The effect of Kan Jang extract on the pharmacokinetics and pharmacodynamics of warfarin in rats.

Significant pharmacokinetic/pharmacodynamic interactions between various herbal products and warfarin have recently been reported. The aim of this study was to determine whether concomitant treatment of rats with Kan Jang (a standardized fixed combination of extracts from Andrographis paniculata and Eleutherococcus senticosus) and warfarin would lead to an alteration in the pharmacological effects of warfarin. Each day for 5 days a group of animals was treated orally with an aqueous solution of Kan Jang at a dose of 17 mg/kg of the active principle andrographolide (a daily dose some 17-fold higher than that recommended for humans): the control group received similar treatment with appropriate volumes of water only. Sixty minutes after the final daily administration of Kan Jang or water, an aqueous solution of warfarin (0.2 mg/ml) was given to each animal at a dose of 2 mg/kg. From each group, 6 animals were sacrificed at 0, 2, 4, 6, 8, 12, 24, 30 and 48 h after warfarin administration and blood samples taken. The concentration of warfarin in blood plasma was measured by capillary electrophoresis using 50 mM borate buffer (pH 9.3) as mobile phase with simultaneous detection of warfarin at 208.1 and 307.5 nm. Prothrombin time in blood plasma was measured using thromboplastin reagent. The concomitant application of Kan Jang and warfarin did not produce significant effects on the pharmacokinetics of warfarin, and practically no effect on its pharmacodynamics.

A double blind, placebo-controlled study of Andrographis paniculata fixed combination Kan Jang in the treatment of acute upper respiratory tract infections including sinusitis.

A double blind, placebo-controlled, parallel-group clinical study was carried out to evaluate the effect of an Andrographis paniculata (N.) extract SHA-10 fixed combination, Kan Jang, in the treatment of acute upper respiratory tract infections, including sinusitis. Ninety-five individuals in the treatment group and 90 individuals in the placebo group completed the study according to the protocol. The medication was taken for 5 days. Temperature, headache, muscle aches, throat symptoms, cough, nasal symptoms, general malaise and eye symptoms were taken as outcome measures with given scores. The total score analysis showed a highly significant improvement in the verum group versus the placebo. This result applied to the group as a whole and to the sinusitis subgroups. The individual symptoms of headache and nasal and throat symptoms together with general malaise showed the most significant improvement while cough and eye symptoms did not differ significantly between the groups. Temperature was moderately reduced in the verum group. It can be concluded that Kan Jang has a positive effect in the treatment of acute upper respiratory tract infections and also relieves the inflammatory symptoms of sinusitis. The study drug was well tolerated.

Effects of heavy physical exercise and adaptogens on nitric oxide content in human saliva.

Since heavy physical exercise increases the content of nitric oxide and cortisol in blood and saliva, standardized extracts of the adaptogen herbal drugs Schizandra chinensis and Bryonia alba roots were applied to several groups of athletes in a placebo controlled double blind study. In the beginning of a test with athletes Schizandra chinensis and Bryonia alba extracts increased the concentration of NO and cortisol in blood plasma and saliva similar to athletes with heavy physical exercise. These results correlate with an increased physical performance in athletes taking adaptogens versus athletes taking placebo. In contrast after treatment with the adaptogen heavy physical exercise does not increase salivary NO and cortisol in athletes, whereas athletes treated with placebo heavy physical exercise increased salivary NO. These results show that the salivary NO test can be used both for evaluation of physical loading and stress protective effect of an adaptogen.

Restoration of the disordered glucose-fatty acid cycle in alloxan-diabetic rats by trihydroxyoctadecadienoic acids from Bryonia alba, a native Armenian medicinal plant.

We studied how administration of trihydroxyoctadecadienoic acids obtained from the roots of the native Armenian plant Bryonia alba L. (0.05 mg/kg/day for 15 days. i.m.) restores the disordered lipid metabolism of alloxan-diabetic rats. Diabetes was accompanied by an increase in total non-esterified fatty acid content of blood together with decreases in muscle and adipose tissue of total non-esterified fatty acids and triglycerides, together with marked alterations of phospholipid fatty acid distribution within the membranes from muscle, including increased short chain fatty acid and decreased arachidonate content. All these metabolic changes induced in diabetes were significantly restored by trihydroxyoctadecadienoic acid treatment towards their normal values (P < 0.005) with the exception of diminished triglyceride content of muscle which was not restored. In experiments on rat neutrophil leukocytes in vitro, it was found that the standardised preparation of Bryonia C-18 fatty acids (a mixture of four diastereoisomeric forms of the positional isomers I 12,13,16-trihydroxy-9Z,14E-octadecadienoic acid, II 12,15,16-trihydroxy-9Z,13E-octadecadienoic acid, III 9,10, 13-trihydroxy-11E,15Z-octadecadienoic acid and IV 9,12,13-trihydroxy-10E,14Z-octadecadienoic acid) had no effect on granular enzyme secretion or 5-lipoxygenase activity at 5-50 micrograms/ml, but dose-dependently reduced thromboxane B2 generation, with a corresponding increase in prostaglandin E2 release. We conclude that trihydroxyoctadecadienoic acids from B. alba can correct major metabolic abnormalities typical of severe diabetes mellitus, and that they can influence the profile of the formation of stable prostaglandins by actions downstream of prostaglandin endoperoxides.

Immunosuppressive effects of hypericin on stimulated human leukocytes: inhibition of the arachidonic acid release, leukotriene B(4) and Interleukin-Iα production, and activation of nitric oxide formation.

The present study describes the influence of hypericin of Hypericum perforatum on TPA- and LPS-induced arachidonic acid (AA) metabolism, as well as interleukin 1 α and nitric oxide (NO) production in human immunocompetent cells. The results show that hypericin inhibits the release of arachidonic acid (AA) from membrane phospholipids in calcium ionphore A23187-TPA stimulated human granulocytes in a dose-dependent manner (IC(50) 4 µM), but that calcium ionophore is not the only inducer. An inhibitory effect could be observed at concentrations of < 0.4 µM and in the presence of low concentrations of TPA (0.16 - 0.32 µM). As a result of this inhibition hypericin inhibits the release of LTB(4) but not of PGE(2). Hypericin also inhibits the production of IL-1α in LPS-stimulated human monocytes and activates NO production in isolated human leukocytes. This effect is comparable to the effect of LPS and is probably not associated with the IL 1 a or intermediates of the cycloxygenase pathway. The results as a whole let us assume that one important mechanism for the antiviral, antiinflammatory and antitumoral effects of hypericin and Hypericum extracts is the inhibition of the PKC-mediated signalling pathway which in turn influences the AA metabolism, and the interleukin-1 α production resulting in an immunosuppressive effect on the host immune system.

Dose dependent reversal effects of plumbagin on metabolism of arachidonic acid in porcine polymorphonuclear leukocytes.

The cytostatic immunostimulating naphthoquinone plumbagin was used as a model to explain the multiple potential of immunostimulants and their interferences with the arachidonic acid metabolism. Plumbagin was found to suppress totally the activity of lipoxygenases and the endogenous production of proinflammatory immunostimulants LTB(4), 5-HETE and 12-HETE in ionophore A-23187 stimulated porcine granulocytes at a concentration of 10(-4) M, whereas it stimulates the AA-metabolism and increases e. g. the 5-lipoxygenase products in a concentration range of 10(-6)-10(-7)M. Surprisingly this stimulating effect is interrupted at a concentration of 10(-8)-10(-9) M resulting in a strong suppression of the biosynthesis of 5-lipoxygenase products. This inhibition might be associated with an increased production of "antiinflammatory" 15-HETE which is known to inhibit 5-lipoxygenase and LTB(4) production. The effects observed for plumbagin support the close linkages of AA metabolism with the unspecific immune system, and might explain the dose dependent antiinflammatory or proinflammatory effects respectively.

Nifedipine kinetics and dynamics in hypertensive patients: a new approach.

Nifedipine tablet in a 20 mg dose was administered orally to 44 patients with arterial hypertension. Nifedipine pharmacokinetics showed wide interindividual variation, for instance maximal concentration varied from 10-90 ng/ml, elimination half-life from 2-9 hours, etc. Cluster analysis classified all variants of nifedipine concentration profiles into 3 more homogeneous groups. Group A was characterized by small maximal nifedipine concentrations and its fast elimination; in group C nifedipine concentration reached high level in plasma and elimination half-life was more than 5.5 hours; in group B intermediate variants of nifedipine concentration profiles were separated. Nifedipine effects on mean blood pressure and platelet aggregation differed between these groups significantly. There were no changes in these parameters in patients from group A whereas in group C nifedipine produced profound and long-term reduction of both blood pressure and platelet aggregation. Using cluster analysis it appears to be possible to objectively classify a variant of nifedipine concentration profile to one of these homogeneous groups using only 3 measurements of nifedipine concentration in plasma at 1, 2 and 3 hours after the administration. It has been suggested that this approach simplifies the estimation of nifedipine pharmacokinetics and it might be useful for introducing the pharmacokinetic investigations to clinical practice.

Trihydroxyoctadecadienoic acids exhibit antiatherosclerotic and antiatherogenic activity.

A standardized mixture of isomeric trihydroxy fatty acids (TFA: 12,13,16-trihydroxy-9Z, 14E-octadecadienoic-, 12,15,16-trihydroxy-9Z, 13E-octadecadienoic-, 9,10,13-trihydroxy-HE, 15Z-octadecadienoic-, and 12,13,16-trihydroxy-9,14Z-octadecadienoic acid), isolated from Bryonia alba L. roots, were found to exhibit antiatherosclerotic (reducing atherosclerotic manifestations) effects as studied in the cell culture obtained from atherosclerotic plaques of the human aorta. TFA, in a concentration range of 10(-8)-10(-4) M, reduced the total cholesterol content to a higher extent than nifedipine, and inhibited the [(3)H]-thymidine incorporation into the cultivated cells. The experiments with deendothelized rabbit aorta also demonstrated that TFA exhibit an antiatherogenic (preventive) effect resulting in a decreased intima thickness and restricted adhesion of blood cells to the surface of the vessel lumen.

Oxyradical-mediated chromosome damage in patients with familial Mediterranean fever.

Increased chromosome breakage is observed in patients with familial mediterranean fever (FMF). Their plasma contains clastogenic material inducing chromosome damage in cells from healthy persons. It is proposed that increased oxyradical generation by activated polymorphonuclear cells in blood and serosal fluids of these patients leads to the formation of a clastogenic factor (CF), as it is observed in other chronic inflammatory diseases. Also similar to these diseases, the clastogenic effects are prevented by superoxide dismutase and partially by inhibitors of arachidonic acid metabolism.

Inhibition of arachidonic acid 5-lipoxygenase of human polymorphonuclear leukocytes by esculetin.

Esculetin (6,7-dihydroxycoumarin) inhibits arachidonic acid 5-lipoxygenase of human polymorphonuclear leukocytes (HPMNL). Complete inhibition of the biosynthesis of 5-HETE, 5,12-DHETE and LTB4 was observed at a concentration of 100 microM (IC50 = = 0.4 microM, 6.0 microM and 0.1 microM, respectively). At these concentrations the formation of the cyclooxygenase product, 12-HHT, is increased. Upon stimulation of the cells with calcium ionophore A-23187, the inhibitory action of esculetin is revealed at the higher concentrations.