Biomedical subjects
Publications and source records attributed to A Minocha.
Sulfasalazine (salicylazosulfapyridine, Azulfidine) has been widely used over the last half century for inflammatory bowel diseases, but overdose has not been reported. A 23 year-old male ingested 25 g of sulfasalazine in a suicide attempt. He underwent prompt treatment and survived with no ill-effects.
A case of meclofenamate-induced pill-esophagitis is reported, and the relevant literature is reviewed. The role of posture, amount of fluid chaser, esophageal obstruction or dysmotility, drug formulation, physical and chemical properties of the drug, and concomitant ingestion of alcohol, as well as the diagnosis and management of such cases, are discussed.
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The actions of the macrolide antibiotic, erythromycin lactobionate (EM), on nerve-mediated and drug-induced contractions of longitudinal and circular muscle of guinea pig small intestine were studied in vitro. Longitudinal muscle contractions, evoked by single transmural electrical stimuli, were inhibited by EM (10-300 microM) with half-maximal inhibition occurring at 161 microM (EC50). EM-induced inhibition of longitudinal muscle contractions was not affected by the alpha-2 adrenergic antagonist, yohimbine (0.3 microM), by the adrenergic neuronal blocker, guanethidine (10 microM), or the opiate receptor antagonist, naloxone (1.0 microM). Bethanechol-induced longitudinal muscle contractions were also reduced by EM. Noncholinergic longitudinal muscle contractions (1 microM scopolamine present), induced by trains of transmural stimuli, were reduced by EM (EC50, 142 microM); substance P (a mediator of noncholinergic contractions)-induced contractions were also reduced by EM. Circular muscle contractions, evoked by brief trains of transmural stimulation, were inhibited by EM but bethanechol- and substance P-induced contractions of the circular muscle were not altered by EM. Segments (2 cm) of small intestine were used to study reflex circular muscle contractions evoked by distention of the segment aboral to the recording point. Reflex contractions were inhibited by EM (EC50, 84 microM). These data indicate that, in the guinea pig small intestine, EM inhibits nerve-mediated contractions by actions on enteric nerves and on longitudinal but not circular muscle.
We investigated the effect of pretreatment with a prostaglandin synthetase inhibitor, ibuprofen, on the pharmacokinetics and pharmacodynamics of ethanol in six fasting subjects. Ibuprofen caused a 10% decrease in the maximum rate of elimination of ethanol. Visual memory, which is a function primarily mediated by the right cerebral hemisphere, was measured by the Benton Visual Retention test and was more impaired during combined ibuprofen and ethanol dosing than during ethanol dosing alone (P = 0.05). The auditory-verbal memory of the subjects, which is primarily a function of the left cerebral hemisphere, was assessed by the Selective Reminding Test and showed decreased impairment during combined ibuprofen and ethanol dosing as compared with ethanol dosing alone (P = 0.04). The opposite effect of ibuprofen on ethanol-induced cognitive impairment as measured by two lateralized functions is consistent with the reports in tissue and animal models that central nervous system effects of ethanol may be mediated at least in part by prostaglandins.
Activated charcoal has been recommended for use in poisonings by ethanol, other toxic alcohols and glycols, but it has been avoided with therapeutic use of oral ethanol. Six healthy young adults drank a dose of ethanol designed to give a peak concentration of 125 mg/dl on two different days after overnight fasting. Each individual drank the same dose on both occasions; but on one of these days, the subjects drank an aqueous slurry of 60 g of superactive charcoal prior to ethanol ingestion. We compared the pharmacokinetic profile of ethanol with and without activated charcoal treatment. The fraction of ethanol absorbed was similar on both protocols. The mean peak ethanol concentration after pretreatment with activated charcoal was 8% greater than ethanol alone (p = 0.08). Thus oral activated charcoal does not significantly impair ethanol absorption and can be used in patients requiring oral ethanol. Our results do not support the use of activated charcoal in overdose of ethanol alone. Extending our results to poisonings by other toxic alcohols and glycols, the use of activated charcoal to reduce their absorption deserves evaluation.
The single-dose pharmacokinetics of amantadine hydrochloride and rimantadine hydrochloride were compared in a randomized, two-period, crossover study involving six young (less than or equal to 35 years) and six elderly (less than or equal to 60 years) adults. Subjects ingested single 200-mg oral doses after an overnight fast, and serial plasma (0 to 96 h), nasal mucus (0 to 8 h), and urine (0 to 24 h) samples were collected for assay of drug concentration by electron capture gas chromatography. For both groups combined, rimantadine differed significantly from amantadine in peak plasma concentration (mean +/- standard deviation, 0.25 +/- 0.06 versus 0.65 +/- 0.22 micrograms/ml), plasma elimination half-life (36.5 +/- 15 versus 16.7 +/- 7.7 h), and percentage of administered dose excreted unchanged in urine (0.6 +/- 0.8 versus 45.7 +/- 15.7%). No significant age-related differences were noted for rimantadine. Urinary excretion (0 to 24 h) of rimantadine and its hydroxylated metabolites averaged 19% of the administered dose. The maximum nasal mucus drug concentration was similar for both drugs (0.42 +/- 0.25 versus 0.45 +/- 0.32 micrograms/g), and the ratio of maximum nasal mucus to plasma concentration was over twofold higher after rimantadine than after amantadine. These findings may in part explain the clinical effectiveness of rimantadine in influenza A virus infections at dosages that have lower toxicity than those of amantadine.
Ethanol is known to impair cognitive and psychomotor function in high doses. We studied the impairment of cognitive, psychomotor and behavioral responses in controlled environment in a group of healthy young social drinkers at below and above legal limit for presumption of intoxication (100 mg/dl). Attention, concentration, auditory-verbal memory and memory for visuospatial information were significantly impaired at both levels. Motor speed was impaired only at higher levels though fine coordination was impaired at both doses. Females showed more impairment on visual as well as auditory-verbal memory functions. With low doses, choice reaction time improved with the nonpreferred hand.
Studies suggest that the anticancer drugs VP16-213 and VM26 produce cytotoxicity by inducing protein-associated DNA breakage in vivo through interaction with a yet unknown nuclear component. The effects of these drugs and their congeners on topoisomerase activities was investigated. VP16-213, VM26, and congeners active toward inducing DNA breaks also inhibited the catenation activity of eukaryote type II topoisomerase in vitro at very low drug concentrations. A structure-activity relationship was obtained for inhibition of catenation that parallels in vivo DNA breakage and cytotoxic activities. Type I topoisomerase activity was totally unaffected by these drugs.
Acute overdose with sustained release formulations presents special problems for the health care system. Proper management requires a basic understanding of the pharmacokinetic and pharmacodynamic characteristics of the drugs taken in overdose because different techniques employed by the manufacturers to produce sustained release formulations lead to differences in these characteristics in comparison with conventional formulations. In general, with sustained-release formulations, there is a prolongation of the time for the patient to manifest toxicity ('preclinical phase'), as well as the period of high drug concentrations and clinical toxicity ('toxic phase') and the resolution phase (clinical improvement with declining drug concentrations). Continued drug absorption over a prolonged period alters the normal drug concentration-time profile. The prolonged absorption half-life may appear as an increase in elimination half-life, even though the clearance of the drug stays the same. Gastrointestinal decontamination is extremely important in the management of overdose with sustained release formulations. We advocate an aggressive decontamination approach to management, especially in the preclinical phase. With a history of potentially toxic ingestion of an adsorbable drug, a charcoal stool following administration of oral activated charcoal should be a minimum requirement for discharge of the patient. Gastrointestinal decontamination is critical in the preclinical and the toxic phases and may be of value during the resolution phase until the drug concentrations decline to the therapeutic range.
We recommend a toxicodynamic approach to the management of the poisoned patient. We define the period between ingestion and onset of toxic manifestations (clinical or laboratory) as the preclinical phase, during which the management of the patient necessarily depends solely on the history of ingestion and the predicted toxicity. In the toxic phase during which the patient shows clinical or laboratory evidence of toxicity, the history, clinical status (signs, symptoms, drug levels, laboratory parameters), and toxicodynamics should guide the therapy. In the resolution phase, when the patient shows clinical improvement and declining drug levels, treatment should be based on clinical status. Gastrointestinal decontamination is critical in the first two phases and may be of value during the resolution phase until the body drug burden declines to safe levels. We recommend an aggressive approach to gastrointestinal decontamination, especially in the preclinical phase. With a history of a potentially toxic ingestion of an absorbable drug, an observation period until passage of a charcoal-laden stool should be achieved before discharge of the patient.
Secondary or complex pneumomediastinum following esophagoscopy is due to an esophageal perforation. Primary or simple pneumomediastinum may be caused by maneuvers such as coughing, gagging, swallowing, choking, and valsalva. These maneuvers are common during upper gastrointestinal endoscopy. Esophageal perforation is a potentially life threatening event, while simple pneumomediastinum is usually a benign self-limited disorder. Although the presentation may be similar, different morbidities compel prompt evaluation for distinction between these two entities and appropriate management. We present a case of pneumomediastinum that developed immediately following upper gastrointestinal endoscopy. Implications of diagnosis, management, and prognosis are discussed.
Activated charcoal in 70% sorbitol enjoys wide use in the management of acute poisonings but the effects of the activated charcoal-sorbitol mixture in healthy individuals have not been characterized. We were concerned about the possibility of sorbitol causing changes in the routinely monitored serum chemistry and hematological parameters, either directly due to the absorbed polyol or due to the diarrhea induced by it, thus complicating the diagnosis and management in an overdose setting. We assessed the action of a single dose of 30g of activated charcoal in 150 ml of 70% sorbitol and its effects on serum osmolality, electrolytes, metabolic profile (SMAC), magnesium, hepatic enzymes, and complete blood count in healthy adult individuals. The only significant change in the laboratory parameters tested was the consistent rise in serum sodium and phosphorus concentrations four hours after drinking the charcoal-sorbitol mixture. However, a similarly consistent rise in the concentrations at the same hours on another day without ingestion of the charcoal-sorbitol mixture suggested the rise was due to circadian rhythm or other factors unrelated to the cathartic. The lack of effect on routinely monitored laboratory parameters, relative palatability and the rapid onset (40-225 minutes), and long duration (7 to 127 hours) of purgation, make charcoal-sorbitol an attractive combination for use as a gastrointestinal decontaminant. Possible effects of multiple dose regimens and the effects in pediatric and geriatric populations need further study.
Activated charcoal-sorbitol mixture is used for the treatment of acute poisoning. Based on our experience with healthy adults, overdosed patients and published reports, we have devised a protocol for use of this mixture in different concentrations of sorbitol. The dose is based on the size of the patient, type of poison, and the clinical status. In seriously ill adult patients, we recommend the use of 1 g/kg of activated charcoal in 4.3 ml/kg body weight of 70% sorbitol every 4 hours until the first stool containing charcoal appears. In children and ambulatory adults, the same dose of activated charcoal may be administered in 4.3 ml/kg body weight of 35% sorbitol. Patients requiring multiple doses may be administered activated charcoal as aqueous and sorbitol suspensions alternately every 2-6 hours after the first charcoal stool has appeared. The patients on multiple dose regimen, especially children, should be closely monitored for any fluid or electrolyte imbalance or depletion of essential vitamins.