In vivo protection studies of bis-quaternary 2-(hydroxyimino)- N-(pyridin-3-yl) acetamide derivatives (HNK oximes) against tabun and soman poisoning in Swiss albino mice.

The study reports antidotal efficacy of three HNK [ bis quaternary 2-(hydroxyimino)-N-(pyridin-3yl) acetamide derivatives] and pralidoxime (2-PAM), against soman and tabun poisoning in Swiss albino mice. Protection index (PI) was determined (treatment doses: HNK oximes, ×0.20 of their median lethal dose (LD50) and 2-PAM, 30 mg/kg, intramuscularly (im)) together with atropine (10 mg/kg, intraperitoneally). Probit log doses with difference of 0.301 log of LD50 of the nerve agents administered and inhibition of acetylcholinesterase (AChE) activity by 50% (IC50) was calculated at optimized time in brain and serum. Using various doses of tabun and soman (subcutaneously (sc)), in multiples of their IC50, AChE reactivation ability of the oximes was studied. Besides, acute toxicity (0.8× LD50, im, 24 h postexposure) of HNK-102 and 2-PAM was also compared by determining biochemical, hematological variables and making histopathological observations. Protection offered by HNK-102 against tabun poisoning was found to be four times higher compared to 2-PAM. However, nearly equal protection was noted with all the four oximes against soman poisoning. HNK-102 reactivated brain AChE activity by 1.5 times more than 2-PAM at IC50 dose of soman and tabun. Acute toxicity studies of HNK-102 and 2-PAM showed sporadic changes in urea, uric acid, aspartate aminotransferase, and so on compared to control group, however, not supported by histopathological investigations. The present investigation showed superiority of newly synthesized HNK-102 oxime over standard 2-PAM, as a better antidote, against acute poisoning of tabun (4.00 times) and soman (1.04 times), in Swiss albino mice.

In vivo protection of diisopropylphosphorofluoridate (DFP) poisoning by three bis-quaternary 2 -(hydroxyimino) -N -(pyridin-3-yl) acetamide derivatives in Swiss mice.

This study reports efficacy of three bis pyridinium derivatives of 2-(hydroxyimino)- N-(pyridine-3-yl) acetamide in terms of survival, reactivation of brain and serum acetylcholinesterase (AChE) activity in diisopropylphosphorofluoridate (DFP) intoxicated Swiss albino male mice. LD50 of DFP (3.9 mg/kg, s.c.) and new oximes, HNK-102, HNK-106, HNK-111, (282.8, 35.0 and 35.0 mg/kg respectively, i.m.) was determined. Various doses of DFP and oximes as treatment doses with atropine (10 mg/kg, i.p.) were used to determine protection index (PI). For time dependent maximum AChE inhibition, two doses of DFP (0.20 and 2.0 LD50) were chosen. At optimized time i.e. Sixty minutes, IC50 value was calculated as 0.249 and 0.017 LD50 of brain and serum AChE, respectively. Shift of DFP induced brain AChE IC50 curves to right was observed at 0.20 LD50 treatment dose of oximes with respect to 2-PAM. These findings propose that new HNK series of oximes are effective antidote, compared to that of 2-PAM in vivo.

Acute inhalation toxicity of smoke of fentanyl and its 1-substituted analogs in Swiss albino mice.

Fentanyl (N-(1-phenethyl-4-piperidinyl)propionanilide) is a synthetic, potent narcotic analgesic agent. However, it is known to have several side effects, which led to synthesis and evaluation of its new analogs for the management of pain. We have earlier reported the comparative bioassay of fentanyl and its eight 1-substituted analogs (1-8) in mice. Three compounds, viz., N-(1-(2-phenoxyethyl)-4-piperidinyl)propionanilide (2), N-isopropyl-3-(4-(N-phenylpropionamido)piperidin-1-yl)propanamide (5), and N-t-butyl-3-(4-(N-phenylpropionamido)piperidin-1-yl)propanamide (6) were found to be more effective and less toxic compared to fentanyl. The present study reports the comparative acute inhalation toxicity of smoke of fentanyl and its three analogs, viz., 2, 5, and 6 in mice. Animals were exposed to different concentrations of smoke generated by heating the compounds. Exposure was performed in a head only all glass static exposure assembly for 15 min to determine the median lethal concentration (LC50). The breathing pattern and various respiratory parameters of the animals were also monitored online using a polygraph. Out of three compounds tested, analog 5 was found to be most toxic (LC50 = 2820 mg/m3) while 2 was least toxic (LC50 = >8000 mg/m3). All the compounds caused long lasting respiratory depression in a dose-dependent manner, which did not completely resolve even after discontinuation of exposure. Aerodynamic median diameter and geometric standard deviation of smoke particles was determined employing eight-stage Andersen sampler. The particles were found to be within the respirable range. The study, however, concludes that due to possible decomposition of the compounds by heating or its poor absorption by the alveolar surface, the present inhalation technique cannot be employed to generate smoke of fentanyl and its analogs for any medical or surreptitious use.

Histoenzymological comparison of the prostate gland of sexually 'quiescent' and 'active' Taphozous melanopogon melanopogon Temmnick (Microchiroptera: Mammalia).

Lysosomal hydrolases (e.g., acid phosphatase, AcPase; adenosine triphosphatase, ATPase, and lipase) and the mitochondrial 'marker' enzyme succinic dehydrogenase (SDH) were evaluated histochemically in the prostate gland of sexually 'quiescent' and 'active' bats. During the former state, AcPase activity was significantly less than in sexually active animals, suggesting that prostate AcPase activity is androgen dependent. Levels of lipase activity also were highest in the prostate of sexually active bats, suggesting the importance of endogenous lipids which may be mobilized and used as a source of energy. SDH and ATPase sites and patterns of distribution in the prostate gland of bats were closely similar during the two reproductive states. Differential enzymological patterns do not seem to have any significant correlation with the morphological changes which occur in the glandular epithelium, musculature, urethra and the luminal fluid, as the animals pass from a 'quiescent' phase to one of activity and vice versa as observed in the present study.