Biomedical subjects

J M Khanna

Publications and source records attributed to J M Khanna.

At least 19 recordsLinked to original sources

PubMed2004

Chemo- and stereoselective synthesis of benzocycloheptene and 1-benzoxepin derivatives as alpha-sympathomimetic and anorexigenic agents.

The synthesis and pharmacological evaluation of cis- and trans-6-amino-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ols 4a-c and 5a-c and cis- and trans-4-amino-2,3,4,5-tetrahydro-1-benzoxepin-5-ols 4d-f and 5d-f were carried out. Chemo- and stereoselective synthesis of 5a-f was achieved by reduction of corresponding alpha-amino ketones 3a-f with LiAl(t-BuO)3H. cis-4-Amino-2,3,4,5-tetrahydro-1-benzoxepin-5-ol 4d and trans-4-amino-2,3,4,5-tetrahydro-1-benzoxepin-5-ol 5d exhibited marked anorexigenic activity in mice at a dose of LD50 800 and 500 mg/kg and ED50 75 and 55 mg/kg, respectively, while the analog cis-2,3-dihydroxy-6-amino-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol 8 showed typical alpha-sympathomimetic activity.

Amphetamines↗

PubMed2002

Effect of NMDA antagonists, an NMDA agonist, and serotonin depletion on acute tolerance to ethanol.

The effect of N-methyl-D-aspartate (NMDA) antagonists [dizocilpine, (+)MK-801, and ketamine], an NMDA agonist (D-cycloserine) and of brain serotonin (5-HT) depletion with p-chlorophenylalanine (p-CPA) on acute tolerance to ethanol was examined, using the tolerance model proposed by Radlow [Psychopharmacology 114 (1994) 1-8] and Martin and Moss [Alcohol Clin Exp Res 17 (1993) 211-216]. This model is based on the concept of a linear increase of acute tolerance with time; the rate of acute tolerance development is the slope of the output function that relates blood alcohol concentrations (BACs) and intoxication. Pretreatment with NMDA antagonists inhibited the development of acute tolerance to ethanol, whereas pretreatment with D-cycloserine enhanced it. Depletion of 5-HT by p-CPA also blocked acute tolerance to ethanol. These results on acute tolerance are similar to those previously found on rapid and chronic tolerance to ethanol.

Animals↗

PubMed1999

Azelnidipine (Sankyov KK).

Azelnidipine (CS-905) is a long-acting, once-daily, orally-administered calcium channel antagonist which is being jointly developed by Sankyo and UBE. An NDA for the treatment of hypertension was filed in Japan in July 1997 [314648,271372,312610]. In a clinical trial presented at the European Meeting on Hypertension in 1995, azelnidipine decreased systolic and diastolic blood pressures at rest and during exercise. There were no significant changes in resting heart rate and cardiac output and the exercise-induced increase of these parameters was also unaffected [179222]. In February 1999, Lehman Brothers predicted a 90% probability that azelnidipine would reach the Japanese market and launch by 1999. Expected Japanese sales are predicted to be US dollar 16 million in 2000, rising to dollar 32 million in 2002. Peak annual sales of US dollar 100 million are predicted for 2008 [319225].

Journal Article↗

PubMed1998

Rapid tolerance and crosstolerance to motor impairment effects of benzodiazepines, barbiturates, and ethanol.

Motor impairment (tilt-plane test) test was used to assess the phenomenon of rapid tolerance and crosstolerance to benzodiazepines, barbiturates, and ethanol. The motor impairment responses to benzodiazepines (chlordiazepoxide and diazepam) and to various barbiturates (pentobarbital, phenobarbital, and barbital) were significantly reduced on day 2 in rats that had been treated on day 1 with benzodiazepines and barbiturates, respectively, compared to the control group treated with saline on day 1. Benzodiazepine treatment on day 1 resulted in rapid crosstolerance to the motor impairment effects of ethanol on day 2. Benzodiazepine treatment, however, did not result in rapid crosstolerance to the three barbiturates (pentobarbital, barbital, and phenobarbital) tested. In contrast to the lack of rapid crosstolerance to barbiturates after treatment with benzodiazepines, barbiturate treatment clearly conferred rapid crosstolerance to benzodiazepines and to ethanol. This asymmetry of rapid crosstolerance raises the possibility that benzodiazepines and barbiturates invoke tolerance by mechanisms that are not wholly identical. Therefore, tolerance to the broad range of actions of barbiturates would include crosstolerance to the effects of benzodiazepines, whereas tolerance to benzodiazepines would include only a weak or partial crosstolerance to some of the effects of barbiturates.

Animals↗

PubMed1998

Effect of NMDA antagonists on development of rapid tolerance to various barbiturates.

We recently reported that the noncompetitive antagonists, (+)-MK-801 and ketamine, block the development of rapid tolerance to ethanol. We now show that pretreatment with these NMDA antagonists also blocks rapid tolerance to the various barbiturates (pentobarbital, barbital, and phenobarbital) examined. Tolerance to pentobarbital occurred under three difference conditions: (a) in groups of rats that were tested at repeated times on day 1 (intoxicated practice or testing group), (b) in groups of rats that were not tested on the apparatus but handled at the same times on day 1 (dummy testing or associative learning group), and (c) in groups of rats that were not subjected to testing at all on day 1 (nontesting). However, NMDA antagonists blocked intoxicated practice and associative tolerance, but not tolerance produced in the nontesting group. In the last experiment NMDA antagonist failed to block tolerance (unlearned) when animals were treated in the animal quarters and tested in a different room (i.e., in the laboratory). These findings suggest that NMDA antagonists affect barbiturate tolerance in a manner similar to their effect on ethanol tolerance.

Animals↗

PubMed1997

Role of adenosine in the ethanol-induced potentiation of the effects of general anesthetics in rats.

Acetate, derived from ethanol metabolism in the liver, is released into the circulation and utilized in many tissues including the brain. The subsequent metabolism of acetate results in the production of adenosine that has a number of effects in the central nervous system. The purpose of the present studies, therefore, was to investigate the contribution of metabolically generated adenosine to the ethanol-induced potentiation of the inhalational agents isoflurane and sevoflurane. Changes in the anesthetic requirement for isoflurane and sevoflurane were determined in rats using the tail-clamp procedure. Both ethanol and sodium acetate reduced anesthetic requirement for isoflurane and sevoflurane in a dose-dependent fashion. The effect of acetate on anesthetic requirement was completely blocked by the administration of the adenosine receptor blocker, 8-phenyltheophylline. The ethanol-induced reduction in anesthetic requirement, however, was only partially blocked by 8-phenyltheophylline. Direct intracerebroventricular (i.c.v.) administration of the water-soluble adenosine receptor blocker, 8-sulfophenyltheophylline, also completely blocked the effect of acetate and partially blocked the effect of ethanol. This i.c.v. administration demonstrates that the actions of ethanol and acetate on anesthetic requirement are a central nervous system effect. The i.c.v. administration of the adenosine A1 receptor subtype agonist, R-phenylisopropyl adenosine, potentiated the anesthetic effects of isoflurane and suggests that the A receptor mediates the observed potentiation of anesthetic effect. This is further supported by the concomitant administration of 5-N-ethylcarboxamido adenosine, a non-selective adenosine agonist, with the selective A1 antagonist, 8-cyclopentyltheophylline, showing A1 receptor potentiation of anesthetic requirements. The studies show that (1) acetate potentiates the anesthetic effects of the inhalational anesthetics, sevoflurane and isoflurane; (2) acetate contributes in part to the effect of ethanol on anesthetic potency through metabolically generated adenosine; (3) these effects are likely mediated via adenosine A1 receptor subtypes.

Acetic Acid↗

PubMed1997

Effect of NMDA antagonists on rapid tolerance to ethanol under two different testing paradigms.

We have recently reported that pretreatment with NMDA receptor antagonists [(+)MK-801 and ketamine] inhibited the development of rapid tolerance to ethanol hypothermia and motor-impairment on day 2 in animals receiving ethanol on day 1, compared to the control group pretreated with saline. In these studies rats were tested at 30, 60, 90 and 120 min after ethanol on both day 1 and 2. In the present report we compared the development of rapid tolerance under 2 different conditions: (1) in groups of rats that were tested on the tilt-plane at all test times (Testing or Intoxicated Practice group), (2) in groups of rats that were not tested on the tilt-plane but were handled at all test times on day 1 (dummy testing). Rats were pretreated with ethanol or saline on day 1 and tested with ethanol on day 2 in all the above studies. Both testing (intoxicated practice) and dummy testing of animals on day 1 after pretreatment with ethanol produced rapid tolerance to ethanol on day 2. However, (+)MK-801 or ketamine pretreatment, which blocked rapid tolerance in the intoxicated practice testing paradigm, failed to block rapid tolerance in the dummy testing paradigm. Similar results were obtained for rapid tolerance and for the effect of ketamine in the hypothermia experiment. These findings suggest that NMDA antagonists block rapid tolerance in the intoxicated testing paradigm but not in the dummy testing paradigm. However, whether the two types of rapid tolerance tested in the present experiments are indeed different or interrelated remains to be further investigated.

Animals↗

PubMed1997

Effect of NMDA antagonists on rapid tolerance to benzodiazepines.

We have reexamined the effect of NMDA antagonists [(+)MK-801 and ketamine] on rapid tolerance to chlordiazepoxide. (+)MK-801 and ketamine blocked the development of rapid tolerance to chlordiazepoxide, but this effect was dependent on the dose ratio of the NMDA antagonist to that of the benzodiazepine used to produce rapid tolerance. Furthermore, NMDA antagonists blocked both learned and unlearned tolerance to chlordiazepoxide. It appears that in addition to impairment of memory and learning, NMDA antagonists may also influence some other mechanism involved in the production of drug-tolerance.

Animals↗

PubMed1996

N-methyl-D-aspartate receptors, nitric oxide, and ethanol tolerance.

Several experimental models have been used to study tolerance to ethanol. The development of tolerance to the motor incoordinating effect of a single administration of ethanol occurs within 8-24 h after the effect of the first dose has disappeared. This form of tolerance is designated rapid tolerance and seems to involve functional rather than pharmacokinetic mechanisms. Like chronic tolerance, rapid tolerance has been shown to be influenced by processes related to learning and memory. It is known that N-methyl-D-aspartate (NMDA) receptor systems are involved in the expression and maintenance of one form of long-term potentiation (LTP), a synaptic adaptive process which has been suggested to be the cellular basis of memory or associative memory. Considering the similarities between learning and tolerance, the effects of NMDA agonists and antagonists on tolerance to ethanol were investigated. Our studies demonstrated that NMDA antagonists that impair learning, such as dizocilpine or ketamine, inhibit tolerance, while NMDA agonists that improve learning, such as D-cycloserine, increase tolerance. Moreover, the nitric oxide synthase inhibitor L-nitroarginine blocks tolerance to the effects of ethanol. Taken together, these data confirm the involvement of the NMDA system in ethanol tolerance and emphasize the participation of learning in this phenomenon.

Animals↗

PubMed1995

D-cycloserine enhances rapid tolerance to ethanol motor incoordination.

In a recent study, we showed that D-cycloserine, an agonist at the glycine site of the NMDA receptor, enhances the development of rapid tolerance to ethanol. In the present study, we report that the acquisition of rapid tolerance to the motor incoordination effect of ethanol (tilt-plane test) was increased only when D-cycloserine was injected before, but not after, the intoxicated practice under ethanol. The effect of D-cycloserine on tolerance when this agonist was administered in divided doses before and after test was similar to that obtained when D-cycloserine was injected before test. Higher doses of D-cycloserine did not produce a further enhancement of rapid tolerance. Moreover, when the dose of ethanol on day 1 was large enough to induce rapid tolerance per se, D-cycloserine did not further enhance the tolerance. The enhancement of tolerance by D-cycloserine was antagonized by previous administration of ketamine. The enhancement of ethanol tolerance by D-cycloserine and the antagonism of this effect by ketamine cannot be attributed to changes in pharmacokinetics of ethanol. Taken together, these results confirm the participation of the NMDA receptor system in the development of tolerance to ethanol, and reinforce earlier findings about the involvement of learning in tolerance.

Animals↗

PubMed1995

Influence of nitric oxide synthase inhibition on the development of rapid tolerance to ethanol.

We recently reported that the nitric oxide (NO) synthase inhibitor L-nitroarginine (L-NA) blocks the development of rapid tolerance to the motor incoordinating effect of ethanol in the tilt-plane test. To clarify the mechanism of L-NA blockade of tolerance, four additional experiments were carried out using the same test. The first demonstrated that L-NA prevented the development of rapid tolerance to ethanol when injected prior to ethanol either on both Days 1 and 2 or only on Day 1. In the second experiment, tolerance was blocked only when L-NA was injected before but not after behavioral testing on Day 1. In the third, L-NA blocked the enhancement of rapid tolerance to ethanol induced by D-cycloserine (CS), an agonist at the N-methyl-D-aspartate (NMDA) receptor. In the last experiment, L-NA pretreatment did not influence blood ethanol disappearance curves on Day 1, or ethanol concentrations in brain, tail blood or decapitated trunk blood on Day 2. These data argue against state-dependent learning as the basis of the L-NA effect, and confirm and extent our previous observation that NO plays a role in the development of rapid tolerance to ethanol.

Amino Acid Oxidoreductases↗

PubMed1994

Effect of NMDA antagonists on rapid and chronic tolerance to ethanol: importance of intoxicated practice.

Recent studies from our laboratory have shown that NMDA antagonists ((+)MK-801 and ketamine) inhibit the development of both rapid and chronic tolerance to the motor-impairing (moving belt test) and hypothermic effects of ethanol. The present experiments were designed to determine a) the generality of this inhibition, by using a different test of motor function, the tilt-plane test, and b) the possible importance of the experimental paradigm (i.e., with and without intoxicated practice), for the effect of the NMDA antagonist on ethanol tolerance. Daily administration of ethanol 3.3 g/kg for 5 days produced the same degree of tolerance on this test, whether it was given as a single dose of 3.3 g/kg before the daily training session or as divided doses of 2.3 g/kg before and 1 g/kg immediately after the session. The inhibitory effect of a single dose of (+)MK-801 (0.25 mg/kg IP) on rapid tolerance did not last longer than 1 day. Therefore, daily administration of the NMDA antagonists was necessary to block development of chronic tolerance. Daily injection of (+)MK-801 (0.25 mg/kg IP) failed to block chronic tolerance, but inclusion of a second dose of (+)MK-801 daily, and progressive increase of this second dose during the chronic treatment period did block chronic tolerance. Unlike (+)MK-801, ketamine does not have motor-impairing effects of its own, and does not potentiate those of ethanol; it was, therefore, used in the remaining experiments. Groups of rats received ethanol (3.3 g/kg) or saline, either before a daily practice session on the tilt-plane or after it.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1994

Interaction between N-methyl-D-aspartate (NMDA) and serotonin (5-HT) on ethanol tolerance.

Earlier work from this laboratory had shown that 5-HT is involved in the development of tolerance to ethanol, and that enhancement of 5-HT levels by L-tryptophan accelerated tolerance development. To explore the possibility that NMDA receptors are involved in the 5-HT effect on tolerance, we examined the effect of a noncompetitive N-methyl-D-aspartate (NMDA) antagonist [(+)MK-801] on the ability of L-tryptophan to enhance tolerance to the effect of ethanol on tilt-plane test performance by the rat. L-Tryptophan treatment resulted in the development of rapid tolerance to a dose of ethanol that failed to produce such tolerance by itself. However, prior administration of (+)MK-801 blocked the L-tryptophan effect on rapid tolerance development, in a dose-dependent manner. These results suggest that NMDA receptors are involved in the 5-HT enhancement of ethanol tolerance.

Analysis of Variance↗

PubMed1993

Effect of NMDA receptor antagonists on rapid tolerance to ethanol.

Hypothermia and motor impairment (tilt-plane test) were used to assess whether N-methyl-D-aspartate (NMDA) receptors play a role in the development of rapid tolerance to ethanol, i.e., tolerance to a second dose of ethanol given 24 h after the effect of the first dose of ethanol had disappeared. Results showed that (+)-MK-801 and ketamine blocked the development of rapid tolerance to ethanol on both tests. Since these drugs did not modify blood or brain alcohol levels in any of the groups, the blockade of ethanol rapid tolerance cannot be attributed to changes in pharmacokinetics of ethanol. These data suggest that the role of NMDA receptors in ethanol tolerance may be similar to their role in memory and learning, involving a facilitation of transmission in certain synapses.

Animals↗

PubMed1993

Effect of D-cycloserine on rapid tolerance to ethanol.

We recently reported that the noncompetitive NMDA antagonists, (+)MK-801 and ketamine, block the development of rapid tolerance to ethanol. In the present article, we show that D-cycloserine (CS), an agonist at the glycine site of the NMDA receptor that enhances learning and memory, also enhances the development of rapid tolerance to ethanol. Rats were pretreated on day 1 with saline or CS, followed 30 min later by ethanol (2.3 g/kg, IP) or saline. At the end of motor impairment testing on the tilt-plane apparatus, a second injection of CS (3 mg/kg, IP, each time) or saline was given, followed 30 min later by ethanol or saline. Ethanol pretreatment alone (at this dose) did not result in rapid tolerance to ethanol on day 2. However, the group pretreated with CS and ethanol on day 1 showed significant tolerance on day 2 compared to other groups. Pretreatment with CS on day 1 did not affect the motor impairment response to the first exposure to ethanol whether this was on day 1 or day 2. In another experiment, administration of (+)MK-801 (0.25 mg/kg, IP) prior to CS abolished the rapid tolerance enhancement by CS. These findings are further evidence that the NMDA system, which requires activation by the glycine receptor, plays a major role in the development of at least some forms of ethanol tolerance.

Animals↗

PubMed1993

Inhibition of nitric oxide synthesis impairs rapid tolerance to ethanol.

To examine whether nitric oxide was involved in the development of rapid tolerance to the motor-incoordinating effects of ethanol (tilt-plane test), three experiments were undertaken in a rapid tolerance paradigm in rats. The first experiment tested the effect of the nitric oxide synthase inhibitor, L-nitro-arginine, on the acquisition of ethanol tolerance. The second compared the effects of L-nitro-arginine with those of its inactive isomer, D-nitro-arginine. The third examined whether overload with the substrate L-arginine would prevent the action of L-nitro-arginine on rapid tolerance. The results demonstrated that L-nitro-arginine prevented the development of rapid tolerance, while D-nitro-arginine was ineffective. An excess of the substrate L-arginine reversed the inhibitory action of L-nitro-arginine on tolerance development. These data suggest that nitric oxide may play a role in the development of tolerance to ethanol. The role of nitric oxide in ethanol tolerance may be similar to its role in memory and learning, involving facilitation of transmission in certain NMDA synapses.

Animals↗

PubMed1992

Differential inhibition by NMDA antagonists of rapid tolerance to, and cross-tolerance between, ethanol and chlordiazepoxide.

We have recently found that the non-competitive N-methyl-D-aspartate (NMDA) antagonists, (+)MK-801 and ketamine, block the development of rapid tolerance to ethanol. In the present report we show that they also block rapid cross-tolerance from chlordiazepoxide to ethanol as well as ethanol to chlordiazepoxide. However, NMDA antagonists fail to block the development of rapid tolerance to chlordiazepoxide. Our results suggest that NMDA antagonists may affect not only the acquisition of rapid tolerance or cross-tolerance to sedatives but also the ability to express that tolerance or cross-tolerance, depending on the drugs used. It is also possible that the phenomena of rapid tolerance and rapid cross-tolerance have basic differences not previously reported in the literature.

Animals↗

PubMed1992

Rapid tolerance and cross-tolerance as predictors of chronic tolerance and cross-tolerance.

Hypothermia and motor impairment (tilt-plane) tests were used to assess the phenomenon of rapid tolerance to ethanol and cross-tolerance to various alcohols, benzodiazepines, and barbiturates that differ in lipid:water partition coefficients. The hypothermic and motor impairment responses to ethanol were significantly reduced on day 2 in rats receiving ethanol (2 doses of 2 g/kg each for the hypothermia test and 2.3 and 1.7 g/kg for the tilt-plane test) 24 and 22 h earlier compared to the control group pretreated with saline. Ethanol pretreatment resulted in rapid cross-tolerance, on both tests, to the various alcohols (n-propanol, n-butanol, and t-butanol) and the benzodiazepines (chlordiazepoxide, diazepam, oxazepam, and flurazepam) tested. Ethanol pretreatment also conferred clear rapid cross-tolerance to barbital and phenobarbital, but did not result in rapid cross-tolerance to pentobarbital, secobarbital, amobarbital, or thiopental. The results on rapid cross-tolerance on both tests seen in these studies parallel the results obtained in chronic tolerance and cross-tolerance studies reported recently. These results suggest that rapid tolerance and cross-tolerance can be used as predictors of chronic tolerance and cross-tolerance.

Alcohols↗