[Regulatory issues of biologically active supplements in Armenia]. / Voprosy reguliatsii biologicheski aktivnykh dobavok v Armenii.

Since 1996 by Drug and Medical Technology Agency of the Ministry of Health of the Republic Armenia there has been a record of biologically active supplements, and up to now it numbers 61 products. There has been created a database on biologically active supplements containing relevant information on producers, composition of the product, indications for applying etc. There have been cited some data on examining biologically active supplements and on criteria of such products appraisal. The parameters of not approved Dietary supplements Applications are included and the requirements for Dietary supplements Labels are described in it. There has been cited the division of registration biologically active supplements as per active ingredients and recommendations on use. According to the results of special questionnaire for the Yerevan policlinic doctors, there have been analyzed the spreading area and dynamics biologically active supplements prescription Also there has been estimated the adequacy of their prescription and doctors opinion this product.

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.

Effect of andrographolide and Kan Jang--fixed combination of extract SHA-10 and extract SHE-3--on proliferation of human lymphocytes, production of cytokines and immune activation markers in the whole blood cells culture.

The immunomodulatory properties of a diterpene lactone andrographolide and Kan Jang--a standardized fixed combination of Andrographis paniculata extract SHA-10 and Eleutherococcus senticosus extract SHE-3 were investigated. Their role on spontaneous and phytohemagglutinin (PHA)-induced proliferation of human peripheral blood lymphocytes (PBL) and on production of interferon-gamma (INF-gamma) and tumor necrosis factor-alpha (TNF-alpha) were determined in vitro. Proliferation of PBL induced by PHA was enhanced by co stimulation with andrographolide and Kan Jang. At the same time andrographolide and Kan Jang inhibit spontaneous proliferation of PBL in vitro. These preparations also have effect on the formation of INF-gamma, TNF-alpha and some immune activation markers such as neopterin (Neo), beta-2-microglobulin (beta2MG), and soluble receptor for interleukin-2 (sIL-2R or sCD25) in blood cells culture. Andrographolide and Kan Jang stimulate the INF-gamma, Neopterin and beta2MG formation, but do not have any significant effect on the production of INF-gamma and Neopterin in PHA stimulated blood cells. An opposite effect on these immune makers was observed in the PHA-stimulated blood cells: both andrographolide and Kan Jang increase the formation of TNF-alpha and beta2MG in cultivated whole blood cells. Thus, andrographolide and Kan Jang can have an in vitro effect on the activation and proliferation of immunocompetent cells as well on the production of key cytokines and immune activation markers. The results show an overall higher effect of the fixed combination as compared with the equivalent amount of the pure substance andrographolide. The data are consistent with results from clinical studies of Kan Jang and contributed to a better understanding of these results.

Pharmacokinetic and oral bioavailability of andrographolide from Andrographis paniculata fixed combination Kan Jang in rats and human.

Validated analytical methods (HPLC, CE and GC-MS) for determining the amount of andrographolide (AND) in the blood plasma of rats and human volunteers following the oral administration of Andrographis paniculata extract (APE) and Andrographis paniculata fixed combination Kan Jang tablets were developed and used for the pharmacokinetic study. Andrographolide was quickly and almost completely absorbed into the blood following the oral administration of APE at a dose of 20 mg/kg body wt. in rats. Its bio-availability, however, decreased four-fold when a 10-times-higher dose was used. Since a large part (55 %) of AND is bound to plasma proteins and only a limited amount can enter the cells, the pharmacokinetics of AND are described well by a one-compartment model. Renal excretion is not the main route for eliminating AND. It is most likely intensely and dose dependently metabolized. Following the oral administration of four Kan Jang tablets (a single therapeutic dose, equal to 20 mg of AND) to humans, maximum plasma levels of approximately 393 ng/ml (approx. 1.12 microM) were reached after 1.5-2 hours, as quantified using a UV diode-array detection method. Half-life and mean residence times were 6.6 and 10.0 hours, respectively. AND pharmacokinetics in humans are explained well by an open two-compartment model. The calculated steady state plasma concentration of AND for multiple doses of Kan Jang (after the normal therapeutic dose regimen, 3 x 4 tablets/day, about 1 mg AND/kg body wt./day) was approximately 660 ng/ml (approx. 1.9 microM), enough to reveal any anti-PAF effect, particularly after drug uptake when the concentration of AND in blood is about 1342 ng/ml (approx. 3.8 microM, while for anti-PAF effect EC50 - 5 microM).

Rhodiola rosea in stress induced fatigue--a double blind cross-over study of a standardized extract SHR-5 with a repeated low-dose regimen on the mental performance of healthy physicians during night duty.

The aim of this study was to investigate the effect of repeated low-dose treatment with a standardized extract SHR/5 of rhizome Rhodiola rosea L, (RRE) on fatigue during night duty among a group of 56 young, healthy physicians. The effect was measured as total mental performance calculated as Fatigue Index. The tests chosen reflect an overall level of mental fatigue, involving complex perceptive and cognitive cerebral functions, such as associative thinking, short-term memory, calculation and ability of concentration, and speed of audio-visual perception. These parameters were tested before and after night duty during three periods of two weeks each: a) a test period of one RRE/placebo tablet daily, b) a washout period and c) a third period of one placebo/RRE tablet daily, in a double-blind cross-over trial. The perceptive and cognitive cerebral functions mentioned above were investigated using 5 different tests. A statistically significant improvement in these tests was observed in the treatment group (RRE) during the first two weeks period. No side-effects were reported for either treatment noted. These results suggest that RRE can reduce general fatigue under certain stressful conditions.

On the mechanism of action of plant adaptogens with particular reference to cucurbitacin R diglucoside.

Cucurbitacin R diglucoside (DCR), one of the active principles of Bryonia alba L. root was found to have an effect on the production of corticosteroids and the biosynthesis of eicosanoids in the adrenal cortex, isolated adrenocortical cells, blood plasma, and leukocytes under stress and stress-free conditions in vitro and vivo. DCR prevents stress-induced alterations of eicosanoids in blood and moderately stimulates the adrenal cortex to adapt organism to stress, because a moderate increase in corticosteroid secretion protects the defense system of organisms from becoming hyperactive. DCR enhances sensitivity to stress due to the effects of eicosanoids and corticosteroids.

Effect of Andrographis paniculata extract on progesterone in blood plasma of pregnant rats.

The effect of the powdered extract of Andrographis paniculata leaves (APE), an active principle of Kan Jang tablets [standardized for content of andrographolide (4.6%) and 14-deoxo-andrographolide (2.3%) content (total andrographolids--6.9%)] on blood progesterone content in rats was studied. Peroral administration of APE during the first 19 days of pregnancy in doses of 200, 600, and 2000 mg/kg (i.e. doses 30, 90, and 300 fold higher than its daily therapeutic dose in humans) does not exhibit any effect on the elevated level of progesterone in the blood plasma of rats. Let us assume then that in therapeutic dose, Andrographis paniculata extract cannot induce progesterone-mediated termination of pregnancy.

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.

Inhibitory effect of andrographolide from Andrographis paniculata on PAF-induced platelet aggregation.

Andrographolide, an active principle of the Chinese drug Andrographis paniculata, used for prevention and treatment of common cold in Scandinavia and known as an antiinflammatory, antiviral, antithrombotic, hypotensive and antiatherosclerotic drug, was investigated for its suggested influence on the biosynthesis of eicosanoids and the platelet-activating factor (PAF). Whereas in isolated human polymorph-nuclear leukocytes (PMNL) no influence on the biosynthesis was found, it could be shown that andrographolide inhibits PAF-induced human blood platelet aggregation in a dose dependent manner (IC50-5 microM). These results indicate that andrographolide has a mechanism of action different from that of non-steroidal antiinflammatory drugs (NSAID) and most likely associated with the cardiovascular and antithrombotic activity described of Andrographis paniculata.

Pharmacological activity of phenylpropanoids of the mistletoe, Viscum album L., host: Pyrus caucasica Fed.

Although a great number of compounds have been isolated from Viscum album (mistletoe, Viscaceae), none of them could be clearly shown to possess the established hypotensive, vasodilator, cardiotonic and antitumor activity of alcoholic preparations. In the course of our investigation of Armenian mistletoe Viscum album, host: Pyrus caucasica, which has been used in Armenian traditional medicine for the treatment of cardiovascular diseases and for stimulation of the immune system, four phenylpropanoid glycosides were isolated from EtOH-extract: coniferyl alcohol 4-O-ß-D-glucopyranoside (coniferin), syringenin 4-O-ß-D-glucopyranoside (syringin), and coniferylalcohol- and syringenin 4-O-ß-D-apiofuranosyl (1→2)-ß-D-glucopyranosides. The structures were established on the basis of the spectral and chemical data. All substances inhibited ADP-induced platelet aggregation, and the apiosyldiglycosides only inhibited leukotriene B4 release from TPA and calcium ionophore A-23187 stimulated human granulocytes. It is suggested that an antitumoral effect of ethanolic extract of Viscum album could be associated with the inhibition of protein kinase C (PKC).

Beditine, a new benzodioxane derivative, as a suppressor of human polymorphonuclear leukocyte and platelet activation.

Beditine, 2-(2-amino-4-thiazolyl)-1,4-benzodioxane hydrochloride is a new substance which reduced platelet activation and degranulation, prevented aggregation and superoxide generation by activated human polymorphonuclear leukocytes (PMNL) and inhibited the activation of arachidonate 5-lipoxygenase. Beditine may, therefore, be a useful agent in the treatment of cardiovascular disease.

Increased nitric oxide deactivation by polymorphonuclear leukocytes in patients with intermittent claudication.

PURPOSE: Local activation of polymorphonuclear leukocytes (PMNLs) is considered an important aspect of the pathogenesis of intermittent claudication, although concrete mechanisms of their effects on circulatory homeostasis in peripheral atherosclerotic disease remain unclear. This study evaluated the ability of PMNLs to deactivate nitric oxide (NO), a key regulator of regional circulation, as a possible factor determining PMNL involvement into ischemic disorders in patients who have intermittent claudication before and after vascular reconstruction. METHODS: A total of 57 patients who had peripheral occlusive disease in an aortofemoral segment before surgical treatment (group 1) and 65 patients who had similar occlusive lesions and other clinical and demographic data 6 to 12 months after undergoing inflow vascular reconstruction (group 2) were examined. All patients from group 2 had anatomically patent grafts; their satisfaction and level of function after surgical treatment were assessed by a five-point questionnaire. The sex- and age-matched control group included 35 subjects. NO activity was bioassayed by measuring its ability to increase cyclic guanosine monophosphate (cGMP) accumulation in rat fetal lung-cultured fibroblasts (RFL-6 cells). The ability of PMNLs to deactivate NO was characterized as the percent decrease in NO-induced cGMP accumulation in RFL-6 cells. RESULTS: Stimulated PMNLs caused inhibition of the activity of authentic NO; accumulation of cGMP induced by sodium nitroprusside was not affected. PMNLs from patients with peripheral atherosclerotic disease either before or after vascular reconstruction had a more marked capacity of NO inactivating than the cells from healthy subjects. For both groups of patients, levels of PMNL-induced NO deactivation were higher for patients with diabetes, and especially both diabetes and arterial hypertension. For both groups of patients, there was no correlation between levels of PMNL-induced NO deactivation and resting ankle-brachial indexes (ABIs). In contrast, close correlation was revealed between levels of PMNL-induced NO deactivation and postexercise ABIs and percent decrease in resting ABIs after exercise in patients evaluated either before or after surgical treatment. CONCLUSIONS: The ability of stimulated PMNLs to deactivate NO is elevated in peripheral occlusive disease and may be implicated in the pathogenesis of intermittent claudication. In patients who underwent successful recanalization of magistral arteries, levels of PMNL-induced NO deactivation remained higher than in control subjects. The increase in the ability of PMNL to deactivate NO positively correlated to ABI decreases after exercise in patients with peripheral occlusive disease either before or after surgical treatment.

Plant adaptogens. II. Bryonia as an adaptogen.

Bryonia, a well-known medicinal plant used mainly in homeopathy as an antiinflammatory, has never been considered an adaptogen. However, much evidence has been accumulated during the last decade indicating that Bryonia roots have adaptogenic properties. This review summarizes the reports (published mainly in Russian) on the chemical composition, the pharmacological and biochemical investigations of the active principles of Bryonia alba roots. It also summarizes reports on clinical trials of a Bryonia extract (tablets prepared from a standardized powder of Bryonia alba root, called "Loshtak" in Armenia) that indicates it is an adaptogenic and restorative drug with immunomodulatory, stress-protective and tonic properties that increase the nonspecific resistance of an organism toward harmful stimuli. The major active components of the Bryonia extract are cucurbitacin glucosides and trihydroxyoctadecadienoic acids (THODA). The biological activities of these compounds are associated with biosynthesis of eicosanoids and corticosteroids, which are important mediators in the immune, endocrine and nervous systems. Clinical trials show that the Bryonia extract was effective in treating workers at the Chernobyl Nuclear reactor who suffered from vegetovessel dystonia and other accompanying illnesses as a result of that facility's well-known accident. It was also effective in preventing radiation-induced disorders and cytostatic side effects in cancer therapy. The use of Bryonia extract in healthy athletes increases their endurance, working capacity and heart rate restoration after physical loading. No side effects caused by Bryonia extract intake were recorded during these trials.

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 Capsaicin on Interleukin-1α production is associated with the metabolism of arachidonic acid (leukotriene B(4) and prostaglandin E(2)) as well as nitric oxide production in human leukocytes.

This study attempts to determine the dose-dependent effects of capsaicin, the pungent principle of red hot pepper, on the early intracellular events after the binding of capsaicin to immunocompetent cells. It shows that capsaicin stimulates the release of AA as well as PGE(2) and LTB(4). At high doses capsaicin activates NO-production in human lymphocytes. At low concentrations (10(-8) to 10(-5) M) it increases the IL-1α-production from human lymphocytes, whereas at concentrations of 10(-4) M this production is inhibited. The possible mechanisms of action of the various pharmacological effects of capsaicin are discussed.

Dynamic component of internal carotid artery stenosis in patients with cerebrovascular disease: effects of nifedipine.

By means of Doppler spectral analysis, it was shown that internal carotid artery stenosis has a dynamic component that determines the possibility of changes in the area of stenosis under various influences. It was demonstrated that cold pressor test may increase the area of stenosis in some patients for up to 3-5 hours. In such cases, reduction of volume blood flow in the commun carotid artery and decrease of cerebral blood flow in the ipsilateral hemisphere of the stenosis are observed. Such a response was effectively prevented by nifedipine. At the same time, nifedipine can itself change the area of stenosis in some patients examined. In 31 cases it decreased the area by 22.9 +/- 5.9% and in 11 cases it increased it by 26.4 + 7.7%. When the decrease in the area of stenosis was observed, nifedipine enhanced cerebral blood flow. However, it provoked a depression of cerebral blood flow in the patients in whom the area of stenosis was increased. The data obtained disclose one of the reasons of the variability of therapeutic effects of vasodilators in patients with cerebrovascular disorders.

Cerebral blood flow and effects of cerebrospinal fluid on calcium transport in patients with cerebral infarction.

BACKGROUND AND PURPOSE: In this study we investigated whether cerebrospinal fluid in patients with brain infarction possesses an activity that contributes to the evolution of brain ischemia. As a test, the effect of cerebrospinal fluid on Ca2+ influx into the intracellular space was chosen because this process is a mechanism for vasospasm, platelet aggregation as thrombi, and neuron damage. METHODS: Effects of cerebrospinal fluid taken from 48 patients with cerebral hemispheric infarction on the concentration of cytosolic free Ca2+ in platelets were studied using the fluorescent probe quin-2. Hemispheric cerebral blood flow was measured using 133Xe intravenous injection. RESULTS: Cerebrospinal fluid in 19 of 48 patients with cerebral hemispheric infarction increased the level of cytosolic free Ca2+ in platelets. The course of the disease in the patients who showed a positive effect of cerebrospinal fluid on Ca2+, when compared with that of patients who showed a negative effect, was characterized by a more severe clinical manifestation and mortality. The decrease in hemispheric cerebral blood flow was more marked in both ischemic and contralateral hemispheres in patients with positive effects of cerebrospinal fluid on the level of Ca2+. CONCLUSIONS: These data suggest that the ability of cerebrospinal fluid to evoke Ca2+ influx into the intracellular space in patients with brain infarction is a factor that aggravates ischemic brain damage.

Noninvasive testing of dynamic component of internal carotid artery stenosis in patients with chronic cerebrovascular disease.

By means of Doppler spectral analysis it was shown that internal carotid artery stenosis has a dynamic component that determines the possibility of changes in the area of stenosis under various influences. It was found that the cold pressor test may increase the area of stenosis in some patients for up to three to five hours. In such cases reduction of blood flow volume in the common carotid artery and decrease of cerebral blood flow in the ipsilateral hemisphere of the stenosis are observed. Such a response was effectively removed by nifedipine. At the same time nifedipine itself is capable of changing the area of stenosis, either enlarging or reducing it. In the first case enhancement of brain blood supply is observed, and in the second case, its decrease. The data obtained disclose one of the reasons for the variability in therapeutic effects of vasodilators in patients with cerebrovascular disorders.

The relationship between the degradation of prostacyclin in blood and antiplatelet drug effects in patients with atherosclerosis.

Blood and plasma from 109 patients with atherosclerosis and 70 healthy volunteers were tested to study the rate of prostacyclin (PGI2) hydrolysis. It has been reported that patients with atherosclerosis have the enhanced velocity of PGI2 degradation. The increase in the velocity was more marked in blood than in plasma. The significant negative correlation between antiaggregation effects of pentoxifylline, nifedipine, and dipyridamole and the velocity of PGI2 degradation in the patients was found. These data suggest that the increase of PGI2 biosynthesis by the drugs studied can enhance their antiaggregation effect if processes of PGI2 degradation in blood are not accelerated.