Kinetic fate of potassium embelate, a non-narcotic centrally acting analgesic after oral and intravenous administration.

The pharmacokinetics of oral and intravenous potassium embelate (20 mg/kg) was studied in rats. The results revealed that this compound follows a biexponential kinetic pattern. Absorption was complete (bioavailability 97%) and fast. The disposition half-life is 9.5 h on intravenous and 11 h on oral administration. High concentrations of the drug were found in brain between 0.25 and 2 h, which is in agreement with its pharmacological action. The kidney plays a major role in the excretion of the drug.

Possible interaction of potassium embelate, a putative analgesic agent, with opiate receptors.

The in vivo studies have been carried out in the rat brain for characterization of binding sites for potassium embelate (ex: Embelia ribes) a potent centrally acting analgesic compound. The results indicate that mixed mu and kappa binding sites in the brain may be involved in the analgesic action of this compound.

Effect of salai guggal ex-Boswellia serrata on cellular and humoral immune responses and leucocyte migration.

Effect of alcoholic extract of salai guggal (AESG) was studied on cellular and humoral immune responses in mice and leucocyte migration in rats. Oral administration of AESG strongly inhibited the antibody production and cellular responses to sheep red blood cells in mice. It inhibited the infiltration of polymorphonuclear leucocytes and reduced the volume of pleural exudate in carrageenan induced pleurisy in rats. It showed no cytotoxic effect.

Pharmacological actions and acute toxicity of methyl- and phenyl-3-methoxy-4-hydroxy styryl ketones.

Some pharmacological actions and acute toxicity effects of methyl- and phenyl-3-methoxy-4-hydroxy styryl ketones have been described in experimental animals. The compounds antagonised the contractions evoked by a variety of agonists on several smooth muscle preparations in vitro. They produced inhibitory effects on spontaneously contracting uteri from pregnant rats and relaxant effects on pendular movements of rabbit duodenum and on dog intestinal movements in vivo. The compounds inhibited the castor oil induced diarrhoea in rat and propulsion of charcoal test meal in mice. Phenylbutazone showed similar effect on castor oil diarrhoea. The compounds failed to modify gestation period or parturition in pregnant rats. They antagonised bradykinin-induced bronchospasm in guinea pig. The compounds showed no significant effect on cardiovascular and respiratory systems: CNS and general behaviour were not affected even at high doses. Oral LD50 for both the compounds was greater than 2 g/kg.

Antiinflammatory actions of methyl- and phenyl-3-methoxy-4-hydroxy styryl ketones.

Methyl- and phenyl-3-methoxy-4-hydroxy styryl ketones (MHSK and PHSK, resp.) upon oral administration displayed marked antiinflammatory activity in a variety of acute tests viz. carrageenan, histamine, 5-hydroxytryptamine, dextran, bradykinin and prostaglandin (PG) induced oedema in rats and carrageenan evoked swelling in mice; the activity was not altered by adrenalectomy. In subacute test of formaldehyde arthritis, they showed significant reduction in paw swelling but were less effective in granuloma tests. In chronic tests, they produced marked antiarthritic effect both in developing and established adjuvant arthritis. The compounds prevented the inflammation induced increase in serum transaminase levels and leucocyte counts. They inhibited the passive cutaneous anaphylaxis and produced reduction in ADP induced platelet aggregation. The compounds showed weaker antipyretic activity than acetylsalicylic acid in pyretic animals. MHSK showed analgesic activity using the tail clip method and antagonised acetic acid induced writhing syndrome. The compounds lacked any local anaesthetic activity. The low ulcerogenic potential of these compounds in animal models may be related to their relative inability to inhibit PG synthetase.

gamma-Glutamyl transpeptidase: a novel biochemical marker in inflammation.

gamma-Glutamyl transpeptidase (gamma-GT) plays an important role in the turnover of glutathione and protein biosynthesis. Because in inflammation both catabolic and anabolic steps are activated together with migration of cells, an alteration in gamma-GT activity was postulated to occur at the site of inflammation with the development of the inflammatory process. We discovered that gamma-GT activity was increased markedly at sites of inflammation produced in several ways in rats. A significant increase in enzyme activity appeared soon after the induction of inflammation. In carrageenin-induced acute inflammation, the paw tissue attained a 3- to 4-fold increase in enzyme activity within 4 hr; in established adjuvant arthritis, a 20- to 24-fold increase over its basal activity occurred in the rat paw tissue. The specific enzyme activity was 20-22 nmoles/min/mg protein in the cellular sediment of carrageenin-induced pleural exudate. In cotton granulomatous tissue it was 5- to 6-fold higher compared to the enzyme activity of the skeletal muscles. The in vivo increase in gamma-GT activity was prevented from occurring in proportion to the anti-inflammatory potencies of the test drugs given orally. The prevention of enzyme activity was observed with indomethacin in carrageenin-induced edematous paw tissue and with phenylbutazone in both adjuvant arthritis and carrageenin-induced pleural exudate. Prednisolone was observed to be the most potent drug against cotton granuloma. Nonsteroidal anti-inflammatory drugs (NSAIDs) were not found to affect enzyme activity in vitro when incubated with cellular infiltrate from a cotton pellet granuloma. Differences in certain physico-chemical characteristics, viz. stability at 50 degrees, pH dependency and effects of solvents, were not discernible in between the enzyme activities of the untreated and edematous paw tissues. The studies thus suggest that measurement of gamma-GT in inflammation may prove to be a valuable biochemical marker for the assessment of anti-inflammatory activity of drugs in vivo.

Immunomodulating agents of plant origin. I: Preliminary screening.

The immunobiological activity was investigated of certain medicinal plants widely used in the Ayurvedic and Unani systems of medicine for treatment of chronic infections and immunological disorders. The effect of an ethanolic extract of each drug was studied on delayed type hypersensitivity, humoral responses to sheep red blood cells, skin allograft rejection, and phagocytic activity of the reticuloendothelial system in mice. Picrorhiza kurroa was found to be a potent immunostimulant, stimulating both cell-mediated and humoral immunity. Tylophora indica, Aconitum heterophyllum and Holarrhena antidysenterica appeared to stimulate phagocytic function while inhibiting the humoral component of the immune system. Tinospora cordifolia and Ocimum gratissimum appeared to improve the phagocytic function without affecting the humoral or cell-mediated immune system. Hemidesmus indicus suppressed both the cell-mediated and humoral components of the immune system.

Ethnomedical and ethnobotanical investigations among some scheduled caste communities of Travancore, Kerala, India.

Investigations were conducted on the traditional life, culture and medical lore of some prominent scheduled caste communities, namely Pulayar, Kuravar, Vedar, Parayar and Nayadi, inhabiting the Travancore region of Kerala. These communities were perhaps some of the original inhabitants of Kerala who have evolved their own peculiar cultural traditions, religious customs, cults, totems, legends, myths, folklores and medicinal practices. But in recent years these communities are being enveloped in the rising tide of civilization and their age old cultural heritage and knowledge systems are fast disappearing. Considering the great importance of conserving/preserving this knowledge system the present study was undertaken. Much interesting information on the cultural life of these communities was gathered. Special attention was paid to the study of their medicinal practices which is essentially a magico-religious-herbal therapy. These tribals have an indepth knowledge of the surrounding flora and utilize over 500 plant species for treating various ailments. The present communication reports only those medical claims for plants that have not been previously published.

Pharmacology of an extract of salai guggal ex-Boswellia serrata, a new non-steroidal anti-inflammatory agent.

Pharmacological evaluation of alcoholic extract of salai guggal (AESG) has been carried out in experimental animals. AESG displayed marked anti-inflammatory activity in carrageenan induced oedema in rats and mice and dextran oedema in rats. It was equally effective in adrenalectomised rats. In formaldehyde and adjuvant arthritis, AESG produced prominent anti-arthritic activity but no significant effect was observed in cotton pellet-induced granuloma test. It inhibited inflammation induced increase in serum transaminase levels and leucocyte counts but lacked any analgesic or anti-pyretic effects. The gestation period or parturition time in pregnant rats or onset time of castor oil-induced diarrhoea was unaffected by AESG and no significant effect was seen on cardiovascular, respiratory and central nervous system functions. No ulcerogenic effects were found in the rat stomach. The oral and intraperitoneal LD50 was greater than 2 g/Kg in mice and rats.

Piperine-mediated inhibition of glucuronidation activity in isolated epithelial cells of the guinea-pig small intestine: evidence that piperine lowers the endogeneous UDP-glucuronic acid content.

Piperine (1-peperoyl piperidine), a major component of the Piper species was reported recently by us to inhibit the activities of rat hepatic monooxygenases and UDP-glucuronyltransferase. This study explores further the basis of inhibition of glucuronidation. The effect of piperine on the rate of glucuronidation of 3-hydroxybenzo(a) pyrene and UDP-glucuronic acid content in the intact isolated epithelial cells of the guinea-pig small intestine was studied. The cells offered a fairly good system to study the modulation of glucuronidation activity. Glucuronidation of 3-hydroxybenzo(a) pyrene was dependent on the time of incubation, cellular protein and substrate concentration. From the kinetics of glucuronidation of 3-hydroxybenzo(a)pyrene in the isolated cell preparation the Vmax of 0.5 nmol of BP-3-glucuronide formed per min/mg of protein and Km of 25 microM were observed. The endogeneous concentration of UDP-glucuronic acid observed was 1.6 to 2.3 nmol/mg of cellular protein. Piperine caused a concentration-related decrease in UDP-glucuronic acid content and the rate of glucuronidation in the cells. It required much lower concentrations of piperine than D-galactosamine to diminish the endogeneous level of UDP-glucuronic acid. Rate of glucuronidation of 3-hydroxybenzo (a) pyrene was dependent on the endogeneous level of UDP-glucuronic acid. At 50 microM piperine, the rate of glucuronidation was reduced to about 50% of the basal rate. Piperine caused noncompetitive inhibition of hepatic microsomal UDP-glucuronyltransferase with Ki of 70 microM. The studies demonstrate that piperine modifies the rate of glucuronidation by lowering the endogeneous UDP-glucuronic acid content and also by inhibiting the transferase activity.

A New Triterpenoid Sapogenin of Epoxy Serratane Type from Primula rosea.

A new sapogenin 14beta, 26-epoxy serratane-3beta, 21alpha-diol has been isolated and characterized in addition to glucose, galactose and rhamnose from PRIMULA ROSEA.

Effect of quercetin and Albizzia saponins on rat mast cell.

In the present work the effect of quercetin obtained from (Allium cepa). Albizzia lebbek (crude extract of seeds) and a pure saponin fraction of Albizzia has been studied on the mast cells in the mesentery and peritoneal fluid of rats subjected to anaphylaxis. The results show a mast cell membrane stabilizing effect of these test drugs.

Biochemical basis of enhanced drug bioavailability by piperine: evidence that piperine is a potent inhibitor of drug metabolism.

Piperine, a major active component of black and long peppers, has been reported to enhance drug bioavailability. The present studies were aimed at understanding the interaction of piperine with enzymatic drug biotransforming reactions in hepatic tissue in vitro and in vivo. Piperine inhibited arylhydrocarbon hydroxylation, ethylmorphine-N-demethylation, 7-ethoxycoumarin-O-deethylation and 3-hydroxy-benzo(a)pyrene glucuronidation in rat postmitochondrial supernatant in vitro in a dose-dependent manner. Piperine inhibition of these reactions in postmitochondrial supernatant from 3-methylcholanthrene- and phenobarbital-treated rats was similar to the controls. Inhibition by piperine of arylhydrocarbon hydroxylase (AHH) from 3-methylcholanthrene-treated rats was comparable to that observed with 7,8-benzoflavone. Piperine caused noncompetitive inhibition of hepatic microsomal AHH from the untreated and 3-methylcholanthrene-treated rats with a Ki of 30 microM which was close to the apparent Km of AHH observed in the controls. Similarly, the kinetics of inhibition of ethylmorphine-N-demethylase from control rat liver microsomes exhibited noncompetitive inhibition with an apparent Km of 0.8 mM and Ki of 35 microM. These studies demonstrated that piperine is a nonspecific inhibitor of drug metabolism which shows little discrimination between different cytochrome P-450 forms. Oral administration of piperine in rats strongly inhibited the hepatic AHH and UDP-glucuronyltransferase activities. The maximal inhibition of AHH observed within 1 hr restored to normal value in 6 hr. Pretreatment with piperine prolonged hexobarbital sleeping time and zoxazolamine paralysis time in mice at half the dose of SKF-525A. These results demonstrate that piperine is a potent inhibitor of drug metabolism.

Non-narcotic orally effective, centrally acting analgesic from an Ayurvedic drug.

Embelin, a p-quinone, is derived from Embelia ribes Burm. The analgesic effect of potassium embelate has been studied in rats and mice. The test drug was found to be effective by oral, i.m. and i.c.v. routes and the results compared well with morphine. Although potassium embelate acts centrally to produce analgesia, its effect is not antagonized by naloxone indicating a different central site of action. There is no precipitation of abstinence syndrome as observed with morphine. Peripheral site of action of the drug is ruled out as it lacks any demonstrable anti-inflammatory action. It can be concluded that high oral efficacy and non-narcotic properties of the test drug make it more acceptable than morphine. In addition, lack of any adverse effects, high therapeutic index and absence of abstinence syndrome confers a long term safety on potassium embelate for use as an analgesic.