosine to cross the blood-brain barrier in rats.

Nucleoside transport inhibitors that cross the blood-brain barrier may be able to potentiate the neuroprotective effects of adenosine. We tested whether nitrobenzylthioinosine (NBMPR) crosses the blood-brain barrier in three types of experiments. First, intravenous injection of [3H]NBMPR and [14C]sucrose was performed. Brain volume of distribution and brain delivery were greater for [3H]NBMPR than for [14C]sucrose. Second, rats were injected intraperitoneally with NBMPR 5'-monophosphate (NBMPR-P), a prodrug form of NBMPR, or vehicle. Perchloric acid extracts of brains from rats treated with NBMPR-P inhibited [3H]NBMPR binding in competition binding assays nearly 3-fold more than extracts from brains of vehicle-treated animals. Third, cerebrospinal fluid (CSF) extracted from rats treated with NBMPR-P (10 mg/kg i.p.) contained 24.1 +/- 4.4 nM NBMPR while levels were undetectable in CSF from vehicle-treated rats. From these data, we conclude that NBMPR crosses the blood-brain barrier.

Animals↗
PubMed1996

Clinical pharmacokinetics of bambuterol.

Bambuterol, a biscarbamate ester prodrug of the beta 2 adrenergic agonist terbutaline, has been approved for the treatment of asthma in 28 countries. It is available in 10 and 20mg (25 and 50 mumol) tablets as the hydrochloride salt. Bambuterol is stable to presystemic elimination and is concentrated by lung tissue after absorption from the gastrointestinal tract. The prodrug is hydrolysed to terbutaline primarily by butyrylcholinesterase, and lung tissue is capable of this metabolic pathway. It is also oxidatively metabolised to products which can be hydrolysed to terbutaline. Peak terbutaline plasma concentrations occur 3.9 to 6.8 hours after bambuterol ingestion, and the peak: trough terbutaline concentration ratio is lower than that after ingestion of terbutaline. Older patients have a greater area under the plasma concentration-time curve for terbutaline over a dose interval at steady-state. Whether genetic variations in the expression of butyrylcholinesterase alter therapeutic response remains to be determined. The efficacy of bambuterol has been demonstrated to last for 24 hours after ingestion; once-daily administration in the evening is recommended. Maximum therapeutic benefit requires more than 1 week of treatment. Except for the suppression of plasma butyrylcholinesterase, the adverse effect profile of bambuterol is essentially that of a beta 2 agonist and is best correlated with circulating terbutaline concentration in plasma. Plasma butyrylcholinesterase activity returns to control values approximately 2 weeks after discontinuation of treatment with bambuterol. This new drug provides oral beta 2 agonist therapy in a more convenient form than was available previously, and may have a better therapeutic: toxic ratio than terbutaline.

Animals↗
PubMed1996

Use of digitalis glycosides to identify the mechanisms of amantadine transport by renal tubules.

The mechanism(s) for uptake of organic cations by renal cortical tubules was (were) examined further. Renal cortical tubules were purified from rat kidneys by a Percoll gradient centrifugation technique. Bicarbonate buffer (Krebs-Henseleit, KHS) conditions were altered, and chemical modulators were used which affect the activity of the basolateral Na+/K+-ATPase. Renal tubule uptake of the achiral organic cation amantadine was determined. The cardiac glycosides digoxin and acetylstrophanthidin and ouabagenin did not alter amantadine uptake by either proximal or distal tubule fragments in KHS. However, ouabain inhibited proximal tubule amantadine uptake in a dose-dependent manner with lower potency than distal tubule amantadine uptake in KHS. Ouabain did not inhibit amantadine tubule uptake in phosphate buffer. However, inhibition of amantadine uptake by ouabain returned in a time-dependent manner upon addition of bicarbonate to the phosphate buffer. Low extracellular sodium or potassium did not alter amantadine uptake by proximal tubules. Hypokalemic and hypokalemic/ hyponatremic conditions decreased the inhibitory potency of ouabain for amantadine uptake by proximal tubules. For distal tubules, both hyponatremic and hypokalemic conditions, alone and together, decreased the inhibitory potency of ouabain, but did not affect amantadine uptake in the absence of ouabain. Hypochloremic conditions decreased affinity for amantadine uptake by distal, but not proximal tubules. No change in maximal transport capacity for amantadine uptake was observed under hypochloremic conditions for either tubule fragment. These studies challenge the widely accepted concept of Na+/ K+-adenosine triphosphatase activity and maintenance of the basolateral membrane potential as rate-limiting steps for the energy-dependent renal tubule uptake of organic cations. Furthermore, these studies suggest a mechanism for ouabain inhibition of organic cation renal tubule uptake that may not involve the Na+/K+-adenosine triphosphatase and may be possibly bicarbonate-dependent.

Amantadine↗
PubMed1996

Bioavailability and pharmacokinetic disposition of tacrine in elderly patients with Alzheimer's disease.

The pharmacokinetic disposition of intravenous and oral doses of tacrine was determined in 5 elderly patients (aged 64 to 96 y) with the clinical diagnosis of Alzheimer's disease. The bioavailability of the oral formulation was low (9.9% to 36.4%), and the plasma half-life was not altered by route of drug delivery. These data indicate that tacrine elimination occurs by a 1st-order process. Plasma clearance of tacrine varied more than its half-life, which is consistent with a modulating effect of apparent volume of distribution (Vd). Our findings, together with other limited published studies, suggest that use of tacrine for the treatment of Alzheimer's disease (AD) will be confounded by the high interindividual variability in its kinetic disposition.

Aged↗
PubMed1995

Prescribing patterns for elderly community-dwelling heavy medicinal drug users in Manitoba, Canada and Jämtland, Sweden.

Patterns of drugs prescribed for elderly community-dwelling heavy medicinal drug users were determined from random samples of data bases and compared between Manitoba, Canada and Jämtland, Sweden for the year 1981. Qualitatively, there was 80% concordance between the 20 most frequently prescribed drugs in Manitoba and in Jämtland. Gender differences were rare, but there were notable quantitative differences for prescription of specific drugs between the two jurisdictions. Drugs to treat cardiovascular diseases were prominent in both groups with thiazides, triamterene and alpha-methyldopa more frequently prescribed for Manitoba patients, and furosemide, potassium supplements and digoxin more frequently prescribed for patients from Jämtland. The frequent prescribing of codeine in combination analgesics in Manitoba and phenothiazines in Jämtland appears to represent geographically disparate approaches to the use of these drugs. Overall, the concordance of prescribed drugs for elderly heavy medicinal drug users from these two jurisdictions appears to outweigh the differences. These results indicate that data from studies of heavy medicinal drug users, at least in the industrialized world, may be more widely applicable than to the geographical location from where they were obtained.

Aged↗
PubMed1995

Methanol half-life during ethanol administration: implications for management of methanol poisoning.

STUDY OBJECTIVE: To determine the half-life of methanol in methanol-poisoned patients who are treated with ethanol but not with hemodialysis. DESIGN: Case series. SETTING: University Hospital, University of Manitoba. PARTICIPANTS: Three methanol-poisoned patients treated with ethanol but not with hemodialysis and three similar patients identified by a literature review. RESULTS: Plots of terminal concentration versus time data were inconsistent with zero-order kinetics and were adequately explained by an apparent first-order process. The median half-life of methanol in these patients was 43.1 hours, with a range of 30.3 to 52.0 hours. CONCLUSION: Because of the significantly increased risk of toxicity and complications during ethanol monotherapy, we suggest that hemodialysis be considered for methanol-poisoned patients who are treated with ethanol infusion.

Adult↗
PubMed1995

Chronic tobacco smoking and gender as variables affecting amantadine disposition in healthy subjects.

Amantadine HCl (3 mg kg-1) was administered orally to 20 young healthy adults. Its apparent volume of distribution (V2/F) was higher in smokers than nonsmokers, 6.05 +/- 0.86 vs 4.87 +/- 0.85 l kg-1; (mean +/- s.d., 10/group, P < 0.011), and no gender-associated effect was observed. Renal clearance did not vary with time-interval, but urinary recovery at 48 h was higher in men than in women (60.2 +/- 7.5% vs 47.0 +/- 15.0%, P < 0.032). Males had higher renal clearances than females when normalised for body mass index (BMI, 0.492 +/- 0.284 vs 0.248 +/- 0.137 l-1 BMI h-1, (10/group, P < 0.032)). On combining data from a previous study, the weight normalised renal clearance was also higher in men than in women, 0.160 +/- 0.075 vs 0.102 +/- 0.053 l kg-1 h-1 (19/group, P < 0.01). Chronic tobacco smoking did not alter the plasma or renal amantadine clearance. We conclude that gender and tobacco smoking are independent variables effecting amantadine disposition.

Administration, Oral↗
PubMed1995

Site-selective effect of bicarbonate on amantadine renal transport: quinine-sensitive in proximal vs quinidine-sensitive sites in distal tubules.

The mechanism for bicarbonate enhancement of amantadine (A+) uptake was studied further. A selective modulatory effect of bicarbonate on the stereoselectivity of inhibition of A+ uptake by the stereoisomers, quinine (Q) and quinidine (QD), as reflected by the reversal of potency (Q > QD in KHS vs. QD > Q in phosphate), is reported. Studies were performed in bicarbonate (KHS) and phosphate buffers using purified cortical proximal (PT) and distal tubules (DT) from rat kidneys. Variations of extracellular K+ and Ca++ were used to assess the effect of membrane depolarization and calcium on A+ uptake by the tubules. K+ concentration manipulation (1.5-100 mM) did not change A+ uptake by PT or DT in KHS buffer. High Ca++ (5.0 mM) decreased A+ uptake by PT in KHS (P < .001), whereas in phosphate buffer, both 2.5 and 5.0 mM Ca++ decreased uptake (P < .001). In DT, 0.25 mM Ca++ enhanced A+ uptake (P < .05) in KHS, but 2.5 and 5.0 mM Ca++ decreased it in both buffers. Inhibition studies with Q and QD were performed to characterize the bicarbonate-dependent and bicarbonate-independent A+ transport sites further. Stereoselectivity of inhibition was observed in PT in all buffers used. Potency of Q was higher than QD in KHS but lower than QD in phosphate-buffered PT. QD potency remained unchanged. In phosphate-plus-bicarbonate-buffered PT, the inhibitory potencies for Q and QD increased, with the potency of QD being greater than in KHS (P < .001). For DT, Q and QD were equipotent in all buffers used.(ABSTRACT TRUNCATED AT 250 WORDS)

Amantadine↗
PubMed1995

L(+)- and D(-)-lactate modulate rat renal tubular accumulation of amantadine in the presence and absence of bicarbonate.

The effect of L(+)-, D(-)- and racemic (DL)-lactate on the energy-dependent renal uptake of the achiral organic cation amantadine was determined with purified proximal and distal cortical tubule fragments isolated from rat kidneys. Kinetic parameters for uptake of amantadine were measured, under constant pH, in bicarbonate buffer (Krebs-Henseleit [KHS]), and in lactate buffers (5 mM) with different proportions of the enantiomers. Km for amantadine uptake increased in all lactate buffers compared with KHS for both proximal and distal tubules. Km for uptake in DL-lactate was similar to that in D(-)-lactate for proximal tubules and to L(+)-lactate in distal tubules, but Km in L(+)-lactate was higher than in D(-)-lactate for both tubules. Maximal transport capacity (Vmax) in DL-lactate and mixtures of enantiomers were similar to KHS but higher than in pure L(+)- and D(-)-lactate. In KHS, lactate inhibited energy-dependent amantadine uptake in a biphasic manner. Graded competitive inhibition of amantadine uptake was observed between 1 and 15 mM lactate for both proximal and distal tubules. This first phase (1-15 mM) inhibited 60% of amantadine uptake. The second phase (15-20 mM lactate) showed a much steeper slope and inhibited the remaining amantadine uptake. There were no differences in inhibitory potencies of the lactate enantiomers for either proximal tubules or distal tubules amantadine tubule uptake. Our present studies suggest that L(+)- and D(-)-lactate modulate amantadine transport by interacting directly with the bicarbonate-dependent transport mechanism(s).

Amantadine↗
PubMed1994

Pharmacokinetic disposition of loracarbef in healthy young men and women at steady state.

The pharmacokinetic disposition of 200- and 400-mg doses of a novel carbacephem, loracarbef, was determined over a dose interval on day 8, after ingestion of drug doses twice daily for 7 days, in 20 young, healthy volunteers of both genders. Drug was analyzed in plasma, urine, saliva, vaginal secretions, and fecal filtrate. Peak plasma concentration was proportional to dose for both men (4.0 +/- 1.3 and 8.8 +/- 3.4 mg/L) and women (8.0 +/- 5.6 and 15.3 +/- 3.3 mg/L), and the observed time to peak increased from 1 to 2 hours with the increased dose. Apparent volume of distribution was greater in men than women (0.385 +/- 0.114 versus 0.270 +/- 0.075 L/kg; P < .03). The drug was virtually quantitatively excreted unchanged in urine, and its renal clearance exceeded creatinine clearance in all subjects. Renal loracarbef clearance correlated with neither weight-corrected dose nor creatinine clearance in these healthy subjects. There was no evidence for drug accumulation in the body with chronic ingestion. Loracarbef was detected in the fecal filtrate of seven volunteers, but did not account for more than 7% of the daily dose. Loracarbef was detected in vaginal secretions of two of five volunteers who ingested the 400-mg dose. No drug was detected in saliva obtained just before dose ingestion. These data are consistent with complete bioavailability for an oral beta-lactam antibiotic drug that is virtually completely eliminated unchanged by the kidney.

Adult↗
PubMed1994

Kynurenic acid distribution into brain and peripheral tissues of mice.

Kynurenic acid (KYN), an antagonist of excitatory amino acid receptors, is a putative antidote against neuroexcitatory amino acid toxicity. We studied various doses (0.05-3.17 mmol/kg, i.p.) and the effects of probenecid coadministration (0.70 mmol/kg, i.p.) on tissue distribution of KYN in male and female Swiss-Webster mice. After injection of [3H]KYN, samples of brain, heart, liver, kidney, skeletal muscle, and gut were collected at selected times and assayed for KYN by liquid scintillation counting. The substance was absorbed rapidly and distributed into all tissues. Its content (nmol/g, mean +/- SE) at 60 min was 0.26 +/- 0.05, 1.80 +/- 0.05, and 40.4 +/- 8.1 in brain (for 0.05, 0.53, and 3.17 mmol/kg), 1.43 +/- 0.11, 14.3 +/- 3.7, and 212 +/- 32 in heart, 1.16 +/- 0.21, 10.6 +/- 2.6, and 254 +/- 21 in liver, and 7.41 +/- 2.65, 180 +/- 63, and 1899 +/- 254 in kidney. Net accumulation of KYN in brain was much lower than in other tissues. Probenecid increased KYN concentration in brain 2.5-fold. Peak brain:blood concentration ratio occurred between 60 and 180 min, was inversely associated with dose, and was not affected by probenecid. Although brain content was similar, female mice had an earlier peak brain:blood ratio (120 min) than males (180 min) for the 0.05 mmol/kg dose. Our results suggest the presence of a restricted transfer process for KYN with delayed egress from brain.

Animals↗
PubMed1994

Bicarbonate-dependent amantadine transport by rat renal cortical proximal and distal tubules.

Transport of the achiral cationic drug amantadine by purified renal cortical rat tubules was investigated in bicarbonate [Krebs-Henseleit solution (KHS)] and nonbicarbonate buffers. Values of the apparent Km for amantadine accumulation were higher (P < .001, mean +/- S.E., n = 5) for all nonbicarbonate buffers compared with those in KHS in both proximal (76 +/- 5 in KHS, 277 +/- 65 in phosphate, 190 +/- 11 in Tris-HEPES, 268 +/- 46 in acetate and 620 +/- 81 microM in lactate) and distal tubules (68 +/- 4 in KHS, 162 +/- 27 in phosphate, 247 +/- 45 in Tris-HEPES, 281 +/- 50 in acetate buffer and 482 +/- 85 microM for lactate). There was a decrease in Vmax for amantadine transport (P < .001) in phosphate, Tris-HEPES and acetate buffers in both proximal (4.83 +/- 0.43 in KHS, 2.38 +/- 0.43 in phosphate, 1.77 +/- 0.31 in Tris-HEPES and 1.47 +/- 0.40 nmol mg protein-1 min-1 in acetate) and distal (4.58 +/- 0.13 for KHS, 1.37 +/- 0.27 for phosphate, 1.82 +/- 0.37 for Tris-HEPES and 1.76 +/- 0.20 nmol mg protein-1 min-1 for acetate) tubules. However, Vmax was not depressed (P < .09) in lactate buffer for proximal (2.87 +/- 0.24 in KHS and 3.12 +/- 0.34 nmol mg protein-1 min-1 in lactate) or distal tubules (2.42 +/- 0.26 in KHS and 3.21 +/- 0.31 nmol mg protein-1 min-1 in lactate), although a slight increase was observed in distal tubules.(ABSTRACT TRUNCATED AT 250 WORDS)

Amantadine↗