Nerve agent poisoning in primates: antilethal, anti-epileptic and neuroprotective effects of GK-11

 Organophosphorus nerve agents are still in use today in warfare and as terrorism compounds. Classical emergency treatment of organophosphate poisoning includes the combined administration of a cholinesterase reactivator (an oxime), a muscarinic cholinergic receptor antagonist (atropine) and a benzodiazepine anticonvulsant (diazepam). However, recent experiments with primates have demonstrated that such treatment, even when administered immediately after organophosphate exposure, does not rapidly restore normal electroencephalographic (EEG) activity and fails to totally prevent neuronal brain damage. The objective of this study was to evaluate, in a realistic setting, the therapeutic benefit of administration of GK-11 (gacyclidine), an antiglutamatergic compound, as a complement to the available emergency therapy against organophosphate poisoning. GK-11 was injected at a dose of 0.1 mg/kg (i.v) after a 45-min latency period to heavily intoxicated (8 LD₅₀) primates. Just after intoxication, man-equivalent doses of one autoinjector containing atropine/pralidoxime/diazepam were administered. The effects of GK-11 were examined on survival, EEG activity, signs of toxicity, recovery after challenge and central nervous system histology. The present data demonstrate that treatment with GK-11 prevents the mortality observed after early administration of classical emergency medication alone. EEG recordings and clinical observations also revealed that GK-11 prevented soman-induced seizures and motor convulsions. EEG analysis within the classical frequency bands (beta, theta, alpha, delta) demonstrated that central activity was totally restored to normal after GK-11 treatment, but remained profoundly altered in animals receiving atropine/pralidoxime/diazepam alone. GK-11 also markedly accelerated clinical recovery of soman-challenged primates. Lastly, this drug totally prevented the neuropathology observed 3 weeks after soman exposure in animals treated with classical emergency treatment alone. GK-11 represents a promising adjuvant therapy to the currently available emergency polymedication to ensure optimal management of organophosphate poisoning in man. This drug is presently being evaluated in a human clinical trial for a different neuroprotective indication. Received: 16 June 1997 / Accepted: 23 September 1997     

Naloxone administration following operant training of sucrose/water discrimination in the rat

 The suppression of food intake observed following naloxone administration has often been ascribed to palatability or taste. Unfortunately, many confounds become apparent when attempts are made to isolate such factors in the investigation of ingestive behaviors. In the present study, rats (two groups) were trained to discriminate either a 10% or 5% sucrose solution from water (0.1 ml). These mildly food deprived subjects (95% of free-feeding weight) were trained to press the appropriate lever in a two-lever operant chamber following sampling of sucrose or water; successful responding was reinforced by delivery of a 45 mg grain food pellet. Following random exposure to reduced sucrose concentrations tested under extinction, a sucrose concentration gradient (1.0, 0.5, 0.1, 0.05, 0.01 and 0.005% sucrose solution) was established for both training groups under IP saline administration. Data collected under IP saline were then compared to those collected following random IP naloxone administration (3.0, 1.0, 0.3 and 0.1 mg/kg). No significant differences were observed between the sucrose concentration gradients obtained under saline and those obtained under naloxone, suggesting that the anorectic effect of naloxone is not primarily determined by discrimination of sweet taste. Received: 4 September 1996 / Final version: 16 October 1996     

Tensile strength of plate osteosynthesis. Comparative biomechanical study of the original autocompression plate and a functional modification using the ZESPOL principle

In order to overcome the problems of stress protection and pressure atrophy of bone, which are associated with the traditional plating technique, in Poland a modified type of plating, ZESPOL has been, developed. In this procedure, the plate is not screwed onto the surface of the bone, but is fixed above the bone by special platform screw bolts in a comblike construction. This paper describes an experimental biomechanical investigation, using cadaver tibia, which compares the stability of the ZESPOL principle with that of the traditionally applied autocompression plate (ACP). In order to make the system biomechanically comparable, instead of the original ZESPOL plates, which are different in dimension, an ACP was used that was specially adapted to fit the ZESPOL criteria. Compared to the ACP, the bending stability of the ZESPOL osteosynthesis was found to be significantly less. When the same stress was applied, the total bending capacity of the ZESPOL system was found to be between 9% and 1348% higher, depending on the position of the plate and the direction of the force applied. In addition, the gap of the osteotomy site was between 6% and 923% greater with the ZESPOL system. Deformation of the bone adjacent to the osteotomy site was more closely approximate to intact bone with ACP than with ZESPOL plate. Our evaluations show that the ZESPOL system has less bending stability than ACP, without having the advantage of a more physiological bone-bending curve. However, the stability of the new system can be regarded as being overall sufficient.     

Disposition in humans of racemic picenadol, an opioid analgesic

Racemic picenadol is being tested clinically as an analgesic. The (+)-enantiomer of picenadol is an opioid agonist and the (-)-enantiomer is a weak agonist/antagonist. The disposition of racemic [14C] picenadol was studied in healthy men after a single dose was administered im (N = 3) and orally (N = 5). After the dose, virtually none of the radioactivity that appeared in blood was associated with the red cells. In plasma, approximately 4% of the radioactivity was attributable to the parent drug, the remainder being picenadol glucuronide (approximately 35%) and other metabolites. The t1/2 for total radioactivity was 6 hr, that for the unchanged drug was 3.5 hr. Picenadol was present in plasma almost exclusively as the (+)-enantiomer. However, after incubation with glucuronidase and sulfatase, plasma contained 2 to 4 times more (-)- than (+)-picenadol, indicating that more conjugated (-)-picenadol than conjugated (+)-picenadol was in the plasma. After im and oral administration of [14C]picenadol, plasma levels of radioactivity were generally 10 and 70 times higher than those in saliva, respectively. More than 90% of the administered radioactivity was excreted in the urine, mostly as picendol glucuronide, and lesser amounts of picenadol sulfate and N-desmethylpicenadol sulfate. Only about 1% of the administered dose of picenadol appeared unchanged in urine. The disposition of racemic picenadol in humans was stereoselective, the (-)-picenadol apparently being metabolized preferentially over the (+)-enantiomer. This finding was of particular interest in view of the dissimilar pharmacologic activities of the enantiomers.(ABSTRACT TRUNCATED AT 250 WORDS)     

Surgeon perspectives on options for ventral abdominal wall hernia repair: results of a postal questionnaire

Background: Ventral abdominal wall hernias are a common cause of morbidity and mortality. Opinion varies as to appropriate management. A recent consensus meeting on incisional hernia identified the need to standardise repair. On this background, a survey of current practice was performed. Method: A questionnaire was sent to 101 practicing general surgeons within the West of Scotland. Incisional, epigastric and para-umbilical defects were subdivided into defect size <2, 2–5 and >5 cm. The surgeons were asked to indicate the most appropriate repair (suture, mayo or mesh) for each. The influence of reducibility on the decision to repair was also assessed. Results: Sixty-one of 101 questionnaires were returned valid giving a response rate of 60%. Suture repair was significantly more likely to be used in all defects <2 cm (P<0.001). Mesh repair was significantly more likely to be recommended in all defects >5 cm (P<0.001). Of defects >5-cm, mesh was recommended for 90% of incisional hernia compared with 81% of epigastric and 76% of para-umbilical hernia (P<0.001). There was no significant difference in choice of repair for defect size 2–5 cm with opinion divided between suture and mesh. Irreducibility increased the likelihood of recommendation for repair. Conclusion: This survey shows a lack of consensus on the appropriate repair of ventral abdominal wall hernia amonge practicing consultant general surgeons. This reflects the contrasting views within the current literature.     

Treatment of iatrogenic biliary obstruction by balloon dilatation of a biliary jejunal fistula

Biliary obstruction and multiple hepatic abscesses occurred in a patient after ligation of a segmental branch of the right hepatic duct. The patient was successfully managed by transhepatic biliary drainage and balloon dilatation of an internal fistula that developed between the ligated duct and a Roux limb of jejunum. Internal biliary fistulas may be dilated using interventioanl radiologic techniques to permit nonobstructed bile flow. Implications for the nonsurgical treatment' of biliary strictures are discussed.     

Pectus excavatum defect on liver-spleen scintigraphy

A 58-year-old man with a pectus excavatum demonstrated a photon-deficient defect within the left lobe of the liver on liver-spleen scintigraphy using Tc-99m SCOL. Computed tomography of the liver clearly revealed the abnormal defect seen on the liver-spleen scan to be due to the pectus excavatum. This case confirms the impression that these skeletal aberrations may cause false-positive hepatic defects.The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Department of the Army or the Department of Defense