Acute human self-poisoning with the N-phenylpyrazole insecticide fipronil--a GABAA-gated chloride channel blocker

OBJECTIVE: Fipronil, a broad spectrum N-phenylpyrazole insecticide that inhibits GABAA-gated chloride channels, has been in use since the mid-1990s. A high affinity for insect compared to mammalian GABA receptors results in lower animal toxicity than other insecticides blocking this channel. To date, only two accidental cases of fipronil poisoning in humans have been published. CASE SERIES: We report seven patients with fipronil self-poisoning seen prospectively in Sri Lanka together with pharmacokinetics for four patients. Non-sustained generalized tonic-clonic seizures were seen in two patients (peak measured plasma fipronil concentrations 1600 and 3744 microg/L); both were managed with diazepam without complications. A patient with a peak measured plasma concentration of 1040 microg/L was asymptomatic throughout his stay. Plasma concentration was still high at discharge 3-4 days post-ingestion when the patients were well. Retrospective review of >1000 pesticide poisoning deaths since 1995 found only one death from fipronil-based products. In contrast to the good outcome of the above cases, this patient required intubation and ventilation and had continuous fits despite therapy with barbiturates and benzodiazepines. CONCLUSIONS: Our experience with prospectively observed patients suggests that fipronil poisoning is characterized by vomiting, agitation, and seizures, and normally has a favorable outcome. Management should concentrate on supportive care and early treatment of seizures. However, further experience is needed to determine whether increased susceptibility to fipronil or larger doses can produce status epilepticus.     

Influence of stressors on the rewarding effects of alcohol in Wistar rats: studies with alcohol deprivation and place conditioning

Rationale and objectives Studies on laboratory animals have provided conflicting results regarding the actions of stressors on the rewarding effects of alcohol. In the present study, we first examined the effects of footshock or social defeat, given during deprivation, on the alcohol deprivation effect (ADE). We then tested the effects of stressors on place conditioning to alcohol, another technique used to measure drug reward.Methods Male Wistar rats were trained to drink 10% alcohol in a 24 h access, free-choice design and received intermittent footshock or defeat 5 times during a 2-week alcohol deprivation period, followed by 2 weeks of free access to alcohol. There were three such cycles. In the place conditioning studies, animals received footshock, defeat, or no stress immediately prior to conditioning sessions where they received alcohol (0.6 or 1.0 g/kg, IP) or vehicle injections.Results Alcohol intake of footshock-treated animals was significantly higher than that of controls following the first and second, but not the third period of alcohol deprivation and stress exposure. Defeat caused a smaller increase in alcohol intake that was significant only after the first deprivation and stress cycle. In the place conditioning studies, we found that either stressor blocked the place aversion induced by 1.0 g/kg alcohol.Conclusions These results demonstrate that stressors can modify the rewarding and aversive properties of alcohol, measured using two different paradigms. Footshock and defeat produced transient, but significant increases in the magnitude of ADE, while exposure to either stressor reduced the aversive effects of a high dose of alcohol measured using the place conditioning paradigm.     

Effect of gestational age on cord blood plasma copper,zinc, magnesium and albumin

BACKGROUND: The transport of essential trace elements from mother to fetus varies throughout gestation, and the role of transport proteins in the neonate and the mother may change during pregnancy. Magnesium, often used as tocolytic agent, may reach the fetus and appear in cord blood at higher than normal concentrations. AIMS: To determine cord blood plasma zinc, copper and magnesium concentrations, as well as plasma albumin in premature and full-term newborns, and correlate these values with those of maternal blood plasma at birth. Also, to examine whether cord blood plasma concentration of these elements varies with gestational age. SUBJECTS: The 35 mother-infant pairs included: 11 in the 38-42-week gestational age (GA), 9 in the 34-37-week GA, 11 in the 29-33-week GA group and 4 in the 24-28-week GA. Magnesium for tocolysis was given to five of the mothers in the 29-33-week GA cohort and two of the women giving birth at 24-28-week GA. RESULTS: Trend analysis showed that while cord plasma zinc decreased with GA at birth, the reverse was observed for copper. There were no differences with GA either in maternal plasma zinc or copper. However, maternal ceruloplasmin tended to decrease with GA (P=0.0174). Maternal and cord blood plasma magnesium exhibited a strong correlation (r=0.942, P<0.001), as well as between cord plasma magnesium and zinc (r=0.448, P<0.01). CONCLUSIONS: While the vigorous mother-to-fetus uphill zinc transfer is clear throughout the last trimester, copper remains in cord blood plasma at much lower concentrations than in the mother, suggesting that prematurity may place the newborn infant at a greater risk than the term infant to copper deficiency. This situation, together with a reduced synthesis in the fetus of the transport protein ceruloplasmin, creates another potential challenge in the nutritional support of the premature infant.     

Successful orthotopic liver transplantation after trimethoprim-sulfamethoxazole associated fulminant liver failure

Trimethoprim-sulfamethoxazole (TMP-SMZ) is one of the most commonly used antibiotics. Although many of its adverse effects are well recognized, TMP-SMZ related hepatotoxicity is considered rare and is usually characterized by cholestasis or mixed hepatocellular-holestatic reactions. In this study, we describe the case of a previously healthy young man with acute fulminant liver failure caused by TMP-SMZ. The patient presented with complaints of 'flu-like' symptoms with myalgia and fever after taking TMP-SMZ for 7 d for otitis externa. The patient subsequently developed fever, worsening jaundice, and a rash on his neck and chest. Liver enzymes peaked on day 3 with alanine aminotransferase (ALT) 11,549, aspartate aminotransferase (AST) 23,289, alkaline phosphatase 245, and total bilirubin 10.3 mg/dL, with a conjugated bilirubin of 8.3 mg/dL, prothrombin time (PT) 60.5 s, partial normalized ratio (PTT) 49 s, and international normalized ratio (INR) 7.5. Of note, acetaminophen level on admission was undetectable. Serology for hepatitis A, B, C, cytomegalovirus, HIV, toxoplasmosis, and blood cultures were all negative. The patient developed hepatic encephalopathy with hallucination on day 4. Laboratory tests revealed a serum ammonia level of 190 U, serum creatinine kinase (CK) 10,466 (42 on admission), serum creatinine 8.2 mg/dL (1.2 on admission), and significant metabolic acidosis. Renal ultrasound was unremarkable. The patient was started on hemodialysis for acute renal failure. Meanwhile, liver transplantation assessment was also initiated. On day 8 post-admission (15 d after taking TMP-SMZ), the patient received a successful orthotopic liver transplant.     

Evaluation of newer diagnostic methods for the detection and differentiation of Entamoeba histolytica in an endemic area

We evaluated the colorimetric polymerase chain reaction (PCR)-based method for the detection and differentiation of Entamoeba spp. and compared the efficacy of E. histolytica-specific antigen detection in faeces with the detection of specific antibodies to E. histolytica-specific antigen in faeces, by enzyme-linked immunosorbent assay. Faecal samples were obtained from patients attending hospital in Chandigarh, India, from March 2001 to February 2002. The PCR-based colorimetric method was found to be the most sensitive (100%) and it could differentiate between pathogenic and non-pathogenic Entamoeba spp. The present study also emphasized that the antigen detection system may prove to be a better diagnostic tool than the antibody detection system in endemic areas.     

Cardiovascular sensory receptors and their regulatory mechanisms

The role of cardiovascular receptors in the neural regulation of circulatory system is now well established. Atrial type B receptors located in the two atria and veno-atrial junctions, which are stimulated by atrial filling are believed to play an important role in the regulation of body fluid volume and heart rate. Heart rate is influenced also by other sensory receptors e.g. arterial baroreceptors, ventricular receptors, pulmonary stretch receptors and chemoreceptors. Of all these visceral receptors, arterial baroreceptors located mainly in the aortic arch and the carotid sinus region are stimulated by intravascular pressure; play a major role in the regulation of blood pressure by changes in heart rate and vascular tone. The vascular tone is also affected by the circulatory levels of various neurotransmitters and hormones. Vasodilatory response to adenosine and acetylcholine is partly mediated through endothelium-derived relaxing factors (EDRF), hyperpolarizing factors (EDHF) and contracting factors (EDCF). The endothelium-dependent mechanisms are altered during hypertension and diabetes. The autonomic control of blood pressure is primarily through arterial baroreceptors. The sensitivity of the baroreceptor heart rate reflex is significantly attenuated on occlusion of left anterior descending coronary artery (LAD) of anaesthetised dogs taken as an experimental model of coronary insufficiency in-patients of coronary heart disease. The fall in the sensitivity of baroreflex on LAD occlusion is mediated primarily by sympathetic limb of the autonomic nervous system. Acute fall in hemoglobin level by hemodilution in dogs produced an increase in cardiac output by increasing the heart rate through inhibition of parasympathetic tone. After parasympathetic blockade the increase in cardiac output on fall in hemoglobin was due to a rise in the stroke volume. Acute fall in hemoglobin level attenuated the baroreflex response. Sustained changes in blood pressure cause resetting of baroreflex i.e. increase in arterial pressure involves reduced activity of baroreceptors at equivalent pressure and vascular stretch. Like in acute hypoxia the altered responsiveness of baroreceptor heart rate reflex during oxygen deficiency due to acute occlusion of LAD or acute normovolemic hemodilution may involve both peripheral and central components and possibility of modulation by circulating hormones also exists.     

Garlic prevents ultrastructural alterations caused by dehydration in mouse cerebral microvessels

Dehydration is known to significantly reduce both the time required for the first platelet aggregate and the time to full occlusion in photochemically-induced thrombosis, in vivo. Ultrastructural changes that contribute to such events remain unknown. Therefore, the effect of water deprivation for 24 hr, (as a model for dehydration) on the ultrastructure of mouse pial microvessels was investigated. The possible beneficial effect of garlic in preventing such ultrastructural changes was also investigated. Four groups of TO strain: control, control-garlic treated, dehydrated, and dehydrated-garlic treated male mice, 10/group, were used. Dehydration was induced by water deprivation for 24 hr. Garlic solution was i.p. injected at 0.1 ml/10g body weight. In urethane-anesthetized (2 mg/g, i.p.) mice, topical and transvessel bimodal fixation of pial microvessels was done with a phosphate buffered mixture of glutaraldehyde and paraformaldehyde, followed by a conventional electron microscopy procedure. Examination of control cerebral pial microvessels showed no evidence of cellular damage. Membranes of endothelial cells were intact. Within pial microvessels there was no evidence of platelet aggregation. Garlic treatments did not cause any ultrastructure abnormalities in control mice. Compared with control, dehydration caused the appearance of thrombi that consisted of platelet aggregates. Discoid platelets containing granules, spheroid degranulated platelets, and those with large pseudopodia were present in 80% of dehydrated mice. The venular endothelial surface of dehydrated mice revealed dilated profiles of endoplasmic reticulum and variously shaped vacuoles. Swelling of nuclear envelopes and mitochondrial distension were also present in dehydrated mice. Concomitant garlic treatment prevented most of these ultrastructural changes. These findings demonstrated the extent of damage to the pial microvessels in response to water deprivation and demonstrated the beneficial effect of garlic as a possible mean of protection against oncoming vascular pathology.     

Premixed solutions of diamorphine in ropivacaine for epidural anaesthesia: a study on their long-term stability

Background. Local anaesthetics and opioid mixtures are commonlyused to provide anaesthesia or analgesia during the perioperativeperiod. In order to facilitate their preparation and storageit is necessary to establish the stability of such solutions. Methods. In our study, diamorphine was added to ropivacaine0.2% 200-ml polybags to give a concentration of 25 µg ml^–1and to ropivacaine 1% 50-ml syringes to give a concentrationof 45 µg ml^–1. The polybags and syringeswere stored at 40°C, 21°C and 4°C for up to 120days. Samples were taken during this period for measurementof diamorphine and ropivacaine content and pH of the solutions. Results. We found that the storage temperature and the initialconcentration influenced the rate of degradation of diamorphinein both the polybags and the syringes. In the syringes, 10%degradation of diamorphine [T (0.9)] was: 6 days at 40°C,16 days at 21°C and 30 days at 4°C. In the polybags,diamorphine T (0.9) was 6 days at 40°C, 28 days at 21°Cand 70 days at 4°C. Conclusions. It is feasible to manufacture such solutions inpharmacy aseptic units and to store them for up to 1 month forroutine use in epidural infusions. Br J Anaesth 2003; 90: 179–82     

Effect of Maharishi Amrit Kalash on age dependent variations in mitochondrial antioxidant enzymes, lipid peroxidation and mitochondrial population in different regions of the central nervous system of guinea-pigs

Age related changes in the mitochondria of different regions of the CNS of two age groups of guinea-pigs (10 months and 32 months) were studied. The activities of glutathione peroxidase (GPx) and glutathione reductase (GRd) decreased significantly (p <0.05) with age in the mitochondrial fractions of cerebral cortex, hypothalamus, cerebellum and spinal cord. A significant (p <0.05) age related decrease in mitochondrial numerical density was observed in all regions studied. Electron microscopic observations revealed various degenerative changes in the mitochondria with age. Treatment of the animals with the Ayurvedic herbal mixture "Maharishi Amrit Kalash" (MAK), 500 mg/kg body wt. daily for 2 months, significantly induced the activity of antioxidant enzymes, and also reversed the pathological changes to a considerable extent. MAK increased the activity of GPx significantly only in the 32 month-old animals. This shows the specificity of the action of MAK.