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Biomedical subjects

D S Sitar

Publications and source records attributed to D S Sitar.

At least 19 recordsLinked to original sources
PubMed2000

Short course antibiotics for acute otitis media.

BACKGROUND: Otitis media is a common pediatric problem, for which antibiotics are frequently prescribed. OBJECTIVES: To determine the effectiveness of a short course of antibiotics (less than seven days) in comparison to a longer course (seven days or greater) for the treatment of acute otitis media in children. SEARCH STRATEGY: The medical literature was searched for randomized controlled studies of the treatment of ear infections in children with antibiotics published from January 1966 to July 1997. Search last updated March 1998. SELECTION CRITERIA: Studies were included if they met the following criteria: subjects one month to 18 years of age, clinical diagnosis of ear infection, no previous antimicrobial therapy and randomization to treatment with less than seven days versus seven days or more of antibiotics. DATA COLLECTION AND ANALYSIS: Data on treatment outcomes were extracted from individual studies, and combined in the form of a summary odds ratio. A summary odds ratio (OR) equivalent to one indicated that the treatment failure rate following less than seven days of antibiotic treatment was similar to the failure rate following seven days or more of antibiotic. MAIN RESULTS: The summary OR for treatment outcomes at eight to 19 days in 1,524 children treated with short-acting antibiotics for five days versus eight to 10 days was 1.52, 95% CI: 1.17-1.98, but by 20 to 30 days outcomes between treatment groups (n=2,115) were comparable (OR=1.22, 95% CI:0.98-1.54). The absolute difference in treatment failure (Random effects model RD=2.9%, 95%CI:-0.3% to 6.1%) at 20 to 30 days suggests that at minimum 17 children would need to be treated with the long course of short-acting antibiotics to avoid one treatment failure. Similarity in outcomes was observed for up to three months following therapy (OR=1.16,95% CI=0.9-1.5). Comparable outcomes were shown between treatment with ceftriaxone or azithromycin, and more than seven days of other antibiotics. REVIEWER'S CONCLUSIONS: This review suggests that five days of short-acting antibiotic is effective treatment for uncomplicated ear infections in children.

Acute Disease↗
PubMed2000

Antibiotic-heparin lock: in vitro antibiotic stability combined with heparin in a central venous catheter.

Long-term hemodialysis frequently requires vascular access through central venous catheters (CVCs). Infection related to these catheters is a significant complication. The use of an antibiotic-heparin lock could decrease the risks associated with infected permanent catheters. As an initial step in developing an antibiotic-heparin lock, we investigated the in vitro stability of antibiotic-heparin combinations in CVCs. Initially, cefazolin, vancomycin, ceftazidime, ciprofloxacin 10 mg/ml each, and gentamicin 5 mg/ml were incubated separately in glass test tubes in the dark at 37 degrees C for 72 hours. Samples were analyzed spectrophotometrically for stability at 24-hour intervals. The procedure was repeated with the addition of heparin (final concentration 5000 U/ml in glass test tubes), and the combination was also examined in CVCs. High-performance liquid chromatography analysis was conducted on the antibiotic-heparin combinations at 72 hours to confirm the spectrophotometric results. Ciprofloxacin produced an immediate precipitate with the addition of heparin and was not analyzed further. Absorbance values decreased for all antibiotics, with the greatest decreases at 72 hours for cefazolin (27.4%), vancomycin (29.7%), ceftazidime (40.2%), and gentamicin (8%) when combined with heparin. These decreases were postulated to be secondary to adsorption of the antibiotics to the luminal surface of the catheters because submitting the catheters to ultrasound with 1% sodium bicarbonate and analyzing the resulting solution for absorbance revealed that some of the drug was recovered. Although free antibiotic in CVC solution was reduced, the concentration should be sufficient (approximately 5 mg/ml) to decrease the frequency of infections associated with CVCs. We conclude that the concentrations of vancomycin, ceftazidime, cefazolin, or gentamicin used in our study should be sufficient for an antibiotic-heparin lock.

Anti-Bacterial Agents↗
PubMed2000

Gastric lavage for liquid poisons.

STUDY OBJECTIVE: This study was conducted to determine whether gastric lavage reduces the absorption of ingested liquids. METHODS: The study design was a randomized controlled human volunteer crossover study in 10 subjects. On 2 separate occasions 2 weeks apart, the volunteers ingested a solution of 4.0 g of acetaminophen in 60 mL of water. Eight blood specimens were obtained over the initial 8 hours for determination of serum acetaminophen concentrations, which were used to calculate routine pharmacokinetic parameters. One hour after 1 drug ingestion, gastric lavage was performed through a 34-F orogastric tube. Serum acetaminophen concentrations were measured by high-performance liquid chromatography and a 2-tailed t test was used for statistical analysis. RESULTS: The mean values for area under the concentration curve (+/-SD) for the control and gastric lavage groups were 195+/-31 and 154+/-52 mg/L.hour, respectively (P <.05). The mean reduction in acetaminophen bioavailability because of gastric lavage was 20%+/-28% (95% confidence interval 3 to 37). CONCLUSION: In this experimental model for the ingestion of liquids, gastric lavage at 1 hour resulted in a significant decrease in the mean serum bioavailability of acetaminophen. Nonetheless, this treatment effect is unlikely to be of clinical value because of its modest extent, unreliable performance, and the availability of a more effective, less risky alternative, activated charcoal.

Acetaminophen↗
PubMed1999

Amyloid beta peptide membrane perturbation is the basis for its biological effects.

Experimental studies have indicated that the mechanisms offered for explaining the neurotoxicity of amyloid beta peptide (AbetaP) are diverse, and include altered enzyme activities, disrupted calcium homeostasis, and increased free radical formation. AbetaP appears to interact at the cell membrane with a multitude of receptor sites and also inserts physically into the membrane matrix. This membrane insertion affects the membrane fluidity and potentially influences the function of resident membrane proteins. We propose a unifying hypothesis to explain the experimental observations of the diverse cellular responses to AbetaP. The indiscriminate physical insertion of AbetaP into the cell membrane unspecifically activates a host of membrane processes by perturbation of the membrane proteins. This recurrent activation of membrane processes eventually culminates in neuronal cell death. We recommend that successful therapeutic interventions should be directed at reducing or preventing the interaction of AbetaP with neuronal cell membranes.

Amyloid beta-Peptides↗
PubMed1999

Tetraethylammonium and amantadine identify distinct organic cation transporters in rat renal cortical proximal and distal tubules.

Tetraethylammonium (TEA) and amantadine are two organic cations that are secreted by the kidney. It appears that each cation may characterize distinct renal tubule organic cation transport pathways. To test this hypothesis, we investigated the renal proximal and distal tubule energy-dependent transport properties of TEA and amantadine. Isolated tubules were incubated at 25 degrees C in bicarbonate buffer (Krebs-Henseleit solution) and nonbicarbonate buffer (Cross-Taggart) with varying concentrations of [14C]TEA or [3H]amantadine to determine initial rates of energy-dependent uptake of TEA and amantadine, respectively. The uptake of TEA could best be described by two transport sites, a high-affinity site and a lower affinity site. TEA uptake was not influenced by the presence of bicarbonate. Consistent with our previously reported data, amantadine uptake could also be described by two transport sites, a high-affinity-capacity site that is bicarbonate-dependent and a lower-affinity-capacity transport site that is bicarbonate-independent. The renal tubule uptake of amantadine into proximal and distal tubules, in Krebs-Henseleit solution or Cross-Taggart buffers, was not inhibited by 10 to 1000 microM of TEA. However, tubule accumulation of TEA could be inhibited (>90%) by amantadine in proximal and distal tubules in Krebs-Henseleit solution and Cross-Taggart buffers. In proximal tubules, N1-methylnicotinamide was not able to inhibit amantadine uptake but it reduced TEA uptake by 60 to 70% at similar concentrations. These data support the existence of multiple renal tubule organic cation transporters that have different substrate affinity and controlling mechanisms. It is also apparent that amantadine characterizes organic cation transporters that are distinct from those characterized by TEA.

Amantadine↗
PubMed1999

In vivo analysis of amantadine renal clearance in the uninephrectomized rat: functional significance of in vitro bicarbonate-dependent amantadine renal tubule transport.

Amantadine transport into renal proximal and distal tubules is bicarbonate dependent. In the present study, we addressed the effects of bicarbonate on renal clearance and urinary excretion of amantadine. Renal clearance of kynurenic acid was also studied to determine whether bicarbonate effects are specific for organic base transport by the kidney. After a moderate diuresis was established, animals received i.v. [(3)H]amantadine or [(3)H]kynurenic acid followed by an acute dose of sodium bicarbonate or physiological saline. Urine and blood samples were analyzed for [(3)H]amantadine or [(3)H]kynurenic acid, blood gases, and pH. Amantadine and kynurenic acid were excreted by the kidneys, and both compounds underwent renal tubular secretion. Amantadine metabolism occurred, and one metabolite was detected in the urine. In the bicarbonate-treated rats, the total amount of amantadine excreted in the urine was decreased, whereas the amount of metabolite recovered was similar in both groups. Bicarbonate treatment caused a sustained increase in blood bicarbonate levels, a mild increase in blood pH, and a decrease in amantadine renal clearance and in the amantadine/creatinine clearance ratio. Only a transient decrease in the renal clearance of kynurenic acid and the kynurenic acid/creatinine clearance ratio was observed. This study demonstrates that short-term changes in bicarbonate concentration may have significant effects on renal organic cation elimination. Coupled with our previous in vitro demonstration of bicarbonate-dependent organic cation transport, the present study suggests that bicarbonate inhibition of renal tubule organic cation secretion may explain the previous observation that bicarbonate dosing decreases amantadine excretion by the kidney.

Amantadine↗
PubMed1999

Heterogeneity among beta-adrenoreceptor blockers in the modulation of energy-dependent uptake of the organic cation amantadine by rat renal tubules.

Eight representative beta-adrenoreceptor blocking drugs, acebutolol, atenolol, labetalol, metoprolol, nadolol, pindolol, propranolol, and timolol, were studied in vitro with respect to their potential to block energy-dependent uptake of [3H]amantadine into proximal and distal rat renal tubule fragments in the presence and absence of bicarbonate. Five of the eight beta-adrenoreceptor blockers showed a dose-dependent inhibition of renal tubule accumulation of amantadine: labetalol, metoprolol, pindolol, propranolol, and timolol. Labetalol was the only beta-adrenoreceptor blocker with greater inhibitory potency in phosphate-based buffer than in bicarbonate-based buffer. Propranolol was the most potent inhibitor of renal tubule amantadine accumulation with IC50 values of 15 +/- 10 and 31 +/- 11 microM for proximal and distal tubule fragments, respectively, in a bicarbonate-based buffer environment. Inhibition in a phosphate-based buffer was less potent only in proximal tubules, with an IC50 of 76 +/- 30 microM. Kinetic studies of propranolol inhibition of amantadine uptake were consistent with both uncompetitive and competitive inhibition mechanisms in bicarbonate-based buffer in both proximal and distal renal tubule segments. There was no chiral preference between the R and S forms of propranolol for the inhibitory effects observed. These data suggest that there is potential for selection among the beta-adrenoreceptor blocking drugs to minimize or restrict the inhibition of amantadine energy-dependent uptake at the organic cation ion uptake sites characterized by amantadine in the presence and absence of bicarbonate.

Adrenergic beta-Antagonists↗
PubMed1998

Phospholipases as mediators of amyloid beta peptide neurotoxicity: an early event contributing to neurodegeneration characteristic of Alzheimer's disease.

There is a consensus that by some still to be defined mechanism amyloid beta peptide, which accumulates in Alzheimer's disease brain tissue, contributes to the characteristic neurodegeneration. We suggest that one of these mechanisms for amyloid beta peptide is the ability to activate cellular phospholipases. Excessive phospholipid hydrolysis would produce a variety of lipidic second messengers. These catabolites would then evoke unnecessary stereotypic responses. This indiscriminate activation of the phospholipases could be responsible for the increased amounts of phospholipid catabolites found in Alzheimer's disease brain tissue. Failure to maintain regeneration of the membrane components would result in a loss of essential cellular neuronal processes.

Alzheimer Disease↗
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↗