PubMed Health⌕ Search

Biomedical subjects

R K Razdan

Publications and source records attributed to R K Razdan.

At least 19 recordsLinked to original sources
PubMed1995

A novel class of potent tetrahydrocannabinols (THCS): 2'-yne-delta 8- and delta 9-THCS.

A series of 3-alkyl-2'-yne (side chain) acetylenic analogs of delta 9-THC were synthesized and evaluated for in vitro and in vivo activity. Analogs were evaluated for receptor affinity in a [3H]CP-55,940 displacement assay and for in vivo pharmacological activity in a mouse procedure utilizing a tetrad of measures. These compounds represent a preliminary exploration of the consequences of restricting the flexibility of the side chain regarding cannabimimetic activity. All analogs proved to have receptor affinities (4-11 nM) that were five to ten times greater than that observed for delta 9-THC. However, the in vivo activities of these compounds varied greatly. All analogs proved to possess the greatest potency for production of antinociception, with activity similar to or less than that observed for the production of hypomotility, hypothermia, and catalepsy. The most potent analog 11b exhibited an ED50 of 0.031 mg/kg in the tail-flick procedure, with values in other measures being between 0.5 and 1.0 mg/kg. The least active compound (11c), though still possessing a KI of 11 nM, exhibited ED50 values of 3.1 and 9.3 mg/kg for tail-flick and temperature procedures, as well as 41 and 48 mg/kg for ring-immobility and spontaneous locomotor activity, respectively. This profile (high receptor affinity but low in vivo potency) would normally be suggestive of a compound with antagonist properties (at least for immobility and activity measures). It is unclear why these acetylenic analogs were so potent in vitro, while only one (11b) exhibited the degree of in vivo potency anticipated based upon comparison to values for delta 9-THC. It is possible these side chain modifications do not interfere with receptor recognition, but limit receptor activation or second messenger signal transduction. Regardless, it is clear these novel analogs provide a basis for the further exploration of the cannabinoid receptor pharmacophore.

Analgesics↗
PubMed1995

Pharmacological and behavioral evaluation of alkylated anandamide analogs.

Anandamide (arachidonylethanolamide), isolated from porcine brain, has been shown to bind to the cannabinoid receptor and also to produce cannabimimetic activity in pharmacological assays. This study examined structure-activity relationships in alkylated anandamide analogs. The analogs were evaluated for their ability to displace [3H]CP-55,940 in a filtration binding assay using rat brain membranes in the presence and absence of the enzyme inhibitor phenylmethylsulfonyl fluoride (PMSF). Behavioral activity was assessed by the ability of the analogs to produce hypomotility and antinociception. Methylations at carbons 2 and 1 produced compounds stable in the absence of PMSF with similar affinities and behavioral activity as anandamide. Addition of larger alkyl groups at these positions or nitrogen methylation reduced receptor affinity and behavioral potency. These results indicate that methylations at specific carbons of anandamide confer stability in vitro.

Alkylation↗
PubMed1995

Pharmacological evaluation of dimethylheptyl analogs of delta 9-THC: reassessment of the putative three-point cannabinoid-receptor interaction.

The basic premise underlying the cannabinoid pharmacophore is that at least three functional groups are involved in the interaction between the ligand and the receptor and that these functional groups in delta 9-THC comprise (a) C11, (b) the phenolic hydroxyl, and (c) the side chain. In order to assess the relative importance of the C11 position and the side chain, a series of C11 substituted analogs were prepared which contained a dimethylheptyl side chain. Consistent with previous studies, incorporation of a dimethylheptyl side chain dramatically enhanced both pharmacological potency in mice and receptor affinity. Incorporation of a hydroxy at C11 along with this branched side chain resulted in an extremely potent cannabinoid with ED50S of 0.01, 0.04, 0.16 and 0.04 mumol/kg in depression of spontaneous activity, reduction in body temperature, antinociception, and immobility, respectively. This compound was also very potent as a discriminative stimulus in a drug discrimination procedure and exhibited an extended duration of action. Its high affinity for the cannabinoid receptor (Ki = 400 pM) was consistent with this pharmacological potency. Incorporation of an oxo rather than a hydroxy reduced potency somewhat, although this analog was much more potent than delta 9-THC in most behavioral assays. The most striking observation was that incorporation of a carboxylic acid to form 11-nor-delta 9-THC-DMH-9-carboxylic acid did not eliminate pharmacological activity. This analog was as potent as delta 9-THC. The improbability that all three of the functional groups are interacting in a similar fashion with the receptor provides further support that the C11 position is not an essential requirement for activity. On the other hand, it is possible that substituents in the C9 region are interacting somewhere within or near the same site, but differently.

Animals↗
PubMed1995

Efficacy of two flowable formulations of Bacillus sphaericus against larvae of mosquitoes.

Laboratory evaluation revealed that the Spherimos and Vectolex formulations of Bacillus sphaericus produced 97 and 100% larval mortality respectively in Culex quinquefasciatus at a dose as low as 0.008 ml/sq m as against 93 and 97% mortality respectively at 1 ml/sq m in Anopheles stephensi. However, in An. culicifacies similar level of mortality was not observed even at 10 ml/sq m of these formulations. Field evaluation revealed 100% reduction of Cx. quinquefasciatus larvae for 2-3 weeks in pools and wells with single application of Spherimos @ 2 ml/sq m as against 95.4% reduction @ 10 ml/sq m in irrigation channel for one week. Vectolex @ 10 ml/sq m provided 99-100% reduction of Cx. quinquefasciatus larvae up to 9 weeks in wells and 1 week in channels.

Animals↗
PubMed1995

Evaluation of cannabinoid receptor binding and in vivo activities for anandamide analogs.

Recent evidence implicates anandamide as the endogenous ligand for the cannabinoid receptor. One purpose of this study was to determine the structural requirements for anandamide's receptor interaction and the influence of phenylmethylsulfonyl fluoride (PMSF), an enzyme inhibitor, on receptor affinity. A second objective was evaluation of the correlation between affinities of the analogs and in vivo pharmacological activities. The ability of anandamide and analogs to displace [3H]CP-55,940 ([3](-)-3-[2-hydroxyl-4-(1,1-dimethylheptyl)phenyl]-4-[3- hydroxylpropyl]cyclohexan-1-ol) was determined by a filtration assay. Displacement curves for anandamide in the presence of PMSF produced a Ki of 89 +/- 10 nM; without PMSF the Ki increased to 5400 +/- 1600 nM. Anandamide analogs were evaluated for their ability to produce antinociception and hypomotility. The levels of saturation of the anandamide structure were critical to receptor affinity and in vivo potency, with complete saturation and hydroxyl substitution with a fluorine moiety resulting in a compound with increased potency in the spontaneous activity and antinociception assays. Substitution of the hydroxyl with a fluorine atom increased affinity only in the presence of PMSF and reduced potency in the antinociception assay. Ethanolamide substitution with bromobenzenesulfonamide produced an inactive compound in all assays. Increasing the length of the N-substituent by one or two carbons decreased receptor binding affinity and potency in the tail-flick assay only. Certain structural modifications, such as methylations, allowed the analogs to retain affinity without the addition of PMSF. Linear correlation between the behavioral and binding assays were performed, and the greatest correlation was obtained with compounds that were either very potent or inactive.

Animals↗
PubMed1995

Characterization of anandamide- and fluoroanandamide-induced antinociception and cross-tolerance to delta 9-THC after intrathecal administration to mice: blockade of delta 9-THC-induced antinociception.

The antinociceptive effects of the putative endogenous cannabinoid ligand anandamide (ANA) and its fluorinated analog, fluoroanandamide (FA), were determined as measured by the tail-flick and p-phenylquinone (PPQ) stretch tests. The ED50 values (confidence limits) for ANA and FA were 77 (52-13) and 7 (2-21) micrograms/mouse, respectively, for the tail-flick test and 30 (23-41) and 0.5 (0.1-2) micrograms/mouse, respectively, for the PPQ test after intrathecal (i.t.) administration. ANA was not significantly less potent than delta 9-tetrahydrocannabinol (THC) in the tail-flick test, but it was less potent in the PPQ test. FA was more potent than either ANA or THC in tail-flick test. The antinociceptive effects of all drugs (administered i.t.) were blocked significantly or nearly abolished by the pretreatment of the mice with pertussis toxin (i.t.). Pretreatment of the mice with 5 and 25 micrograms forskolin per mouse or 10 micrograms 8-(4-chlorophenyl-thio)-adenosine-3',5'-monophosphate cyclic monosodium salt per mouse (both i.t.) significantly attenuated the antinociception produced by THC but not by ANA or FA. Various calcium modulators were tested in combination with THC, ANA, and FA, but they failed to alter the antinociceptive effects of the drugs. Various potassium channel blockers were tested in combination with the drugs. Apamin, a blocker of small (low)-conductance calcium-gated potassium channels that attenuates THC-induced antinociception, failed to alter ANA- or FA-induced antinociception. In contrast to THC, which is blocked by the kappa antagonist nor-binaltorphimine, ANA- and FA-induced antinociception was not altered by classic opioid antagonists. Also in contrast to THC, which enhances mu and delta opioid-induced antinociceptive effects, ANA failed to significantly alter opioid antinociception. ANA significantly shifted the THC dose-effect curve to the right. Thus, ED50 for DMSO/THC in the tail-flick test was shifted from 14 (7-29) to 54 (38-77) micrograms/mouse and was shifted in the hot-plate test from 22 (12-42) to 63 (43-92) micrograms/mouse. The magnitude of the shift in the ED50 was 3.8-fold in the tail-flick test and 2.9-fold in the hot-plate test. The shifts were parallel and significant. The Ki for the displacement of 3H-CP 55,940 binding by ANA and FA was 214 nM (+/- 45 S.E.M.) and 72 nM (+/- 5 S.E.M.), respectively, in pure spinal cord synaptosomes from the rat. ANA and FA were significantly cross-tolerant to THC. Although similarities between ANA and cannabinoids were shown, several marked differences were observed between ANA and the classic cannabinoids. ANA appears to function as both a cannabimimetic and a blocker of cannabinoid-induced antinociception.

Analgesics↗
PubMed1994

Field trial of esbiothrin-impregnated rope in Ramgarh village, Dadri PHC, District Ghaziabad (U.P.).

A village-scale field trial was carried out to assess the operational feasibility and efficacy of smouldering 250 ppm esbiothrin-impregnated rope in repelling mosquitoes and its impact on transmission of malaria. Entomological monitoring revealed that smoke from smouldering rope resulted in 67.2-97.9% reduction of An. culicifacies densities in human and mixed dwellings. The reduction was obviously due to diversion of An. culicifacies population to cattlesheds where ropes were not burnt. The impact was more pronounced when indoor mosquito landing rate on human bait was compared with that of experimental and control areas. This was also reflected in reduced anthropophilic index and curtailment of malaria transmission in experimental area.

Allethrins↗
PubMed1994

Repellent action of Cymbopogan martinii martinii Stapf var. sofia oil against mosquitoes.

Studies were carried out to evaluate the repellent action of Cymbopogan martinii martinii Stapf var. sofia (F. Gramineae) against mosquitoes under field conditions. Results revealed that the oil has strong repellent action and provided absolute protection for 12 h against Anopheles culicifacies, a principal vector of malaria in the country. Similar degree of protection was evident against An. annularis and An. subpictus. The protection against Culex quinquefasciatus, a pest mosquito was 96.3% for 12 h. Results of evaluation in captivity revealed complete protection against this species for 5 h.

Animals↗
PubMed1994

The pharmacological activity of anandamide, a putative endogenous cannabinoid, in mice.

The arachidonic acid derivative anandamide (arachidonylethanolamide) has been isolated from porcine brain and has been shown to bind competitively to the cannabinoid receptor. Although the pharmacological activity of this compound has not yet been fully determined, preliminary data suggest that it produces several effects similar ot the cannabinoids. In the present experiments anandamide produced effects similar to those of delta 9-tetrahydrocannabinol, including antinociception (as determined in a latency to tail-flick evaluation), hypothermia, hypomotility and catalepsy in mice after i.v., i.t. and i.p. administration. In general, the effects of anandamide occurred with a rapid onset, but with a rather short duration of action. Prominent antinociceptive effects (> 80% maximal possible effect) were measured immediately after i.v. and i.t. administration. Anandamide produced significant decreases in rectal temperature (2-4 degrees C) after either i.v. or i.t. injection. Maximal effects on motor activity (approximately 85% inhibition) were observed immediately after i.v. and i.p. administration and 10 min after i.t. administration. Maximum immobility observed after i.v. administration was over 80%, yet that produced after i.p. and i.t. administration was too small (< or = 20%) to be considered pharmacologically relevant. Anandamide was less potent (1.3 to 18 times) than delta 9-tetrahydrocannabinol in all behavioral assays. Pretreatment with nor-binaltorphimine, a kappa opioid antagonist which blocks i.t. delta 9-tetrahydrocannabinol-induced antinociception, failed to alter antinociception after i.t. anandamide administration. Binding studies demonstrating that anandamide displaces [3H]CP-55,940 from rat whole brain P2 membrane preparations with a KD of 101 +/- 15 nM. These findings demonstrate that anandamide produces effects in a tetrad of tests used to predict cannabimimetic activity and supports the contention of its role as an endogenous cannabinoid ligand. However, there appear to be distinct differences between anandamide and the cannabinoids with regard to their antinociceptive properties, and other properties vary as a function of route of administration.

Analgesics↗
PubMed1993

Use of kerosene lamp containing synthetic pyrethroids to repel mosquitoes.

An indigenous and appropriate method of personal protection was developed and tested in rural areas. It consists of an ordinary kerosene lamp made of tin with a regulator to adjust the wick. Different concentrations of esbiothrin, a synthetic pyrethroid, were mixed in kerosene and allowed to burn in living rooms and cattlesheds from dusk to dawn to observe hourly entry of mosquitoes. The tin lamp (100 ml capacity) without chimney provided the most efficient protection from mosquito bites. The protection varied from 84.2 +/- 8.2 to 97.8 +/- 2.8. Maximum protection was observed against An. culicifacies. Esbiothrin kerosene lamp (0.01%) lighted in living room provided 99.7% protection to exposed human baits seated at a distance of 1 m from the lamp. The technique is simple, cost-effective and does not require electricity and can be used both for illumination and repelling mosquitoes in remote and inaccesible areas.

Allethrins↗
PubMed1993

Mosquito repellent action of neem (Azadirachta indica) oil.

Two percent neem oil mixed in coconut oil, when applied to the exposed body parts of human volunteers, provided complete protection for 12 h from the bites of all anopheline species. Application of neem oil is safe and can be used for protection from malaria in endemic countries.

Animals↗
PubMed1992

Esbiothrin-impregnated ropes as mosquito repellent.

Esbiothrin [(+/-)-3-allyl-2-methyl-4-oxocylopent-2-enyl-(+)-trans- chrysanthemate] is an improved isomeric composition of allethrin series and consists essentially of esters of chrysanthemic acid and allethrolone. Jute rope was impregnated with esbiothrin and the smoke from smouldering ropes was evaluated as mosquito repellent in human dwellings and cattlesheds with open doors and windows at different dosages. Esbiothrin-impregranted (500 ppm) ropes prevented the entry of more than 95% An. culicifacles and other anophelines, 90.9-88.8% Culex quinquefasciatus and 96-95.1% total mosquitoes in open rooms of houses and cattlesheds respectively. The impact of ropes was more pronounced on the biting rate of mosquitoes. Indoors and outdoors human baits seated at a distance of about 3 m from smouldering esbiothrin ropes experienced no bite at all from An. culicifacies. An iron mesh around the rope prevents fire hazards.

Allethrins↗
PubMed1991

Behavioral, biochemical, and molecular modeling evaluations of cannabinoid analogs.

Numerous cannabinoids have been synthesized that are extremely potent in all of the behavioral assays conducted in our laboratory. An important feature in increasing potency has been the substitution of a dimethylheptyl (DMH) side chain for the pentyl side chain. Our previous studies have shown that (-)-11-OH-delta 8-THC-dimethylheptyl was 80-1150 times more potent than delta 9-THC. Stereospecificity was demonstrated by its (+)-enantiomer which was more than 1400-7500 times less potent. A related series of DMH cannabinoid analogs has recently been synthesized and preliminary evaluations reported here. (-)-11-OH-delta 9-THC-DMH was found to be equipotent with (-)-11-OH-delta 8-THC-DMH. The aldehyde (-)-11-oxo-delta 9-THC-DMH was 15-50 times more potent than delta 9-THC. Surprisingly, (-)-11-carboxy-delta 9-THC-DMH was also active, being slightly more potent than delta 9-THC. In the bicyclic cannabinoid series, the length and bulk of the side chain were found to be equally important. Aminoalkylindoles, which are structurally dissimilar from classical cannabinoids, have been found to exhibit a pharmacological profile similar to delta 9-THC. Though not extremely potent in vivo, they appear to represent an entirely new approach to studying the actions of the cannabinoids. The structural diversity and wide-ranging potencies of the analogs described herein provide the opportunity to develop a pharmacophore for the cannabinoids using molecular modeling techniques.

Analgesics↗
PubMed1991

Synthesis and pharmacological evaluation of ether and related analogues of delta 8-, delta 9-, and delta 9,11-tetrahydrocannabinol.

The primary goal of this research was to synthesize a series of ether analogues of the cannabinoid drug class and to evaluate their agonist and antagonist pharmacological properties in either the mouse or the rat. Agonist and antagonist activity was evaluated in mice using a multiple-evaluation procedure (locomotor activity, tail-flick latency, hypothermia, ring immobility) and activity in rats determined in a discriminative stimulus paradigm. Additionally, novel analogues were evaluated for their ability to bind to the THC receptor site labeled by 3H-CP-55,940. None of the cannabinoid analogues were capable of attenuating the effects of delta 9-THC (3 mg/kg) in either the rat (doses up to 10 mg/kg) or in the mouse (doses up to 30 mg/kg). It also appears that the compounds with minimal in vivo activity are not mixed agonist/antagonists. These data would suggest that the phenolic hydroxyl is important for receptor recognition (binding) and in vivo potency. Additionally, cannabinoid methyl ethers previously considered inactive have been found to produce limited activity. Lastly, data suggest that delta 9,11-THC is more potent than previous reports indicated, and does possess pharmacological activity.

Animals↗
PubMed1991

Genetic markers in refractory and susceptible malaria patients in village Bhanera, Distt. Ghaziabad, U.P.

Malaria 'susceptible' and 'refractory' subjects from village Bhanera in District Ghaziabad (Uttar Pradesh) were examined for various genetic markers, viz., ABO, haptoglobin, haemoglobin and glucose-6-phosphate dehydrogenase polymorphism. One hundred and nine susceptible and 36 refractory subjects were studied. No significant differences with respect to distribution patterns of the genetic markers were observed in the two groups except for AB blood group. In general, a high incidence of ahaptoglobinaemia was observed in this population and incidence increased with the increase in malaria attacks, suggesting that repeated malaria attacks cause ahaptoglobinaemia.

ABO Blood-Group System↗
PubMed1991

Evaluation of juvenile hormone analogue JHM/S-31183 against immature stages of mosquitoes in natural habitats.

A study was carried out to evaluate the potentiality of Juvenile hormone compound JHM/S-31183 against immatures of mosquitoes in natural habitats. Of two formulations tested 1% emulsifiable formulation was marginally superior than the granule formulation. Adult emergence of An. stephensi was completely inhibited upto 12 weeks when 0.5% granule formulation was applied at 0.04 ppm in wells as against 50% inhibition upto 8 weeks in pools. However, in Culex quinquefasciatus the per cent inhibition of adult emergence varied from 52 to 90 per cent. 100% inhibition in pools upto one week at 0.04 ppm in An. stephensi was also obtained with 1% emulsifiable formulation but the effect was diluted in successive weeks. The impact of this formulation was not much pronounced against Culex quinquefasciatus.

Animals↗
PubMed1990

Synthesis and pharmacological evaluation of amino, azido, and nitrogen mustard analogues of 10-substituted cannabidiol and 11- or 12-substituted delta 8-tetrahydrocannabinol.

The synthesis of a variety of novel 10-substituted cannabidiol (CBD) and 11- or 12-substituted delta 8-tetrahydrocannabinol (delta 8-THC) analogues containing amino, alkylamino, azido, or a N,N-bis(2-chloroethyl)amino functional group is described, as well as their pharmacological evaluation in mice. These analogues, which possess only a portion of the full pharmacological spectrum of activity of delta 9-THC, indicate that cannabinoid-mediated reduction of spontaneous locomotor activity, hypothermia, antinociception, and/or catalepsy need not be produced simultaneously, possibly suggesting the existence of more than one mechanism of action. The 10-substituted CBD analogues 3, 4, and 5 with an ethylamino, propylamino, or azido functional group, respectively, proved to be largely inactive, except for the production of central nervous system (CNS) depression concomitant with toxicity. Toxicity and CNS depression may be related phenomena in these nitrogenous compounds since 12-amino and 12-ethylamino analogues (8 and 11) of delta 8-THC also proved to be very toxic. Antinociceptive and hypothermic responses (without reduction of motor activity) were observed at a dose of 10 mg/kg of the 11-ethylamino analogue (9) of delta 8-THC, while a dose of 50 mg/kg of the nitrogen mustard 11-[N,N-bis(2-chloroethyl)amino]-delta 8-THC (12) was necessary to produce any observable pharmacological effect. When selected analogues were evaluated for antagonistic properties, they failed to attenuate the effects of delta 9-THC. Some nitrogen mustard analogues were capable of producing minimal pharmacological effects after either peripheral or direct CNS administration; however, these analogues also failed to attenuate the effects of delta 9-THC either immediately after administration or 24-48 h later.

Analgesics↗