Protective drugs in acute large-dose exposure to organophosphates: a comparison of metoclopramide and tiapride with pralidoxime in rats

Weak and reversible inhibitors of cholinesterase(s), when coadministered in excess with a more potent inhibitor such as organophosphates, can act in a protective manner. The benzamide compound, metoclopramide, confers some protection (putatively via this mechanism) for cholinesterases against inhibition by paraoxon both in vitro and in vivo, after chronic small-dose exposure. Tiapride is a related benzamide. In this study, we compared the protection by metoclopramide and tiapride in rats acutely exposed to large doses of paraoxon with the therapeutic "gold standard," pralidoxime. Group 1 received 1 micromol paraoxon (approximately 75% lethal dose), Group 2 received 50 micromol metoclopramide, Group 3 received 50 micromol tiapride, Group 4 received 50 micromol pralidoxime, Group 5 received 1 micromol paraoxon + 50 micromol metoclopramide, Group 6 1 micromol paraoxon + 50 micromol tiapride, and Group 7 1 micromol paraoxon + 50 micromol pralidoxime. All substances were administered intraperitoneally. The animals were monitored for 48 h and mortality was recorded at 30 min, 1, 2, 3, 4, 24, and 48 h. Blood was taken for red blood cell acetylcholinesterase measurements at baseline, 30 min, 24, and 48 h. With the exception of Group 7, in which some late mortality was observed, mortality occurred mainly in the first 30 min after paraoxon administration with minimal changes occurring thereafter. Mortality at 30 min was 0% in the metoclopramide, tiapride, and pralidoxime groups and 73 +/- 20 (paraoxon), 65 +/- 15 (paraoxon + metoclopramide), 38 +/- 14 (paraoxon + tiapride), and 13 +/- 19 (paraoxon + pralidoxime). Mortality at 48 h was 75 +/- 18 (paraoxon), 67 +/- 17 (paraoxon + metoclopramide), 42 +/- 16 (paraoxon + tiapride), and 27 +/- 24 (paraoxon + pralidoxime). Metoclopramide does not significantly influence mortality after acute large-dose paraoxon exposure. Both tiapride and pralidoxime significantly decreased mortality in our model. The protection conferred by tiapride was significantly less than that conferred by pralidoxime at 30 min, but was not significantly different at 24 and 48 h.     

Delirium Tremens

The varied clinical manifestations and management of 14 male patients with delirium tremens (DT) have been studied. Eight patients were initially hospitalised for diseases unrelated to ethanol abuse i.e. 2 each for gun shot wound, myocardial infarction and stroke, and one each for pneumonia and gastroenteritis. One patient was going through withdrawal because of prodrome of viral hepatitis before he was hospitalised for uncontrolled agitation and delirium. Two known cases of mild essential hypertension on dietary therapy reported for agitation, abnormal behaviour, a single episode of tonic clonic seizure and hypertensive encephalopathy as they could not/did not get alcohol for 3 days. Three patients presented denovo with DT without concomitant illness. The other features besides delirium and hallucinations were tremulousness in 10, tachycardia in 12, fever in 3, diaphoresis in 2 and tonic clonic seizures in 4 patients. The symptoms fluctuated markedly at short intervals and 2 patients did not have any features of sympathetic overactivity. Altered hepatic biochemical parameters and ketonuria with normal blood sugar were noted in 4 and one patients respectively. Other biochemical parameters including serum electrolytes were normal. CT scan brain done for 5 patients revealed subdural haematoma in one. Cerebro spinal fluid (CSF) and EEG findings were noncontributory. All made good recovery with heavy doses of intravenous vitamin B complex, glucose and oral benzodiazepine. Short course of haloperidol was used in 2 patients. Two patients developed pancreatitis during follow up. All patients made complete recovery, and 8 patients have been followed for 8 to 12 months without relapse. The reason for hospitalisation in such cases is often unrelated to alcohol abuse; hence a detailed history of alcoholism is mandatory to identify those at risk as well as for prompt treatment and decreasing the mortality.Key Words: Alcohol withdrawal, Concomitant illnesses, Delirium, Precipitating events     

Thirty-year follow-up of a patient with leber congenital amaurosis and novel RPE65 mutations

PURPOSE: To present long-term follow-up on a North American patient with Leber congenital amaurosis (LCA) and novel compound heterozygous mutations in the RPE65 gene. DESIGN: Case report. METHODS: RPE65 mutation screening and search for sequence changes using Single Strand Conformation Polymorphism and direct DNA sequencing. Ophthalmic examination and electrophysiologic testing. RESULTS: A 35-year-old female carried two RPE65 mutations: a maternal 961A>T (K303X) nonsense mutation and a paternal 1346A>G (Y431C) missense mutation. She had severe visual deficits and an absence of rod and cone Electroretinogram responses. Visual acuity of 20/60 both eyes and normal color recognition during early childhood declined to 2/200 in the right eye and 1/200 in the left eye at the age of 35. CONCLUSIONS: The RPE65 mutations K303X and Y431C in compound heterozygous form cause progressive visual compromise that starts in childhood and advances to severe visual loss by the fourth decade of life.     

Endocrine and metabolic response in the human newborn to first feed of breast milk

The hormonal and metabolic response to the first feed of breast milk was studied in 12 infants at 4-6 hours of age. After the feed there was an increase in blood glucose concentration but no changes in the concentrations of lactate, pyruvate, alanine, or ketone bodies. The feed was followed by an increase in the concentrations of plasma insulin, growth hormone, gastrin, and enteroglucagon, but no change in levels of plasma glucagon or gastric inhibitory peptide. Several hormone systems are functionally active at birth and are stimulated by the first feed of milk.