In vivo studies with ICI 154,129, a putative delta receptor antagonist

We studied the in vivo pharmacology of ICI 154,129, a new antagonist that is claimed to show selectivity for delta opiate receptors. At s.c. doses of 30 and 100 mg/kg, ICI 154,129 had no marked effect on the gastrointestinal transit of a charcoal meal in mice. In this test, ICI 154,129 reversed the inhibitory action of metkephamid (a proposed delta receptor agonist) but not that of levorphanol. ICI 154,129 was proconvulsant in the mouse picrotoxin potentiation test; the dose-response curve had a low ceiling and was biphasic. Naloxone (1 mg/kg, s.c.) enhanced the proconvulsant action of ICI 154,129 (40 mg/kg, s.c.) by an unknown mechanism.     

The persistence of DNA damage in the pancreas of Syrian golden hamsters treated with N-nitrosobis(2-oxopropyl)amine

DNA damage was estimated in the liver, pancreas and salivary gland of Syrian hamsters given N-nitrosobis(2-oxopropyl)amine (BOP) by alkaline sucrose gradient centrifugation. A single BOP dose (10 mg/kg) produced in all 3 tissues extensive DNA damage that was largely repaired in the salivary gland by 4 weeks, while in the liver and pancreas, some DNA damage persisted until 4 weeks. When higher BOP doses (20 and 40 mg/kg) were used, considerable DNA damage was still evident in the pancreas, but not in the liver at 6 weeks. Greater damage persisted in hamsters given 40 mg/kg, compared with those administered 20 mg/kg.     

Evaluation of medetomidine/ketamine for short-term immobilization of variable flying foxes (Pteropus hypomelanus)

Four medetomidine/ketamine (M/K) doses (30 microg/kg/3 mg/kg; 40/4; 50/5; 60/6), administered by intramuscular injection, were evaluated for short-term immobilization of adult male variable flying foxes (Pteropus hypomelanus). The highest dose (60 microg/kg/6 mg/kg) produced a significantly faster induction (31 +/- 46 sec) than the lowest dose (30/3) (125 +/- 62 sec). The highest dose levels (50/5, 60/6) produced significantly longer immobilization times (52.5 +/- 25.7 min and 60.6 +/- 20.8 min, respectively) than did the lower doses (30/3, 40/4) (18.8 +/- 8.7 min and 31.0 +/- 14.3 min, respectively). The dose at which 50% of the bats were immobilized for > or = 30 min (ED(50)) was approximately 40 microg/kg/4 mg/kg. This dose produced a mean immobilization time of 31 +/- 14 min, bradypnea and bradycardia. In conclusion, a M/K dose of 50 microg/kg/5 mg/kg is recommended for greater than 30 min of relaxed immobilization in free-living variable flying foxes and is sufficient for safe collection of samples.     

Involvement of nitric oxide (NO) signalling pathway in the antidepressant activity of essential oil of Valeriana wallichii Patchouli alcohol chemotype

Valeriana wallichii DC (Valerianaceae), popularly named as Indian valerian has been shown to exist as three chemotypes. The present study evaluated the antidepressant like effect of root essential oil of Valeriana wallichii patchouli alcohol chemotype in both acute and chronic treatment study using forced swim test (FST). Mice (n = 6 per group) received 10, 20 and 40 mg/kg p.o. doses of test drug. Single administration of oil significantly inhibited the immobility period (57.6% and 46.9%) at doses 20 and 40 mg/kg respectively without changing the motor function (p < 0.05). Similarly, daily administration of essential oil (20 mg/kg) for 14 days significantly reduced the immobility period (69.9%) in FST (p < 0.05). The neurotransmitter levels in mouse brain were estimated on day 14 after the behavioral study. Significant increase in the level of norepinephrine (29%) and serotonin (19%) (p < 0.05) was found at 20 mg/kg dose, while no change was observed at 10 and 40 mg/kg doses. The antidepressant-like effect of essential oil (20 mg/kg) was prevented by pretreatment of mice with l-arginine (750 mg/kg i.p.) and sildenafil (5 mg/kg i.p). On the contrary, pretreatment of mice with l-NAME (10 mg/kg i.p.) or methylene blue (10 mg/kg i.p.) potentiated the antidepressant action of essential oil (10 mg/kg). Taken together, these findings demonstrated that nitric oxide pathway is involved in mediating antidepressant like effect of essential oil from this chemotype.     

Pro-convulsant effect of cefazolin sodium against pentylenetetrazol- or picrotoxin-induced convulsions in mice

Cefazolin injection (3000 mg/kg, i.v.) in mice showed several behavioral excitations such as wild running, jumping, rolling, and finally undergoing severe convulsions followed by death. It's lower doses (500-2000 mg/kg, i.v.) were unable to produce any convulsions or behavioral excitations in mice. However, cefazolin (500 or 1000 mg/kg, i.v.) when administered before different doses of pentylenetetrazol (PTZ; 40 or 60 mg/kg, i.p.) or picrotoxin (PTX; 4 or 8 mg/kg, i.p.), it produced severe tonic-clonic convulsions in mice. The convulsions or behavioral excitations produced by 3000 mg/kg, i.v. cefazolin was also reversed by different doses of diazepam (0.5-2 mg/kg, i.p.) further proving the GABAergic modulatory effect of cefazolin. The results conclude the pro-convulsant action of cefazolin on PTZ- or PTX-induced convulsions, and further confirm the clinical reports.     

Metkephamid (Tyr-D-Ala-Gly-Phe-N(Me)Met-NH2), a potent opioid peptide: Receptor binding and analgesic properties

The interaction of metkephamid (Tyr-D-Ala-Gly-Phe-N(Me)Met-NH₂) with ³H-dihydromorphine and ³H-D-Ala²-D-Leu⁵-enkephalin binding has been examined in rat brain homogenates. Displacements of both ³H-ligands by metkephamid indicate that metkephamid interacts competitively with greatest potency to the high affinity binding component for both ligands (mu₁ site). Unlike most enkephalins and opiates, metkephamid binds equipotently to both morphine-selective (mu₂) and enkephalin-selective (delta) binding sites. Metkephamid is differentiated from morphine by its better than 12-fold higher affinity for the delta receptor. Blockade of the high affinity (mu₁) binding in vivo with high doses of naloxazone dramatically reduces metkephamid's analgesic potency.     

Anthelmintic Activity In Vivo of Epiisopiloturine against Juvenile and Adult Worms of Schistosoma mansoni

Schistosomiasis is a serious disease currently estimated to affect more that 207 million people worldwide. Due to the intensive use of praziquantel, there is increasing concern about the development of drug-resistant strains. Therefore, it is necessary to search for and investigate new potential schistosomicidal compounds. This work reports the in vivo effect of the alkaloid epiisopiloturine (EPI) against adults and juvenile worms of Schistosoma mansoni. EPI was first purified its thermal behavior and theoretical solubility parameters charaterised. In the experiment, mice were treated with EPI over the 21 days post-infection with the doses of 40 and 200 mg/kg, and 45 days post-infection with single doses of 40, 100 and 300 mg/kg. The treatment with EPI at 40 mg/kg was more effective in adult worms when compared with doses of 100 and 300 mg/kg. The treatment with 40 mg/kg in adult worms reduced parasite burden significantly, lead to reduction in hepatosplenomegaly, reduced the egg burden in faeces, and decreased granuloma diameter. Scanning electron microscopy revealed morphological changes to the parasite tegument after treatment, including the loss of important features. Additionally, the in vivo treatment against juvenile with 40 mg/kg showed a reduction of the total worm burden of 50.2%. Histopathological studies were performed on liver, spleen, lung, kidney and brain and EPI was shown to have a DL50 of 8000 mg/kg. Therefore EPI shows potential to be used in schistosomiasis treatment. This is the first time that schistosomicidal in vivo activity of EPI has been reported.     

Schistosoma mansoni: Astiban-induced damage to tegument and the male reproductive system

Astiban produced structural damage in male Schistosoma mansoni (Puerto Rican strain) in mice. The degree of disorganization was directly related to the dosage administered, although initial changes in structure for the first three doses (3 × 30–40 mg/kg) varied between individual worms of the same infection. More consistent damage to the tegument, parenchyma, and reproductive organs occurred after 6 × 40 mg/kg of Astiban injections. Exposure of the subtegumentary musculature preceded appearance of an increased number of noncytoplasmic spaces in various tissues, probably a result of osmotic stress. Testicular disorganization was prominent initially in spermatozoa and spermatids, but became more generalized with drug accumulation. The sustentacular cells showed increased phagocytic activity with testicular damage. Continuous administration of drug resulted in a general distortion of the worm's morphology. However, partial recovery occurred within 22 days following cessation of drug administration.     

Cardiovascular and behavioral responses of gray wolves to ketamine-xylazine immobilization and antagonism by yohimbine

Adult wolves (Canis lupus) were immobilized with 6.6 mg/kg ketamine hydrochloride (KET) and 2.2 mg/kg xylazine hydrochloride (XYL) administered intramuscularly. Induction time was 4.6 +/- 0.3 min (mean +/- SE). Immobilization resulted in significant bradycardia and hypertension (P less than 0.05). Twenty min after induction, the wolves were given 0.05-0.60 mg/kg yohimbine hydrochloride (YOH). Yohimbine given intravenously produced dose-related increases in heart rate (HR) with doses greater than 0.15 mg/kg resulting in extreme tachycardia (greater than 300 bpm). All doses of YOH caused a temporary decrease in mean arterial blood pressure (MABP) with some individual animals manifesting profound hypotension (less than 30 torr) at doses greater than 0.15 mg/kg. Increasing the dose of YOH above 0.15 mg/kg did not significantly decrease either arousal or ambulation times. Administering YOH at 40 or 60 min after induction resulted in decreased arousal and ambulation times. Stimulation by weighing and taking repeated blood samples during anesthesia did not shorten arousal times. We recommend that wolves immobilized with XYL-KET be antagonized with doses of YOH less than 0.15 mg/kg.     

Applications of the hexanic fraction of Agave sisalana Perrine ex Engelm (Asparagaceae): control of inflammation and pain screening

The present study evaluated the anti-inflammatory and analgesic properties of Agave sisalana Perrine in classic models of inflammation and pain. The hexanic fraction of A. sisalana (HFAS) was obtained by acid hydrolysis followed by hexanic reflux. Anti-inflammatory properties were examined in three acute mouse models (xylene ear oedema, hind paw oedema and pleurisy) and a chronic mouse model (granuloma cotton pellet). The antinociceptive potential was evaluated in chemical (acetic-acid) and thermal (tail-flick and hot-plate test) models of pain. When given orally, HFAS (5, 10, 25 and 50 mg/kg) reduced ear oedema (p < 0.0001; 52%, 71%, 62% and 42%, respectively). HFAS also reduced hind paw oedema at doses of 10 mg/kg and 25 mg/kg (p < 0.05; 42% and 58%, respectively) and pleurisy at doses of 10 mg/kg and 25 mg/kg (41% and 50%, respectively). In a chronic model, HFAS reduced inflammation by 46% and 58% at doses of 10 mg/kg and 25 mg/kg, respectively. Moreover, this fraction showed analgesic properties against the abdominal writhing in an acetic acid model (at doses of 5-25 mg/kg) with inhibitory rates of 24%, 54% and 48%. The HFAS also showed an increased latency time in the hot-plate (23% and 28%) and tail-flick tests (61% and 66%) for the 25 mg/kg and 50 mg/kg doses, respectively. These results suggest that HFAS has anti-inflammatory and analgesic properties.     

Participation of the components of L-arginine/nitric oxide/cGMP cascade by chemically-induced abdominal constriction in the mouse

The purpose of this study was to investigate the role of the L-arginine/nitric oxide (NO)/cGMP pathway in p-benzoquinone-induced writhing model in mouse. L-arginine, a NO precursor, displayed antinociceptive effects at the doses of 0.125-1.0 mg/kg. When the doses of L-arginine were increased gradually to 10-100 mg/kg, a dose-dependent triphasic pattern of nociception-antinociception-nociception was obtained. The NO synthase (NOS) inhibitor, NG-nitro-L-arginine methyl ester (L-NAME) (18.7515 mg/kg), possessed antinociceptive activity. Methylene blue (MB), a guanylyl cyclase and/or NOS inhibitor, (5-160 mg/kg) also produced a dose-dependent triphasic response. When L-arginine (50 mg/ kg) was combined with L-NAME (75 mg/kg). L-arginine-induced antinociception did not change significantly. Cotreatment of L-arginine with 5 mg/kg MB significantly decreased MB-induced antinociception and reversed the nociception induced by 40 mg/kg MB to antinociception. It is concluded that the components of L-arginine/nitric oxide/cGMP cascade may participate in nociceptive processes both peripherally and centrally by a direct effect on nociceptors or by the involvement of other related pathways of nociceptive processes induced by NO.     

Prolactin secretion in cattle as affected by haloperidol and α-Methyl-p-Tyrosine

Prolactin (PRL) secretion in response to i.v. injection of different doses of α-Methyl-p-Tyrosine (αMT) and haloperidol (HAL) was studied in one cow and three bulls. HAL was tested at doses of 0.033, 0.1, and 0.33 mg/kg body weight (BW), and αMT was tested at doses of 0.1, 1.0, 10, and 30 mg/kg BW. Blood was collected via an indwelling catheter into the external jugular vein, and plasma PRL was analysed by radioimmunoassay. Dose-related increases in plasma PRL concentrations were observed after administration of both αMT and HAL. Peak PRL concentrations after injection of HAL at a low, medium, and high dose were 22, 45, and 70 ng/ml, respectively. Peak PRL concentrations after injection of increasing doses of αMT were 3.0, 10, 40 and 70 ng/ml. HAL (0.1 mg/kg BW) and αMT (10 mg/kg BW) were administered intravenously to four heifers during summer and winter. Response to both drugs, as measured by changes in PRL secretion, was greater in summer than winter. Peak plasma PRL levels after HAL injection were 327 ± 58 ng/ml in June and 149 ± 27 ng/ml in January, whereas peak levels after αMT were 166±29 and 60±9 ng/ml, respectively. Basal PRL secretion was also greater in summer than winter. The results of this study demonstrate that PRL in peripheral plasma of cattle is increased in response to administration of antidopaminergic drugs and that this increase is greater during the summer than the winter.     

Ketamine prevents seizures and reverses changes in muscarinic receptor induced by bicuculline in rats

The cholinergic system has been implicated in several experimental epilepsy models. In a previous study bicuculline (BIC), known to antagonize GABA-A postsynaptic receptor subtype, was administered to rats at subconvulsant (1 mg/kg) and convulsant (7.5 mg/kg) doses and quinuclidinyl benzilate ([³H]-QNB) binding to CNS membranes was determined. It was observed that ligand binding to cerebellum increases while it decreases in the case of hippocampus. Saturation binding curves showed that changes were due to the modification of receptor affinity for the ligand without alteration of binding site number. The purpose of this study was to assay muscarinic receptors employing other BIC dose (5 mg/kg), which induces seizures and allows the analysis of a postseizure stage as well. To study further muscarinic receptor involvement in BIC induced seizures, KET was also employed since it is a well known anticonvulsant in some experimental models. The administration of BIC at 5 mg/kg to rats produced a similar pattern of changes in [³H]-QNB binding to those recorded with 1.0 and 7.5 mg/kg doses. Here again, changes were observed in receptor binding affinity without alteration in binding site number for cerebellum or hippocampus membranes. Pretreatment with KET (40 mg/kg) prevented BIC seizures and reverted [³H]-QNB binding changes induced by BIC administration. The single administration of KET invariably resulted in [³H]-QNB binding decrease to either cerebellar or hippocampal membranes. KET added in vitro decreased ligand binding likewise. Results of combined treatment with KET plus BIC are hardly attributable to the single reversion of BIC effect since KET alone invariably decreased ligand binding. It is suggested that besides alteration of cholinergic muscarinic receptor other(s) neurotransmitter system(s) may well also be involved.     

Chemotherapy of rodent malaria: transfer of resistance vs mutation

Pyrimethamine-resistant strains of Plasmodium berghei and P. vinckei were produced by exposing populations of erythrocytic parasites to the selection pressure of increasing doses of drug as well as by single-step mutations. Pyrimethamine-sensitive parasites of both rodent plasmodia were found to mutate at a rate of 1–2 × 10^?11 when exposed to a single course of drug therapy, consisting of 15 mg/kg/day for 4 consecutive days, given subcutaneously. Resistance obtained by either method, was found to be stabile for at least 40 passages in the absence of drug pressure, the longest number of passages tested. Parasites exposed to 15 mg/ kg/day were also found to be resistant to 160 mg/kg/day, the maximum dose of pyrimethamine tolerated by the rodent host.Plasmodium berghei chloroquine-sensitive parasites were found to have a mutation rate of 1.5 × 10^?10, when exposed to a single course of chloroquine therapy, consisting of 30 mg/kg/day chloroquine base given for 4 consecutive days, subcutaneously. These parasites were also found to be resistant to 60 mg/kg/day the highest dose of chloroquine tolerated by the rodent host. Chloroquine-resistant strains of P. vinckei could not be developed by a single-step mutation nor by selection by slow increases in drug pressure.Pyrimethamine-resistant strains of P. berghei, whether, the resistance was developed by single-step mutation, or by slowly increasing the pyrimethamine doses over extended periods of time, demonstrated dihydrofolate reductases which were similar in activity, Michaelis constants, and inability to be stimulated by increased concentrations of KCl. The same was found to be true for the dihydrofolate reductases (EC 1.5.1.3) isolated from pyrimethamine-resistant P. vinckei strains. The enzymes isolated from the resistant strains differed in all respects from their sensitive counterparts.Attempts at drug resistance-transfer, using both a biological filter system, and a dual drug resistant system, were both unsuccessful. The origin of all drug resistant strains studied and reported in this paper, can best be explained by the occurrence of mutation, most probably involving the change of a single nucleotide base in the DNA.     

Efficacy of Praziquantel against Schistosoma mekongi and Opisthorchis viverrini: A Randomized, Single-Blinded Dose-Comparison Trial

Background

Schistosomiasis and opisthorchiasis are of public health importance in Southeast Asia. Praziquantel (PZQ) is the drug of choice for morbidity control but few dose comparisons have been made.

Methodology

Ninety-three schoolchildren were enrolled in an area of Lao PDR where Schistosoma mekongi and Opisthorchis viverrini coexist for a PZQ dose-comparison trial. Prevalence and intensity of infections were determined by a rigorous diagnostic effort (3 stool specimens, each examined with triplicate Kato-Katz) before and 28–30 days after treatment. Ninety children with full baseline data were randomized to receive PZQ: the 40 mg/kg standard single dose (n = 45) or a 75 mg/kg total dose (50 mg/kg+25 mg/kg, 4 hours apart; n = 45). Adverse events were assessed at 3 and 24 hours posttreatment.

Principal Findings

Baseline infection prevalence of S. mekongi and O. viverrini were 87.8% and 98.9%, respectively. S. mekongi cure rates were 75.0% (95% confidence interval (CI): 56.6–88.5%) and 80.8% (95% CI: 60.6–93.4%) for 40 mg/kg and 75 mg/kg PZQ, respectively (P = 0.60). O. viverrini cure rates were significantly different at 71.4% (95% CI: 53.4–84.4%) and 96.6% (95% CI: not defined), respectively (P = 0.009). Egg reduction rates (ERRs) against O. viverrini were very high for both doses (>99%), but slightly lower for S. mekongi at 40 mg/kg (96.4% vs. 98.1%) and not influenced by increasing diagnostic effort. O. viverrini cure rates would have been overestimated and no statistical difference between doses found if efficacy was based on a minimum sampling effort (single Kato-Katz before and after treatment). Adverse events were common (96%), mainly mild with no significant differences between the two treatment groups.

Conclusions/Significance

Cure rate from the 75 mg/kg PZQ dose was more efficacious than 40 mg/kg against O. viverrini but not against S. mekongi infections, while ERRs were similar for both doses.

Trial Registration

Controlled-Trials.com ISRCTN57714676     

Discriminative stimulus,antagonist, and rate-decreasing effects of cyclorphan: Multiple modes of action

The discriminative effects of cyclorphan were studied in pigeons trained to discriminate 0.32 mg/kg ethylketazocine, 1.8 mg/kg cyclazocine, or 32 mg/kg naltrexone from saline. A fourth group of pigeons was administered 100 mg/kg/day morphine and trained to discriminate 0.1 mg/kg naltrexone from saline. Cyclorphan produced dose-related ethylketazocine-appropriate responding that reached a maximum of 83% of the total session responses at 0.3 mg/kg. Higher cyclorphan doses produced less ethylketazocine-appropriate responding. In pigeons trained to discriminate cyclazocine from saline, maximum drug-appropriate responding of greater than 90% occured at 5.6–10.0 mg/kg cyclorphan. In narcotic-naive pigeons trained to discriminate 32 mg/kg naltrexone from saline, cyclorphan produced a maximum of less than 50% drug-appropriate responding. In contrast, in pigeons chronically administered morphine and trained to discriminate 0.1 mg/kg naltrexone from saline, 1.0 mg/kg cyclorphan resulted in 100% drug-appropriate responding. In pigeons responding under a multiple fixed-interval, fixed-ratio schedule of food delivery, cyclorphan produced a complete dose-related reversal of the rate-decreasing effects of 10 mg/kg morphine, the maximally effective antagonist doses being 1.0–3.2 mg/kg. Higher cyclorphan doses (10 mg/kg) resulted in response rate decreases that were not reversed by naloxone (1 mg/kg). Thus, cyclorphan has discriminative effects that are similar to those of both ethylketazocine and, at 20-fold higher doses, cyclazocine. In addition, in morphine-treated pigeons, cyclorphan, across the same range of doses that produce ethylketazocine-appropriate responding, has discriminative effects that are similar to those of naltrexone, an effect that is probably related to the antagonist action of the drug.     

Thermoregulatory, motor, behavioural, and nociceptive responses of rats to 3 long-acting neuroleptics

We investigated physiological effects of intramuscular injections of the following 3 long-acting neuroleptics commonly used in wildlife management: haloperidol (0.05, 0.1, and 0.5 mg/kg body mass), zuclopenthixol acetate (0.5, 1, and 5 mg/kg), and perphenazine enanthate (1, 3, and 10 mg/kg), in a rat model. Body temperature and cage activity were measured by intra-abdominal telemeters. Nociceptive responses were assessed by challenges to noxious heat and pressure. Haloperidol (0.5 mg/kg) produced a significant nocturnal hypothermia (p < 0.05) and decreased nighttime cage activity and food intake. Zuclopenthixol (5 mg/kg) significantly decreased nighttime body temperature and cage activity and, at 1 mg/kg and 5 mg/kg, significantly decreased food intake 5-17 h after injection (p < 0.05). Perphenazine (10 mg/kg) significantly decreased nighttime body temperature and cage activity and, at all doses, significantly decreased food intake 5-17 h after injection (p < 0.05). Significant analgesic activity was evident in rats given 5 mg/kg zuclopenthixol up to 40 h after injection, and 10 mg/kg perphenazine from 48 to 96 h after injection (p < 0.0001). Zuclopenthixol (5 mg/kg) and perphenazine (10 mg/kg) had significant antihyperalgesic activities at 16 h postinjection and 24-48 h postinjection, respectively (p < 0.0001). Haloperidol had no significant antinociceptive activity at doses tested. Motor function was impaired in rats given 0.5 mg/kg haloperidol, 5 mg/kg zuclopenthixol and 10 mg/kg perphenazine. Effects of long-acting neuroleptics on body temperature, feeding, and activity were short-lasted and should not preclude their use in wildlife. Antinociceptive actions were longer-lasting, but were nonspecific, and we recommend additional analgesics for painful procedures during wildlife management.     

Naloxone antagonism of diazepam-induced feeding in the Syrian hamster

Three experiments investigated the effects of the intragastric administration of the benzodiazepine diazepam on feeding in non-deprived Syrian hamsters ($\text{mesocricetus auratus}$). In the first experiment diazepam (0, 0.5, 1.0, 2.0, and 4.0 mg/kg) produced dose dependant increases in feeding. 4.0 mg/kg of diazepam produced significantly more feeding than the other doses tested and the lowest dose tested (0.5 mg/kg) produced a significant increase in feeding. In the second experiment naloxone (10 mg/kg) partially antagonized the effect of 4 mg/kg of diazepam on feeding. In the third experiment the ability of naloxone (0.1, 1.0, 5.0, 10.0 or 20 mg/kg) to reduce feeding produced by either 4 mg/kg or 2 mg/kg of diazepam was tested. Naloxone partially antagonized the effects of 4 mg/kg of diazepam on feeding in a dose dependant manner. While 2 mg/kg of diazepam produced significantly less feeding than 4 mg/kg, naloxone did not antagonize the effect of 2 mg/kg on feeding. The results suggest that two mechanisms are involved in diazepam-induced feeding in hamsters. The high dose of diazepam may produce increased feeding by activating the endorphin system while the low dose of diazepam produces increased feeding via a naloxone insensitive mechanism.     

Betaine (N,N,N-trimethylglycine) averts photochemically-induced thrombosis in pial microvessels in?vivo and platelet aggregation in?vitro

Betaine (N,N,N-trimethylglycine) is an important food component with established health benefits through its homocysteine-lowering effects, and is used to lower total homocysteine concentration in plasma of patients with homocystinuria. It is well established that hyperhomocysteinemia is an established risk factor for cardiovascular disease and stroke. However, the possible protective effect of betaine on coagulation events in vivo and in vitro has thus far not been studied. Betaine was given to mice at oral doses of either 10 mg/kg (n = 6) or 40 mg/kg (n = 6) for seven consecutive days, and control mice (n = 6) received water only. The thrombotic occlusion time in photochemically induced thrombosis in pial arterioles was significantly delayed in mice pretreated with betaine at doses of 10 mg/kg (P < 0.001) and 40 mg/kg (P < 0.01). Similar effects were observed in pial venules with 10 mg/kg (P < 0.05) and 40 mg/kg (P < 0.05) betaine. In vitro, in whole blood samples collected from untreated mice (n = 3–5), betaine (0.01–1 mg/mL) significantly reversed platelet aggregation induced by adenosine diphosphate (5 µM). The number of circulating platelets and plasma concentration of fibrinogen in vivo were not significantly affected by betaine pretreament compared with the control group. Lipid peroxidation (LPO) in mice pretreated with betaine was significantly reduced compared with the control group. Moreover, betaine (0.01–1 mg/mL) caused a dose-dependent and significant prolongation of PT (n = 5) and aPTT (n = 4–6). In conclusion, our data show that betaine protected against coagulation events in vivo and in vitro and decreased LPO in plasma.     

Acute toxicity of combinations of sodium dichromate, sodium arsenate and copper sulphate in the rat

1. The intraperitoneal treatment of adult male Wistar rats with various combinations of low doses of sodium dichromate (5 mg/kg), sodium arsenate (25 mg/kg) and copper sulphate (5.9 mg/kg) tended to counteract the inherent acute toxicity of each compound. 2. The co-administration of low doses of one or more of the test compounds with a high dose of sodium dichromate (35 mg/kg), sodium arsenate (90 mg/kg) or copper sulphate (23.5 mg/kg) resulted in a significant increase in acute toxicity in comparison with that produced by the administration of high doses of dichromate, arsenate or Cu2+ alone.