The potential effects of silver and gold nanoparticles as molluscicides and cercaricides on Schistosoma mansoni.

Schistosomiasis seriously affects human health in tropical regions. Its prevention is more important than treatment, raising the need for effective control methods. Recently, the role of nanomaterials in medical science has been growing. The present study aimed to evaluate the potential effects of silver (Ag) and gold (Au) nanoparticles (NPs) on Biomphalaria alexandrina snails and Schistosoma mansoni cercariae in vitro and to assess their effects on the infectivity of cercariae in vivo. The in vitro study proved that Ag and Au NPs were effective in killing B. alexandrina snails, with 30 µg/ml Ag and 160 µg/ml Au causing 100% mortality. The LC50 of 9.68 µg/ml for Ag NPs and 133.7 µg/ml for Au NPs prevented snail infection with S. mansoni miracidia. Furthermore, Ag NPs at 50 µg/ml and Au NPs at 100 µg/ml increased the mortality of S. mansoni cercariae in a dose- and time-dependent manner, reaching 100% mortality after 1 h. The in vivo study found that Ag NPs prevented the occurrence of infection when cercariae were treated before the infection by either the tail immersion (TI) or subcutaneous (SC) route, as proven by parasitological parameters and by the absence of granuloma formation in hepatic tissue. Meanwhile, infection of mice by untreated cercariae followed by treatment with NPs 1 h post-infection (PI) caused a decrease in egg count/g intestine and egg count/g liver in the TI-infected group only. The oogram patterns and granuloma formation results were similar between infection control and the SC-infected group. On the other hand, Au NPs led to a decrease in total worm burden (TWB) in all tested groups, with a decrease in egg count/g intestine and egg count/g liver in TI-infected groups with either pre-treated or post-treated cercariae, in contrast to SC-infected groups. However, the oogram patterns and granuloma formation showed similar results to infection control. Ag and Au NPs have potential as molluscicides and cercaricides in vitro and can prevent or modulate the infectivity of cercariae in vivo.

Role of adenosine A2A receptor in cerebral ischemia reperfusion injury: Signaling to phosphorylated extracellular signal-regulated protein kinase (pERK1/2).

Following brain ischemia reperfusion (IR), the dramatic increase in adenosine activates A2AR to induce further neuronal damage. Noteworthy, A2A antagonists have proven efficacious in halting IR injury, however, the detailed downstream signaling remains elusive. To this end, the present study aimed to investigate the possible involvement of phospho-extracellular signal-regulated kinase (pERK1/2) pathway in mediating protection afforded by the central A2A blockade. Male Wistar rats (250-270 g) subjected to bilateral carotid occlusion for 45 min followed by a 24-h reperfusion period showed increased infarct size corroborating histopathological damage, memory impairment and motor incoordination as well as increased locomotor activity. Those events were mitigated by the unilateral intrahippocampal administration of the selective A2A antagonist SCH58261 via a decrease in pERK1/2 downstream from diacyl glycerol (DAG) signaling. Consequent to pERK1/2 inhibition, reduced hippocampal microglial activation, glial tumor necrosis factor-alpha (TNF-α) and brain-derived neurotropic factor (BDNF) expression, glutamate (Glu), inducible nitric oxide synthase (iNOS) and thiobarbituric acid reactive substances (TBARS) were evident in animals receiving SCH58261. Additionally, the anti-inflammatory cytokine interleukin-10 (IL-10) increased following nuclear factor (erythroid-derived 2)-like 2 (Nrf-2). Taken all together, these events suppressed apoptotic pathways via a reduction in cytochrome c (Cyt. c) as well as caspase-3 supporting a crucial role for pERK1/2 inhibition in consequent reduction of inflammatory and excitotoxic cascades as well as correction of the redox imbalance.

Nanosuspension as an ophthalmic delivery system for certain glucocorticoid drugs.

Poorly-water-soluble compounds are difficult to develop as drug products using conventional formulation techniques. The use of nanotechnology to formulate poorly-water-soluble drugs as nanosuspensions offers the opportunity to address many of the deficiencies associated with this class of molecules. In the present study, the high pressure homogenization method used to prepare nanosuspensions of three practically insoluble glucocorticoid drugs; hydrocortisone, prednisolone and dexamethasone. The effect of particle size in the micron and nano-size ranges as well as the effect of viscosity of the nanosuspension on the ocular bioavailability was studied by measuring the intraocular pressure of normotensive Albino rabbits using shiØetz tonometer. The results show that compared to solution and micro-crystalline suspensions it is a common feature of the three drugs that the nanosuspensions always enhance the rate and extent of ophthalmic drug absorption as well as the intensity of drug action. In the majority of cases nanosuspensions extend the duration of drug effect to a significant extent. The data presented confirms that nanosuspensions differ from micro-crystalline suspensions and solution as ophthalmic drug delivery systems and that the differences are statistically, highly to very highly significant. The results confirm also the importance of viscosity of nanosuspension especially in increasing the duration of drug action.

Clinical evaluation of novel buccoadhesive film containing ketorolac in dental and post-oral surgery pain management.

Ketorolac tromethamine (KT), a non-steroidal anti-inflammatory drug, was formulated in buccoadhesive film to overcome the limitations in the currently available routes of administration which in sequence will increase patients' compliance. The film was formulated using aqueous solvents by means of two bioadhesive polymers namely: hydroxylpropyl methyl cellulose (HPMC) and Carbopol 934. The prepared film was subjected to investigations for its physical and mechanical properties, swelling behavior, in vitro bioadhesion, and in vitro, in situ and in vivo release. Anti-inflammatory efficacy and analgesic activity of the prepared buccoadhesive film were investigated in rats using the hind-paw oedema test and the hot plate method. The analgesic efficacy and tolerability of a single 30 mg dose of KT formulated into the buccoadhesive film was clinically evaluated using a standard, widely accepted post-oral surgery pain model. In this study, the prepared film has been administrated to dental post-operative patients for relieving pain in dental hospital clinic. Results indicate that the concentration of KT in the oral cavity was maintained above 4.0 microg/ml for a period of at least 6 h. The buccal KT film was excellently tolerated in all patients and no complains of GI side effects were reported. It is concluded from this clinical evaluation that KT formulated into a buccoadhesive film is effective as a potent analgesic in dental and postoperative oral surgery in a single dose of 30 mg with minimal GI side effects.

Absorption, distribution, metabolism and excretion of daily oral doses of [14C]methyl parathion in hens.

Adult hens were given oral daily doses of 2 mg (2 microC(i))/kg/day (14% of oral LD(50) in male rats) of [14C]methyl parathion (O,O-dimethyl O-4-nitrophenyl phosphorothioate) for 10 consecutive days. Five treated hens were sacrificed at 1, 2, 4, 8, 12, 24, and 48 h after the last dose. Methyl parathion was absorbed from the gastrointestinal tract and distributed rapidly. Maximum radioactivity was detected in tissues within 8 h of dosing, (ng methyl parathion equivalent/g fresh tissue or ml plasma): Plasma (189.2), liver (94.7), kidney (146.2), brain (61.4), gastrointestinal tissues (106.7). Methyl parathion was detected in the plasma, kidney and liver, while methyl parathion metabolite p-nitrophenol was detected in the liver and in the kidney. Elimination of methyl parathion from plasma was monophasic with a terminal half-life of 17.5 h, corresponding to an elimination rate constant of 0.039 ng/hr. Most of the absorbed radioactivity was excreted in the combined fecal-urine excreta (98%). Analysis of the metabolites in the excreta revealed that non-conjugated metabolites accounted for 13% of the total excretion. Conjugated metabolites accounted for 87% of the total excretion; of that, 6% as p-nitrophenyl-glucoronide conjugate, 7% as p-nitrophenyl-sulfate conjugate, 23% as bound hot sulfuric acid hydrolyzable residues, and 51% as water soluble metabolites. The presence of majority of radioactivity in the excreta as conjugated metabolites indicates that determining only unbound p-nitrophenol as a biological marker for methyl parathion exposure underestimates total fecal-urine excretion of p-nitrophenol. The slow elimination rate of methyl parathion is significant, since hens are more comparable to humans with respect to their cytochrome P450 activities.

Synthesis of some 2-methylthiouracil nucleosides and its 5-halo analogues of 2-acetamido-2-deoxy-D-glucose.

This paper describes the regiospecific synthesis of 5-halo-2-methylthiouracil nucleosides by direct glycosylation followed by halogenation by an electrophilic halogen reagent and sodium azide under mild conditions. The compounds were suggested to be effective as antiviral agents.

Evidence for the involvement of central I1 imidazoline receptor in ethanol counteraction of clonidine hypotension in spontaneously hypertensive rats.

Our previous studies have shown that ethanol counteracts centrally mediated hypotensive responses to clonidine. In this study, we investigated the relative roles of central alpha2-adrenergic and I1 imidazoline receptors in the antagonistic ethanol-clonidine hemodynamic interaction. The effects of selective blockade of alpha2- or I1 receptor by 2-methoxyidazoxan and efaroxan, respectively, on the blood pressure and heart rate responses to clonidine and subsequent ethanol administration were evaluated in conscious spontaneously hypertensive rats. Intracisternal administration of clonidine (1.5 microg/kg) produced significant (30 mm Hg; p < 0.05) and sustained (at least 60 min) decreases in blood pressure and heart rate. Systemic ethanol (1 g/kg), administered 10 min after clonidine, counteracted the hypotensive response and restored blood pressure to the preclonidine levels. Treatment with 2-methoxyidazoxan (0.16 microg/kg, intracisternal) or efaroxan (0.45 microg/kg, intracisternal) produced similar attenuation of the hypotensive and bradycardic responses to clonidine. The ability of ethanol to counteract the hypotensive action of clonidine was significantly (p < 0.05) attenuated in rats pretreated with efaroxan. The pressor response to ethanol lasted only 10 min compared with at least 60 min in the absence of efaroxan. In contrast, ethanol counteraction of clonidine-evoked hypotension was not altered when alpha2-adrenoceptors were blocked by 2-methoxyidazoxan. These findings suggest that centrally mediated hypotensive and bradycardic effects of clonidine in conscious spontaneously hypertensive rats involve activation of both alpha2-adrenergic and I1 imidazoline receptors. Furthermore, the findings suggest the dependence of a fully expressed ethanol counteraction of the hypotensive action of clonidine on functional I1 receptor within the central nervous system.

An association between the estrogen-dependent hypotensive effect of ethanol and an elevated brainstem c-jun mRNA in female rats.

We have recently demonstrated that chronic ethanol administration lowers blood pressure (BP) in female rats and this effect is significantly attenuated by ovariectomy. The present study investigated whether ethanol hypotension is estrogen dependent. Further, since estrogen regulates AP-1 activity, the study was extended to determine whether estrogen/c-jun interaction is involved in the estrogen-dependent hypotensive effect of ethanol. Changes in BP and heart rate (HR) were evaluated in radiotelemetered pair-fed sham-operated (SO), ovariectomized (OVX), and OVX estradiol (E2)-treated rats receiving liquid diet with or without ethanol (5%, w/v) for 12 weeks. The in situ hybridization technique was used to measure the c-jun mRNA expression in two brainstem areas, the nucleus tractus solitarius (NTS) and the rostral ventrolateral medulla (RVLM). Ethanol feeding caused significant (P<0.05) decreases in BP in SO rats that started at week 1 and reached its maximum (approximately 10 mmHg) at week 6 and remained at that level till the end of week 12. In OVX rats, ethanol had no effect on BP during the first 5 weeks after which a decrease of 5 mmHg was demonstrated and remained thereafter. Estrogen replacement (17beta-estradiol subcutaneous pellet, 14.2 microg/day) restored the hypotensive effect of ethanol to a level similar to that of SO rats both in terms of magnitude and duration. Densitometric analysis of the in situ hybridization autoradiograms revealed that OVX and E2 replacement had no effect on c-jun mRNA expression in the NTS or RVLM. Ethanol feeding produced a significant (twofold) increase in c-jun mRNA expression in the RVLM of SO rats versus no effect in the NTS. The increased expression of c-jun mRNA observed following ethanol treatment in the RVLM of SO rats was abolished in OVX rats and restored to SO levels after E2 replacement. These findings suggest a link between the estrogen-dependent hypotensive effect of chronically administered ethanol and the increased expression of c-jun mRNA in the brainstem of female rats.

Effect of long-term ethanol feeding on brainstem alpha(2)-receptor binding in Wistar-Kyoto and spontaneously hypertensive rats.

Our previous studies have shown that ethanol attenuates baroreflex function in Wistar-Kyoto (WKY) but not in spontaneously hypertensive rats (SHRs). The present study determined the effects of chronic ethanol administration on alpha(2)-binding sites in brainstem areas that modulate baroreflexes. In vitro autoradiography was utilized to evaluate the effect of a 3-month ethanol feeding on the density (B(max)) and affinity (K(D)) of alpha(2)-adrenoceptors in the middle (mNTS) and rostral (rNTS) portions of the nucleus tractus solitarius of SHRs and WKY rats. Autoradiographic examination of brainstem sections preincubated with [125I]p-iodoclonidine revealed no inter-strain differences in alpha(2)-binding in control rats. Ethanol feeding caused strain-dependent changes in alpha(2)-binding activity, which comprised significant (P<0.05) decreases in the density of alpha(2)-binding sites in both areas of the NTS in SHRs versus no effect in WKY rats. These findings do not favor a role for brainstem alpha(2)-adrenoceptors in ethanol-induced attenuation of baroreflexes. Interestingly, the ethanol-evoked reduction in the NTS alpha(2)-receptor density in SHRs may explain reported findings that ethanol abolishes the hypotensive effect of the alpha(2)-adrenoceptor agonist clonidine in this rat model.

Effects of daily dermal application of DEET and epermethrin, alone and in combination, on sensorimotor performance, blood-brain barrier, and blood-testis barrier in rats.

DEET and permethrin were implicated in the development of illnesses in some veterans of the Persian Gulf War. This study was designed to investigate the effects of daily dermal application of these chemicals, alone or in combination, on the permeability of the blood-brain barrier (BBB) and blood-testes barrier (BTB) and on sensorimotor performance in male Sprague-Dawley rats. Groups of five rats were treated with a dermal daily dose of 4, 40, or 400 mg/kg DEET in ethanol or 0.013, 0.13, or 1.3 mg/kg permethrin in ethanol for 60 d. A group of 10 rats received a daily dermal dose of ethanol and served as controls. BBB permeability was assessed by injection of an iv dose of the quaternary ammonium compound [3H]hexamethonium iodide. While permethrin produced no effect on BBB permeability, DEET alone caused a decrease in BBB permeability in brainstem. A combination of DEET and permethrin significantly decreased the BBB permeability in the cortex. BTB permeability was decreased by treatment with DEET alone and in combination with permethrin. The same animals underwent a battery of functional behavior tests 30, 45, and 60 d after exposure to evaluate their sensorimotor abilities. All treatments caused a significant decline in sensorimotor performance in a dose- and time-dependent manner. These results show that daily dermal exposure to DEET, alone or in combination with permethrin, decreased BBB permeability in certain brain regions, and impaired sensorimotor performance.

Imidazoline I(1) receptor-induced activation of phosphatidylcholine-specific phospholipase C elicits mitogen-activated protein kinase phosphorylation in PC12 cells.

In the present study, we tested the hypothesis that the activation of imidazoline I(1)-receptor, which is coupled to phosphatidylcholine-specific phospholipase C, results in downstream activation of mitogen-activated protein kinase (p42(mapk) and p44(mapk) isoforms) in PC12 cells. PC12 cells pretreated with nerve growth factor (50 ng/ml, 48 h) to initiate neuronal differentiation were incubated with [methyl-3H]choline and [3H]myristate. Activation of imidazoline I(1) receptor by rilmenidine (10 microM) caused time-dependent increases in diacylglycerol accumulation and phosphocholine release. The Western blotting analysis showed that rilmenidine (10 microM) produced a time-dependent activation of p42(mapk) and p44(mapk) that reached its maximum at 15 min and returned to control levels after 30 min. This finding was confirmed by immunofluorescence labeling of activated mitogen-activated protein kinase in the same model system. Efaroxan (imidazoline I(1)-receptor antagonist) or tricyclodecan-9-yl-xanthogenate (D609, phosphatidylcholine-specific phospholipase C inhibitor) attenuated the phosphorylation of p42(mapk) and p44(mapk) induced by rilmenidine. Nerve growth factor-induced phosphorylation of both mitogen-activated protein kinase isoforms was not affected by D609. These results support the hypothesis that the activation of the imidazoline I(1) receptor coupled phosphatidylcholine-specific phospholipase C results in the downstream activation of mitogen-activated protein kinase.

Locomotor and sensorimotor performance deficit in rats following exposure to pyridostigmine bromide, DEET, and permethrin, alone and in combination.

Since their return from Persian Gulf War (PGW), many veterans have complained of symptoms including muscle and joint pain, ataxia, chronic fatigue, headache, and difficulty with concentration. The causes of the symptoms remain unknown. Because these veterans were exposed to a combination of chemicals including pyridostigmine bromide (PB), DEET, and permethrin, we investigated the effects of these agents, alone and in combination, on the sensorimotor behavior and central cholinergic system of rats. Male Sprague-Dawley rats (200-250 gm) were treated with DEET (40 mg/kg, dermal) or permethrin (0.13 mg/kg, dermal), alone and in combination with PB (1.3 mg/kg, oral, last 15 days only), for 45 days. Sensorimotor ability was assessed by a battery of behavioral tests that included beam-walk score, beam-walk time, incline plane performance, and forepaw grip on days 30 and 45 following the treatment. On day 45 the animals were sacrificed, and plasma and CNS cholinesterase, and brain choline acetyl transferase, muscarinic and nicotinic acetylcholine receptors were evaluated. Animals treated with PB, alone or in combination with DEET and permethrin, showed a significant deficit in beam-walk score as well as beam-walk time as compared with controls. Treatment with either DEET or permethrin, alone or in combination with each other, did not have a significant effect on beam-walk score. All chemicals, alone or in combination, resulted in a significant impairment in incline plane testing on days 30 and 45 following treatment. Treatment with PB, DEET, or permethrin alone did not have any inhibitory effect on plasma or brain cholinesterase activities, except that PB alone caused moderate inhibition in midbrain acetylcholinesterase (AChE) activity. Treatment with permethrin alone caused significant increase in cortical and cerebellar AChE activity. A combination of DEET and permethrin or PB and DEET led to significant decrease in AChE activity in brainstem and midbrain and brainstem, respectively. A significant decrease in brainstem AChE activity was observed following combined exposure to PB and permethrin. Coexposure with PB, DEET, and permethrin resulted in significant inhibition in AChE in brainstem and midbrain. No effect was observed on choline acetyl transferase activity in brainstem or cortex, except combined exposure to PB, DEET, and permethrin caused a slight but significant increase in cortical choline acetyltransferase activity. Treatment with PB, DEET, and permethrin alone caused a significant increase in ligand binding for m2 muscarinic acetylcholine receptor (mAChR) in the cortex. Coexposure to PB, DEET, and permethrin did not have any effect over that of PB-induced increase in ligand binding. There was no significant change in ligand binding for nicotinic acetylcholine receptor (nAChR) associated with treatment with the chemical alone; a combination of PB and DEET or coexposure with PB, DEET, and permethrin caused a significant increase in nAChR ligand binding in the cortex. Thus, these results suggest that exposure to physiologically relevant doses of PB, DEET, and permethrin, alone or in combination, leads to neurobehavioral deficits and region-specific alterations in AChE and acetylcholine receptors.

Clonidine diminishes c-jun gene expression in the cardiovascular sensitive areas of the rat brainstem.

The present study investigated the effect of clonidine on the basal and inducible c-jun and c-fos mRNA expression in the nucleus tractus solitarius (middle, mNTS, and rostral, rNTS) and the rostral ventrolateral medulla (caudal, cRVLM, and rostral, rRVLM). Conscious rats received saline, clonidine (30 microg/kg, i.v.), saline plus sodium nitroprusside (NP), or clonidine plus NP. Under basal conditions (saline-infused rats), c-jun mRNA was expressed in the mNTS and rRVLM but not in the rNTS or cRVLM whereas c-fos mRNA was not detectable. Clonidine attenuated the increases in c-fos in the mNTS and cRVLM and c-jun gene expression in the mNTS and rRVLM caused by NP-evoked hypotension and also reduced the basal expression of c-jun mRNA in the mNTS and rRVLM. These findings establish a causal link between clonidine inhibition of c-fos expression in brainstem and its hypotensive action, and provide the first evidence that clonidine attenuates the expression of the closely linked c-jun gene in neurons implicated in centrally mediated hypotension.

Effect of long-term ovariectomy and estrogen replacement on the expression of estrogen receptor gene in female rats.

OBJECTIVE: Estrogen exerts a wide variety of actions involving many target tissues. We studied the effects of long-term ovariectomy (OVX) and OVX with 17beta-estradiol treatment (OVXE2) on the level of estrogen receptor (ER) gene expression in target tissues of female rats. DESIGN: Three groups of Sprague-Dawley female rats were utilized in this study: sham operated (SO), OVX and OVXE2. METHODS: SO and OVX were performed 2 weeks before starting the 17beta-estradiol treatment. All groups were maintained on liquid diet for 12 weeks from the time of estradiol treatment. Total RNA was prepared from the tissues of the rats and relative quantitative reverse transcription PCR was utilized to compare the ER alpha-subtype (ERalpha) mRNA level in the three groups for each target tissue. RESULTS: Following long-term OVX, the levels of ERalpha expression showed a significant increase in the uterus, kidney and cerebral cortex and no significant change in the liver, cerebellum, brainstem, heart and thoracic and abdominal aorta compared with their SO levels. On the other hand, a 12-week treatment of OVX rats with 17beta-estradiol restored the previously upregulated ERalpha mRNA to near SO levels except for the liver where the 17beta-estradiol treatment resulted in a significant increase in the ERalpha mRNA level compared with that in SO rats. CONCLUSIONS: We conclude that the regulation of ERs by its ligand is tissue specific.

Neurotoxicity of ethyl methacrylate in rats.

Ethyl methacrylate (ethyl 2-methyl-2-propenoate, EMA) has been implicated in the development of neurologic impairment following occupational exposure. The potential of EMA to produce neurotoxicity was investigated in adult male Sprague-Dawley rats in two experiments. In the first experiment, animals were administered 100, 200, 400, or 800 mg/kg by daily intraperitoneal (i.p.) injections for 60 d. Control rats received daily i.p. injections of 1 ml saline/kg. Clinical observations, spontaneous motor activity, and performance in the Morris water maze were assessed. Alterations in clinical parameters in the higher dose groups included lethargy, impaired breathing, decreased weight gain, and increased mortality. Alterations in motor activity were observed at 100 mg/kg, a dose that did not cause alterations in clinical parameters, body weight gain, or mortality. There was also a dose-dependent impairment in performance in the Morris water maze. In the second experiment, animals were administered EMA in drinking water at concentrations of 0.1, 0.2, or 0.5% for 60 d. Control rats were administered tap water. Animals were perfused at the termination of exposure and samples of brain, spinal cord, and sciatic nerve were prepared for histological examination. Spongiform alterations were observed in fiber tracts of the forebrain, brainstem, and spinal cord. Clusters of axonal swellings were scattered throughout the dorsal, ventral, and lateral columns of the spinal cord, and typically involved internodal segments of two or three neighboring axons. Shrunken axons with separated myelin lamellae and large axons with thinner than normal myelin sheaths were apparent in the sciatic nerve. The patterns of alterations in the white matter of the spinal cord and the sciatic nerve are consistent with myelinopathy, but additional experiments are necessary to confirm whether oligodendroglia and Schwann cells are the primary sites of injury. In addition to the alterations associated with myelin, there was a decrease in the density of neurons in the ventral horn of the spinal cord. While the observed effects of EMA on the nervous system of rats are consistent with neurologic symptoms of workers exposed to EMA, additional experiments are necessary to determine if the level and route of exposures associated with occupational use produce these impairments in experimental animals.

Placental transfer and pharmacokinetics of a single dermal dose of [14C]methyl parathion in rats.

The pharmacokinetics and placental transfer of a single dermal 10.0 mg (10microCi)/kg dose of uniformly phenyl-labeled [14C] methyl parathion (0,0-dimethyl 0-4-nitrophenyl phosphorothioate) were investigated in pregnant Sprague-Dawley rats at 14-18 days of gestation. Three rats were killed at each time interval: 1, 2, 4, 12, 24, 48, 72, and 96 h after dosing. Radioactivity disappeared biexponentially from the administration sites, which retained 50% and 3% of the dose after 1 h and 96 h, respectively. Most of the absorbed radioactivity was excreted in the urine (91%). Only 3% of the 14C was recovered in the feces. One h after the administration, radioactivity was detected in all tissues, including fetal tissue. The peak maternal plasma concentration of radioactivity (ng methyl parathion equivalent/ml) was 1005 at 2 h, compared to 318 ng for fetal plasma at 12 h. The maximum concentrations of radioactivity (ng methyl parathion equivalent/g), detected in most tissues within 12 h of dosing, were, in descending order: adipose tissue (67,532), kidney (1,571), spleen (1,256), spinal cord (1,004), heart (729), liver (706), brain (546), placenta (389), and fetus (256). The metabolism studies showed that methyl parathion, detected by HPLC, was the major compound identified in plasma and tissues. The maximum concentration detected was in plasma, at 513 ng/ml, and in the following tissues (ng/g fresh tissue): kidney (819), fetus (668), placenta (394), liver (375), and brain (282). The metabolite methyl paraoxon was detected in maternal brain and liver at maximum concentrations (ng/g fresh tissue) of 135 and 64 after 12 h and 4 h respectively, while p-nitrophenol was only detected in liver at a maximum concentration of 21 ng/g 72 h after dosing. Pharmacokinetic studies showed that methyl parathion disappeared monoexponentially from plasma and tissues. The half-life of elimination of methyl parathion from plasma was 11 h corresponding to a constant rate value of 0.06 h(-1). The results indicate that skin and placenta are poor barriers against methyl parathion permeability, resulting in a rapid and extensive dermal absorption of this insecticide and extensive placental transfer. This is indicated by the relative residence (R(R)) of methyl parathion in the plasma, which was largest in the placenta followed by the fetus. This study suggests that pregnant women and fetuses may be at risk of cholinergic toxicity following dermal exposure to methyl parathion.

Ovariectomy alters the chronic hemodynamic and sympathetic effects of ethanol in radiotelemetered female rats.

This study determined the chronic hemodynamic effects of ethanol in telemetered freely moving female Sprague-Dawley rats. The role of ovarian hormones and sympathetic activity in the modulation of ethanol responses was also investigated. Changes in blood pressure (BP), heart rate (HR), and plasma estrogen and norepinephrine (NE, as index of sympathetic activity) were evaluated in pair-fed sham-operated (SO) and ovariectomized (OVX) rats receiving liquid diet with or without ethanol (5%, w/v) for 12 weeks. OVX caused a significant increase (about 40 g) in body weight, compared with the sham operation, which was apparent after two weeks and remained so for the duration of the study. The body weight showed gradual and similar increases in both ethanol and control groups. Ethanol feeding had no effect on the plasma estrogen level in SO or OVX rats. Daily ethanol intake was significantly (P < 0.05) less in OVX compared with SO rats whereas the blood ethanol concentration were similar in the two groups except for a significantly (P < 0.05) higher level in OVX rats at weeks 8, 10, and 11. Ethanol feeding caused significant (P < 0.05) decreases in BP in SO rats that started at week land reached maximal response (approximately 10 mmHg) at week 6 and remained at that level till the end of week 12. In OVX rats, ethanol had no effect on BPduring the first 5 weeks of the study. A slight but significant reduction in BP (about 5 mmHg) by ethanol in OVX rats started to appear at week 6 and remained for the following 5 weeks. The reduced hypotensive effect of ethanol in OVX rats was associated with an increase in the sympathetic activity as indicated by the significant (P < 0.05) increases in plasma NE levels. This sympathoexcitatory effect of ethanol was not demonstrated in SO rats. The HR was not affected by ethanol in the two groups of rats except for significant (P < 0.05) increases at weeks 1 through 3 in SO rats. The present findings suggest that the ovarian hormones modulate, at least partly, the hemodynamic and neurohumoral effects of chronic ethanol feeding in female rats. Ethanol lowers BP in female rats and this effect was delayed and diminished in OVX rats due possibly to the associated increase in sympathetic activity.

Radiotelemetric evaluation of hemodynamic effects of long-term ethanol in spontaneously hypertensive and Wistar-Kyoto rats.

This study determined the hemodynamic effects of chronic ethanol in telemetered freely moving age-matched spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats. Changes in blood pressure (BP), heart rate (HR), and plasma norepinephrine (as index of sympathetic activity) were evaluated in pair-fed rats receiving liquid diet with or without ethanol (5%, w/v) for 12 weeks. The SHRs exhibited higher baseline BP and lower HR compared with WKY rats. When normalized for body weight, daily ethanol intake was higher in SHRs compared with WKY rats. However, blood ethanol concentration was similar except for a higher level in SHRs at weeks 7 through 9. Ethanol had no effect on BP in WKY rats but caused decreases in BP in SHRs that reached a maximum (approximately 30 mm Hg) at week 5 and remained thereafter. Ethanol also caused reductions in the BP variability and the circadian fluctuations in BP in SHRs but not in WKY rats. Plasma norepinephrine levels were elevated by ethanol in WKY rats, but not in SHRs. The HR was not affected by ethanol in SHRs and showed increases in WKY rats. These findings suggest that chronic ethanol feeding differentially affects BP in SHRs (hypotension) and WKY rats (no effect). The lack of a hypotensive response to ethanol in WKY rats may relate, at least partly, to the associated sympathoexcitation. The present study used the telemetry technique for BP measurement, which eliminates the confounding and stressful effects of other conventional techniques.

Subchronic effects following a single sarin exposure on blood-brain and blood-testes barrier permeability, acetylcholinesterase, and acetylcholine receptors in the central nervous system of rat: a dose-response study.

Subchronic neurotoxic effects of sarin (O-isopropyl methylphosphonofluoridate) treatment at various doses in male Sprague Dawley rats were studied. The animals were treated with a single intramuscular (im) injection of 0.01, 0.1, 0.5, or 1 x LD50 (100 microg/kg). The animals were maintained for 90 d thereafter. [3H]Hexamethonium iodide was used to monitor the changes in blood-brain barrier (BBB) permeability in cortex, brainstem, midbrain, and cerebellum. Brainstem exhibited a significant decrease (approximately 58% of control) in uptake of [3H]hexamethonium iodide at 1 x LD50 dose. No significant changes were observed in BBB permeability in cortex, midbrain, and cerebellum at any dose. Plasma butyrylcholinesterase (BChE) activity remained unchanged, reflecting recovery of the enzyme activity from the initial inhibition following single exposure of 1 x LD50 sarin. Acetylcholinesterase (AChE) activity in the cortex remained inhibited (approximately 29%), whereas in the brainstem there was an increase (approximately 20%) at 1 x LD50 dose of sarin. The m2-selective muscarinic acetylcholine receptor (m2-mAChR) ligand binding was inhibited significantly at 1 x LD50 in the cortex, whereas brainstem showed significantly increased (approximately 45%) ligand binding at 1 x LD50 dose. Nicotinic acetylcholine receptor (nAChR), on the other hand, showed a biphasic response in ligand binding in the cortex with a decrease (approximately 30%) at 0.01 x LD50 but an increase (approximately 40%) at 1 x LD5O. Brainstem did not show any significant change in nAChR ligand binding. These results suggest that single exposure of sarin could lead to changes that may play an important role in neuropathological abnormalities in the central nervous system.

Sexually dimorphic hemodynamic effects of intragastric ethanol in conscious rats.

This study investigated the gender-related differences in hemodynamic effects of small to moderate doses of intragastrically (i.g.) administered ethanol in conscious rats. Changes evoked by ethanol (0.25, 0.5 or 1 g/kg) in mean arterial pressure (MAP), heart rate, cardiac index (CI), stroke volume (SV), and total peripheral resistance (TPR) were followed for 90 min in age-matched male and female Sprague-Dawley rats. Baseline values of MAP (121+/-2 vs. 124+/-2 mm Hg) were similar whereas CI (55+/-2 vs. 43+/-2 ml/min/100 g) and TPR (2.2+/-0.1 vs. 3.0+/-0.1 mm Hg/ml/min/100 g) were significantly (P<0.05) higher and lower, respectively, in female compared with male rats. In male rats, the middle dose (0.5 g/kg) of ethanol caused a slight increase in MAP due to significant (P<0.05) increases in CO whereas the other two doses (0.25 and 1 g/kg) had no effect on MAP. In female rats, MAP was not affected by ethanol (0.25 and 0.5 g/kg) and showed a significant reduction by the higher dose (1 g/kg) that was associated with decreases in CO and SV while TPR did not change. The hypotensive effect of ethanol (1 g/kg) in female rats started after 50 min, was maximal (13+/-1.7 mm Hg) at 70 min and remained so for the remaining 20 min of the study. Blood ethanol concentrations were similar in male and female rats. These findings suggest that the hemodynamic responses to i.g. ethanol are gender-related and that ethanol-evoked hypotension in female rats appears to involve a reduction in cardiac output.