Biomedical subjects

R K Razdan

Publications and source records attributed to R K Razdan.

At least 19 recordsLinked to original sources

PubMed2006

Bioefficacy of Olyset nets against mosquitoes in India.

Olyset nets are highly effective in killing anopheline mosquitoes within 3 min of exposure, as evidenced in cone bioassay tests. These nets also showed their efficacy on other vector mosquitoes (Aedes aegypti and Cx. quinquefasciatus) at higher exposure periods. The efficacy remained at approximately 90% even after 20 washings at an interval of 24 h against Anopheles culicifacies and Cx. quinquefasciatus. Use of the nets inside the house also resulted in drastic reduction of daytime resting density of mosquitoes because of high repellency, excitorepellency, and killing action of the nets. Pilot studies are indicated to evaluate the impact of use of Olyset nets on vector-borne diseases, particularly malaria, and its cost-effectiveness in comparison to conventional indoor residual spraying.

Aedes↗

PubMed2005

Laboratory and field evaluation of Hilmilin against mosquitoes.

Hilmilin (diflubenzuron), an insect growth regulator, was tested for efficacy against Anopheles stephensi, Anopheles culicifacies, Aedes aegypti, and Culex quinquefasciatus in the laboratory and in field conditions. Fifty percent and 90% lethal concentrations (LC50 and LC90) of Hilmilin formulations were determined by exposing early 4th-stage larvae to serial dilutions of the formulation, and data were subjected to log probit analysis. Two doses (0.004 and 0.008 g/m2) were applied in different breeding habitats of mosquitoes with the help of stirrup pumps. Percent inhibition of adult emergence was compared according to a previously described procedure. Laboratory results revealed that both 25WP (wettable powder) and 22SL (semiliquid) formulations showed more or less the same degree of efficacy against tested mosquito species (P < 0.05). Of 4 species tested, An. stephensi was more susceptible, followed by An. culicifacies, Ae. aegypti, and Cx. quinquefasciatus. One hundred percent inhibition of adult emergence was observed at a dose of 0.0125 ppm (25WP and 22SL) against all mosquitoes tested in the laboratory. Both formulations showed almost similar effect when applied in the field at doses of 0.004 and 0.008 g/m2 in their respective preferential breeding habitats. However, the effect was more pronounced at a higher concentration (0.008 g/m2) against all species of mosquitoes. Hilmilin at a dose of 0.008 g/m2 can be used to contain mosquito breeding in stone quarries, pools, cement tanks, unused wells, unused coolers, and irrigation channels.

Aedes↗

PubMed2005

Larvicidal and mosquito repellent activities of Pine (Pinus longifolia, family: Pinaceae) oil.

BACKGROUND AND OBJECTIVES: Various plant-based products are safe and biodegradable alternatives to synthetic chemicals for use against mosquitoes. Oil of Pinus longifolia is traditionally used for protection against mosquitoes in some rural areas but there is no documented report of its use against mosquitoes. The present study was undertaken to scientifically evaluate the activity of Pine oil against mosquitoes. METHODS: The oil was procured from the market and its contents were chemically analysed. Larvicidal activity of oil was tested in laboratory bioassays, while repellent action was studied during whole night bait collections in field by direct application on the skin and after its impregnation on mats. RESULTS: Results showed varying degree of larvicidal activity of Pine oil against mosquitoes with LC50 values ranging between 82 and 112 ppm. The Pine oil had strong repellent action against mosquitoes as it provided 100% protection against Anopheles culicifacies for 11 h and 97% protection against Culex quinquefasciatus for nine hours respectively. Electrically heated mats prepared from Pine oil provided, 94 and 88% protection against An. culicifacies and Cx. quinquefasciatus for 10 and seven hours respectively. INTERPRETAION AND CONCLUSION: Pine oil is effective against mosquito larvae at very higher doses which are not of any practical utility. However, Pine oil showed strong repellent action against An. culicifacies (malaria vector) and Cx. quinquefasciatus (pest mosquito). Thus its use could be popularised as mosquito repellent.

Animals↗

PubMed2002

Recent advances in the synthesis of endocannabinoid related ligands.

The chemical strategies used for the synthesis of various ligands related to the endocannabinoid system namely anandamide (AEA), 2-arachidonylglycerol (2-Ara-Gl), CB1/(vanilloid receptors) VR1, anandamide membrane transporter (AMT) and fatty acid amide hydrolase (FAAH) are described in this review. In general, the chemical synthesis of analogs with changes in the head group of AEA was quite straightforward involving the conversion of an acid to an amide or an ester. Analogs which had modifications in the end pentyl chain were more difficult to synthesize and required multistep synthetic sequences to prepare the target compounds. A facile total synthesis of 2-Ara-Gl was reported and an HPLC procedure for its identification and quantification was developed, but because of the instability of 2-Ara-Gl another synthesis was developed so that it can be stored as the more stable phenylboronate ester. Similarly the chemical synthesis of various ligands in the remaining areas of CB1/VR1, AMT and FAAH are described. A summary of the present state of knowledge about the SAR in each area is presented to help in the design and synthesis of novel ligands for the future.

Amidohydrolases↗

PubMed2001

Highly selective CB(1) cannabinoid receptor ligands and novel CB(1)/VR(1) vanilloid receptor "hybrid" ligands.

Anandamide and the metabolically stabler analogs, (R)-1'-methyl-2'-hydroxy-ethyl-arachidonamide (Met-AEA) and N-(3-methoxy-4-hydroxy-benzyl)-arachidonamide (arvanil), are CB(1) cannabinoid and VR(1) vanilloid receptors agonists. We synthesized 1',1'-dimethylheptyl-arvanil (O-1839) and six other AEA analogs obtained by addition of either a hydroxy, cyano, or bromo group on the C-20 atom of 1,1'-dimethylpentyl-Met-AEA (O-1811, O-1812 and O-1860, respectively) or 1,1'-dimethylpentyl-arvanil (O-1856, O-1895 and O-1861, respectively). The compounds were tested for their (i) affinity for CB(1) and CB(2) receptors, (ii) capability to activate VR1 receptors, (iii) inhibitory effect on the anandamide hydrolysis and on the anandamide membrane transporter, and (iv) cannabimimetic activity in the mouse 'tetrad' of in vivo assays. O-1812 is the first ligand ever proven to be highly (500- to 1000-fold) selective for CB(1) vs both VR(1) and CB(2) receptors, while O-1861 is the first true "hybrid" agonist of CB(1)/VR(1) receptors and a compound with potential therapeutic importance. The activities of the seven compounds in vivo did not correlate with their activities at either CB(1) or VR(1) receptors, thus suggesting the existence of other brain sites of action mediating some of their neurobehavioral actions in mice.

Animals↗

PubMed2001

Separation of cannabinoid receptor affinity and efficacy in delta-8-tetrahydrocannabinol side-chain analogues.

1. The activities of a number of side-chain analogues of delta-8-tetrahydrocannabinol (Delta(8)-THC) in rat cerebellar membrane preparations were tested. 2. The affinities of each compound for the CB(1) receptor were compared by their respective abilities to displace [(3)H]-SR141716A and their efficacies compared by stimulation of [(35)S]-GTPgammaS binding. 3. It was found that the affinities varied from 0.19+/-0.03 nM for 3-norpentyl-3-[6'-cyano,1',1'-dimethyl]hexyl-Delta(8)-THC to 395+/-66.3 nM for 5'-[N-(4-chlorophenyl)]-1',1'-dimethyl-carboxamido-Delta(8)-THC. 4. The efficacies of these compounds varied greatly, ranging from the very low efficacy exhibited to acetylenic compounds such as 1'-heptyn-Delta(8)-THC and 4'-octyn-Delta(8)-THC to higher efficacy compounds such as 5'-(4-cyanophenoxy)-1',1'-dimethyl-Delta(8)-THC and 5'-[N-(4-aminosulphonylphenyl)]-1',1' dimethyl-carboxamido Delta(8)-THC. All agonist activities were antagonized by the CB(1)-selective antagonist SR141716A. 5. It was found that a ligand's CB(1) affinity and efficacy are differentially altered by modifications in the side-chain. Decreasing the flexibility of the side-chain reduced efficacy but largely did not alter affinity. Additionally, the positioning of electrostatic moieties, such as cyano groups, within the side-chain also has contrasting effects on these two properties. 6. In summary, this report details the characterization of a number of novel Delta(8)-THC analogues in rat cerebellar membranes. It provides the first detailed pharmacological analysis of how the inclusion of electrostatic moieties in the side-chain and also how alteration of the side-chain's flexibility may differentially affect a CB(1) cannabinoid receptor ligand's affinity and efficacy.

Animals↗

PubMed2001

Novel pyrazole cannabinoids: insights into CB(1) receptor recognition and activation.

Synthesis of an antagonist, SR141716A, that selectively binds to brain cannabinoid (CB(1)) receptors without producing cannabimimetic activity in vivo, suggests that recognition and activation of cannabinoid receptors are separable events. In the present study, a series of SR141716A analogs were synthesized and were tested for CB(1) binding affinity and in a battery of in vivo tests, including hypomobility, antinociception, and hypothermia in mice. These analogs retained the central pyrazole structure of SR141716A with replacement of the 1-, 3-, 4-, and/or 5-substituents by alkyl side chains or other substituents known to impart potent agonist activity in traditional tricyclic cannabinoid compounds. Although none of the analogs alone produced the profile of cannabimimetic effects seen with full agonists, several of the 3-substituent analogs with higher binding affinities showed partial agonism for one or more measures. Cannabimimetic activity was most noted when the 3-substituent of SR141716A was replaced with an alkyl amide or ketone group. None of the 3-substituted analogs produced antagonist effects when tested in combination with 3 mg/kg Delta(9)-tetrahydrocannabinol (Delta(9)-THC). In contrast, antagonism of Delta(9)-THC's effects without accompanying agonist or partial agonist effects was observed with substitutions at positions 1, 4, and 5. These results suggest that the structural properties of 1- and 5-substituents are primarily responsible for the antagonist activity of SR141716A.

Analgesics, Non-Narcotic↗

PubMed2001

Concurrent control of mosquitoes and domestic pests by use of deltamethrin-treated curtains in the New Delhi Municipal Committee, India.

A field trial was conducted in Block F of the Moti Bagh area of New Delhi Municipal Committee to demonstrate composite control of Anopheles stephensi and Aedes aegypti by spraying deltamethrin at 100 mg/m2 on window and door curtains of habitations. Results revealed drastic reduction (87.9-93.7%, P < 0.05) of target species in the experimental area. The impact of deltamethrin-treated curtains was also evident against nontarget species (67.9-85.7%. P < 0.05). Treated curtains provided 100% kill of An. stephensi and Ae. aegypti for 3-4 months, followed by a gradual decline in successive months. Use of deltamethrin-treated curtains resulted in 92.0 reduction in slide positivity rate and 95.4% reduction in malaria cases per thousand population. The cost of deltamethrin treatment was Rs 41.15 (<$1 U.S.) per house per annum. Insecticide-treated mosquito window and door curtains, along with legislative measures, may provide cost-effective concurrent control of mosquitoes and other domestic pests.

Aedes↗

PubMed2000

Neurobehavioral activity in mice of N-vanillyl-arachidonyl-amide.

We studied the cannabimimetic properties of N-vanillyl-arachidonoyl-amide (arvanil), a potential agonist of cannabinoid CB(1) and capsaicin VR(1) receptors, and an inhibitor of the facilitated transport of the endocannabinoid anandamide. Arvanil and anandamide exhibited similar affinities for the cannabinoid CB(1) receptor, but arvanil was less efficacious in inducing cannabinoid CB(1) receptor-mediated GTPgammaS binding. The K(i) of arvanil for the vanilloid VR(1) receptor was 0.28 microM. Administered i.v. to mice, arvanil was 100 times more potent than anandamide in producing hypothermia, analgesia, catalepsy and inhibiting spontaneous activity. These effects were not attenuated by the cannabinoid CB(1) receptor antagonist N-(piperidin-1-yl)-5-(4-chloro-phenyl)-1-(2, 4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide.HCl (SR141716A). Arvanil (i.t. administration) induced analgesia in the tail-flick test that was not blocked by either SR141716A or the vanilloid VR(1) antagonist capsazepine. Conversely, capsaicin was less potent as an analgesic (ED(50) 180 ng/mouse, i.t.) and its effects attenuated by capsazepine. The analgesic effect of anandamide (i.t.) was also unaffected by SR141716A but was 750-fold less potent (ED(50) 20.5 microg/mouse) than capsaicin. These data indicate that the neurobehavioral effects exerted by arvanil are not due to activation of cannabinoid CB(1) or vanilloid VR(1) receptors.

Analgesics↗

PubMed2000

Novel cannabinol probes for CB1 and CB2 cannabinoid receptors.

The observation that the phenolic hydroxyl of THCs was important for binding to the CB1 receptor but not as critical for binding to the CB2 receptor prompted us to extend this finding to the cannabinol (CBN) series. To study the SAR of CBN analogues, CBN derivatives with substitution at the C-1, C-3, and C-9 positions were chosen since these positions have played a key role in the SAR of THCs. CBN-3-(1',1'-dimethylheptyl) analogues were prepared by sulfur dehydrogenation of Delta(8)-THC-3-(1',1'-dimethylheptyl) analogues. 9-Substituted CBN analogues were prepared by the standard sulfur dehydrogenation of 9-substituted Delta(8)-THC analogues (Scheme 1), which in turn were prepared following our previous procedure using selenium dioxide oxidation of the corresponding Delta(8)-THCs followed by sodium chlorite oxidation to give the 9-carboxy-Delta(8)-THC derivatives. 11-Hydroxy-CBN analogues were prepared from the corresponding 9-carbomethoxy-CBN analogues by reduction with LiAlH(4). Deoxy-CBN analogue 14 was prepared from the corresponding Delta(8)-THC analogue 11 by conversion of the phenolic hydroxyl to the phosphate derivative 12, followed by lithium ammonia reduction to provide the deoxy-Delta(8)-THC analogue 13, which in turn was dehydrogenated with sulfur to provide the deoxy-CBN analogue 14 (Scheme 2). The various analogues were assayed for binding both to the brain and the peripheral cannabinoid receptors (CB1 and CB2). We have found that the binding profile differs widely between the CBN and the THC series. Specifically, in the CBN series the removal of the phenolic hydroxyl decreases binding affinity to both the CB1 and CB2 receptors, whereas in the THC series, CB1 affinity is selectively reduced. Thus, in the CBN series, the selectivity of binding observed with the removal of the hydroxy group is decreased severalfold as compared to what occurs in the THC series. Generally, high affinity for the CB2 receptor was found in analogues when the phenolic hydroxyl was present. The 3-(1', 1'-dimethylheptyl) derivatives were found to have much higher affinities than the CBN analogues, which is in complete agreement with previously reported work by Rhee et al.

Animals↗

PubMed2000

Pharmacological evaluation of aerosolized cannabinoids in mice.

The reemergence on the debate of the use of marijuana for medicinal purposes has been the impetus for developing an acceptable delivery form of aerosolized cannabinoids. The goals of the present study were to: (1) develop and characterize the physical properties of an aerosolized form of Delta(9)-tetrahydrocannabinol (Delta(9)-THC), the major psychoactive constituent present in marijuana; and (2) assess the pharmacological effects of cannabinoid inhalation in mice. A Small Particle Aerosol Generator (SPAG) nebulizer, used to generate the aerosol, had an output of approximately 0.154 mg/l of aerosolized Delta(9)-THC with a 2.0 microm mass median aerodynamic diameter and a 2.2 geometric standard deviation (GSD). Virtually all the particles were less than 5.0 microm in diameter suggesting that they were sufficiently small to penetrate deeply into the lungs. Inhalation exposure to aerosolized Delta(9)-THC in mice elicited antinociceptive effects that were dependent on concentration and exposure time with an estimated Delta(9)-THC dose of 1.8 mg/kg. On the other hand, inhalation exposure to Delta(9)-THC failed to produce two other indices indicative of cannabinoid activity, hypothermia and decreases in spontaneous locomotor activity. The antinociceptive effects occurred within 5 min of exposure and lasted approximately 40 min in duration. The cannabinoid receptor antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2, 4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide HCl (SR 141716A), but not naloxone, blocked these antinociceptive effects (AD(50)=0.09 mg/kg) indicating a cannabinoid receptor mechanism of action. Similarly, inhalation exposure to a water soluble cannabinoid analog, 3-(5'-cyano-1', 1'dimethylheptyl)-1-(4-N-morpholinobutyrloxy)-Delta(8)-te trahydrocann abinol (O-1057), produced antinociception that was blocked by SR 141716A. These results demonstrate that the development of an aerosolized form of cannabinoids for human medicinal use is feasible.

Administration, Inhalation↗

PubMed2000

Antinociceptive effects of tetrahydrocannabinol side chain analogs: dependence upon route of administration.

The role of flexibility of the alkyl side chain in the tetrahydrocannabinols to cannabinoid activity has been delineated in previous studies with side chain analogs of Delta(8)-tetrahydrocannabinol with double or triple bonds. This study investigated the site of antinociceptive action for these analogs through analysis of structure-activity relationships following different routes of administration. In analogs without terminal substitutions, potency was greater following intrathecal (i. t.) injection than with intracerebroventricular (i.c.v.). Further, optimal structural features differed for each route of administration. Absolute position of the double or triple bond best predicted i.t. potency. In contrast, i.c.v. potency was best predicted by the size of the alkyl substituent beyond the point of unsaturation. Terminal substitutions tended to increase i.c.v. potency while decreasing or not affecting i.t. These results suggest that receptor mechanisms for cannabinoid antinociceptive effects differ in brain and spinal cord, although potential pharmacokinetic differences in rate of local distribution cannot be eliminated.

Analgesics, Non-Narcotic↗

PubMed2000

QSAR analysis of Delta(8)-THC analogues: relationship of side-chain conformation to cannabinoid receptor affinity and pharmacological potency.

A novel quantitative structure-activity relationship (QSAR) for the side-chain region of Delta(8)-tetrahydrocannabinol (Delta(8)-THC) analogues is reported. A series of 36 side-chain-substituted Delta(8)-THCs with a wide range of pharmacological potency and CB1 receptor affinity was investigated using computational molecular modeling and QSAR analyses. The conformational mobility of each compound's side chain was characterized using a quenched molecular dynamics approach. The QSAR techniques included a modified active analogue approach (MAA), multiple linear regression analyses (MLR), and comparative molecular field analysis (CoMFA) studies. All three approaches yielded consistent results. The MAA approach applied to a set of alkene/alkyne pairs identified the most active conformers as those with conformational mobility constrained within an approximately 8 A radius. MLR analyses (restricted to 15 hydrocarbon side-chain analogues) identified two variables describing side-chain length and terminus position that were able to fit the pharmacological data for receptor affinity with a correlation coefficient for pK(D) of 0.82. While chain length was found to be directly related to receptor affinity, the angle made by the side chain from its attachment point to its terminus (angle defined by C3-C1'-side-chain terminus carbon, see Figure 1) was found to be inversely related to affinity. These results suggest that increased side-chain length and increased side-chain ability to wrap around the ring system are predicted to increase affinity. Therefore, the side chain's conformational mobility must not restrict the chain straight away from the ring system but must allow the chain to wrap back around toward the ring system. Finally, the CoMFA analyses involved all 36 analogues; they also provided data to support the hypothesis that for optimum affinity and potency the side chain must have conformational freedom that allows its terminus to fold back and come into proximity with the phenolic ring.

Animals↗

PubMed2000

Comparison of novel cannabinoid partial agonists and SR141716A in the guinea-pig small intestine.

The controversial nature of the CB(1) receptor antagonist, SR141716A, in the guinea-pig small intestine was investigated by comparing it with four analogues of Delta(8)-tetrahydrocannabinol (Delta(8)-THC): O-1184, O-1238, O-584 and O-1315. These compounds (10 - 1000 nM) inhibited the electrically-evoked contractions with a rank order of potency of O-1238>O-1184>O-584>O-1315. Log concentration-response curves for O-1238, O-1184 and O-1315 were significantly shifted to the right by SR141716A and the maxima were significantly less than that of the CB(1) agonist, WIN55212-2, an indication of partial agonism. Partial saturation of the triple bond in O-1184 to a cis double bond (O-1238) increased its potency as an agonist (pEC(50) from 6.42 to 7.63) and as an antagonist of WIN55212-2, (pK(B), from 8.36 to 9.49). Substitution of the terminal azide group by an ethyl group (O-584) or removal of the phenolic hydroxyl group (O-1315) had no significant effect on the agonist or antagonist potency. None of these analogues increased the twitch response in a manner resembling that of SR141716A. O-1184 (10 and 100 nM) shifted the log concentration-response curve of WIN55212-2 for inhibition of the twitch responses to the right with pK(B) values of 8.29 and 8.38, respectively. We conclude that these Delta(8)-THC analogues behave as partial agonists rather than silent antagonists at CB(1) binding sites in this tissue. There was no evidence of antagonism of endocannabinoids thus supporting the hypothesis that, in this tissue, SR141716A is an inverse agonist of constitutively active CB(1) receptors.

Animals↗

PubMed2000

O-1057, a potent water-soluble cannabinoid receptor agonist with antinociceptive properties.

Cannabinoids have low water solubility, necessitating the use of a solubilizing agent. In this paper we investigated whether a novel water-soluble cannabinoid, 3-(5'-cyano-1', 1'-dimethylpentyl)-1-(4-N-morpholinobutyryloxy)-Delta(8)- tetrahydroca nnabinol hydrochloride (O-1057), would interact with cannabinoid receptors when water or saline were used as the only vehicle. O-1057 displaced [(3)H]-CP55940 from specific binding sites on Chinese hamster ovary (CHO) cell membranes expressing CB(1) or CB(2) cannabinoid receptors, with pK(i) values of 8.36 and 7.95 respectively. It also displaced [(3)H]-CP55940 from specific binding sites on rat brain membranes (pK(i) = 7.86). O-1057 inhibited forskolin-stimulated cyclic AMP production by both CB(1)- and CB(2)-transfected CHO cells (pEC(50) = 9.16 and 9.72 respectively), its potency matching that of CP55940 and exceeding that of Delta(9)-tetrahydrocannabinol. In the mouse isolated vas deferens, O-1057 inhibited electrically-evoked contractions with pEC(50) and E(max) values of 9.73 and 76.84% respectively. It was antagonized by 100 nM SR141716A, the pK(B) of SR141716A against O-1057 (8.90) approximating to that against CP55940 (8.97). O-1057 also behaved as a CB(1) receptor agonist in vivo, reducing mouse spontaneous activity and rectal temperature when injected intravenously and inducing antinociception in the mouse tail flick test when given intravenously (ED(50) = 0.02 mg kg(-1)), intrathecally, intracerebroventricularly or by gavage. In all these assays, O-1057 was more potent than Delta(9)-tetrahydrocannabinol and, at 0.1 mg kg(-1) i.v., was antagonized by SR141716A (3 mg kg(-1) i.v.). These data demonstrate the ability of the water-soluble cannabinoid, O-1057, to act as a potent agonist at CB(1) and CB(2) receptors and warrant investigation of the clinical potential of O-1057 as an analgesic.

Analgesics↗

PubMed2000

Levels, metabolism, and pharmacological activity of anandamide in CB(1) cannabinoid receptor knockout mice: evidence for non-CB(1), non-CB(2) receptor-mediated actions of anandamide in mouse brain.

Anandamide [arachidonylethanolamide (AEA)] appears to be an endogenous agonist of brain cannabinoid receptors (CB(1)), yet some of the neurobehavioral effects of this compound in mice are unaffected by a selective CB(1) antagonist. We studied the levels, pharmacological actions, and degradation of AEA in transgenic mice lacking the CB(1) gene. We quantified AEA and the other endocannabinoid, 2-arachidonoyl glycerol, in six brain regions and the spinal cord by isotope-dilution liquid chromatography-mass spectrometry. The distribution of endocannabinoids and their inactivating enzyme, fatty acid amide hydrolase, were found to overlap with CB(1) distribution only in part. In CB(1) knockout homozygotes (CB(1)-/-), the hippocampus and, to a lesser extent, the striatum exhibited lower AEA levels as compared with wild-type (CB(1)+/+) controls. These data suggest a ligand/receptor relationship between AEA and CB(1) in these two brain regions, where tonic activation of the receptor may tightly regulate the biosynthesis of its endogenous ligand. 2-Arachidonoyl glycerol levels and fatty acid amide hydrolase activity were unchanged in CB(1)-/- with respect to CB(1)+/+ mice in all regions. AEA and Delta(9)-tetrahydrocannabinol (THC) were tested in CB(1)-/- mice for their capability of inducing analgesia and catalepsy and decreasing spontaneous activity. The effects of AEA, unlike THC, were not decreased in CB(1)-/- mice. AEA, but not THC, stimulated GTPgammaS binding in brain membranes from CB(1)-/- mice, and this stimulation was insensitive to CB(1) and CB(2) antagonists. We suggest that non-CB(1), non-CB(2) G protein-coupled receptors might mediate in mice some of the neuro-behavioral actions of AEA.

Amidohydrolases↗

PubMed2000

Cardiovascular effects of 2-arachidonoyl glycerol in anesthetized mice.

Cannabinoids, including the endogenous ligand anandamide, elicit pronounced hypotension and bradycardia through the activation of CB1 cannabinoid receptors. A second endogenous cannabinoid, 2-arachidonoyl glycerol (2-AG), has been proposed to be the natural ligand of CB1 receptors. In the present study, we examined the effects of 2-AG on mean arterial pressure and heart rate in anesthetized mice and assessed the role of CB1 receptors through the use of selective cannabinoid receptor antagonists and CB1 receptor knockout (CB1(-/-)) mice. In control ICR mice, intravenous injections of 2-AG or its isomer 1-AG elicit dose-dependent hypotension and moderate tachycardia that are unaffected by the CB1 receptor antagonist SR141716A. The same dose of SR141716A (6 nmol/g IV) completely blocks the hypotensive effect and attenuates the bradycardic effect of anandamide. 2-AG elicits a similar hypotensive effect, resistant to blockade by either SR141716A or the CB2 antagonist SR144528, in both CB1(-/-) mice and their homozygous (CB1(+/+)) control littermates. In ICR mice, arachidonic acid (AA, 15 nmol/g IV) elicits hypotension and tachycardia, and indomethacin (14 nmol/g IV) inhibits the hypotensive effect of both AA and 2-AG. Synthetic 2-AG incubated with mouse blood is rapidly (<2 minutes) and completely degraded with the parallel appearance of AA, whereas anandamide is stable under the same conditions. A metabolically stable ether analogue of 2-AG causes prolonged hypotension and bradycardia in ICR mice, and both effects are completely blocked by SR141716A, whereas the same dose of 2-AG-ether does not influence blood pressure and heart rate in CB1(-/-) mice. These findings are interpreted to indicate that exogenous 2-AG is rapidly degraded in mouse blood, probably by a lipase, which masks its ability to interact with CB1 receptors. Although the observed cardiovascular effects of 2-AG probably are produced by an arachidonate metabolite through a noncannabinoid mechanism, the CB1 receptor-mediated cardiovascular effects of a stable analogue of 2-AG leaves open the possibility that endogenous 2-AG may elicit cardiovascular effects through CB1 receptors.

Anesthesia↗

PubMed2000

Relative efficacy of insecticide treated mosquito nets (Diptera: Culicidae) under field conditions.

The relative efficacy of insecticide treated mosquito nets was evaluated under field conditions in Dehra village of Dhaulana PHC, District Ghaziabad, U.P., India, during 1996. Nylon nets were impregnated with deltamethrin, cyfluthrin, lambdacyhalothrin, and etofenprox at 25 mg/m2 by standard methods. Repellent, excito-repellency, killing, and airborne actions were monitored from dusk to dawn by hourly collection of mosquitoes that entered and rested in rooms and also females that landed on treated and untreated mosquito nets. Results revealed 15.3-22.9% repellent action, 98.3-99.3% excito-repellency action, and 100% mortality of females that landed on treated fabrics. No significant differences were observed in the efficacy of different synthetic pyrethroids against anophelines. However, against Culex quinquefasciatus Say there was a significant difference between deltamethrin and etofenprox. Control of anophelines was more pronounced than Cx. quinquefasciatus. There was no pronounced airborne action with any insecticide tested. Synthetic pyrethroids with strong airborne action may be more appropriate for impregnation of mosquito nets.

Animals↗