Alexander Panossian

Pharmacology of Schisandra chinensis Bail.: An overview of Russian research and uses in medicine

Schisandra chinensis (Turcz.) Bail. is often referred to as an example of a medicinal plant with use in modern Chinese medicine. However, Schisandra chinensis first gained recognition as an adaptogen in the official medicine of the USSR in the early 1960s, principally as a result of the large number of pharmacological and clinical studies carried out by Russian scientists in the preceding two decades. Schizandra has now secured an established position within the medicine of Russia/USSR as evidenced by the inclusion of the drug in recent editions of the National Pharmacopoeia of the USSR and in the State Register of Drugs. Pharmacological studies on animals have shown that Schizandra increases physical working capacity and affords a stress-protective effect against a broad spectrum of harmful factors including heat shock, skin burn, cooling, frostbite, immobilisation, swimming under load in an atmosphere with decreased air pressure, aseptic inflammation, irradiation, and heavy metal intoxication. The phytoadaptogen exerts an effect on the central nervous, sympathetic, endocrine, immune, respiratory, cardiovascular, gastrointestinal systems, on the development of experimental atherosclerosis, on blood sugar and acid-base balance, and on uterus myotonic activity. Studies on isolated organs, tissues, cells and enzymes have revealed that Schizandra preparations exhibit strong antioxidant activities and affect smooth muscles, arachidonic acid release, biosynthesis of leukotriene B(4) in leukocytes, platelet activating factor activity, carbohydrate-phosphorus metabolism, the formation of heat shock protein and polyamines, tissue respiration and oxygen consumption, and the tolerance of an organism to oxygen intoxication. In healthy subjects, Schizandra increases endurance and accuracy of movement, mental performance and working capacity, and generates alterations in the basal levels of nitric oxide and cortisol in blood and saliva with subsequent effects on the blood cells, vessels and CNS. Numerous clinical trials have demonstrated the efficiency of Schizandra in asthenia, neuralgic and psychiatric (neurosis, psychogenic depression, astheno-depressive states, schizophrenia and alcoholism) disorders, in impaired visual function, hypotension and cardiotonic disorders, in epidemic waves of influenza, in chronic sinusitis, otitis, neuritis and otosclerosis, in pneumonia, radioprotection of the fetoplacental system of pregnant women, allergic dermatitis, acute gastrointestinal diseases, gastric hyper- and hypo-secretion, chronic gastritis, stomach and duodenal ulcers, wound healing and trophic ulcers. This review describes the considerable diversity of pharmacological effects of Schisandra chinensis reported in numerous studies carried out in the former USSR and which have been confirmed over more than 40 years of use of the plant as an official medicinal remedy. Such knowledge can be applied in the expansion of the use of Schizandra in the pharmacotherapy of European and other countries as well as for the further discovery of new drugs based on the lignans that constitute the main secondary metabolites of this plant.

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.

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).

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.

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.

Adaptogens exert a stress-protective effect by modulation of expression of molecular chaperones

Adaptogens are medicinal plants that augment resistance to stress, and increase concentration, performance and endurance during fatigue. Experiments were carried out with BALB/c mice taking ADAPT-232 forte, a fixed combination of three genuine (native) extracts of Eleutherococcus senticocus, Schisandra chinensis and Rhodiola rosea, characterised for the content of active markers eleutherosides, schisandrins, salidroside, tyrosol and rosavin and in doses of about 30, 90 and 180 mg/kg for seven consecutive days followed by forced swimming test to exhaustion. ADAPT-232 forte strongly augments endurance of mice, increasing the time taken to exhaustion (TTE) in a dose-dependent manner from 3.0+/-0.5 to 21.1+/-1.7 min, approximately seven fold. Serum Hsp72 was measured by EIA both in normal and stressful conditions before and after swimming test. Repeated administration of adaptogen dose dependently increases basal level of Hsp72 in serum of mice from 0.8-1.5 to 5.5-6.3 pg/ml. This effect is even stronger than the effect of stress, including both physical (swimming) and emotional impacts: 3.2+/-1.2 pg/ml. Cumulative effect of stress and adaptogen was clearly observed in groups of animals treated with adaptogen after swimming to exhaustion, when serum Hsp72 increased to 15.1+/-1 pg/ml and remained at almost the same level during the 7 days. It can be concluded that adaptogens induce increase of serum Hsp72, regarded as a defense response to stress, and increase tolerance to stress (in our model combination of physical and emotional stresses). It can be suggested that increased tolerance to stress induced by adaptogen is associated with its stimulation of expression of Hsp70 and particularly with Hsp72 production and release into systemic circulation, which is known as a mediator of stress response involved in reparation of proteins during physical load. Our studies suggest that this could be one of the mechanisms of action of plant adaptogens.

The Adaptogens Rhodiola and Schizandra Modify the Response to Immobilization Stress in Rabbits by Suppressing the Increase of Phosphorylated Stress-activated Protein Kinase, Nitric Oxide and Cortisol

Trypanosomiasis and leishmaniasis are two debilitating disease groups caused by parasites of Trypanosoma and Leishmania spp. and affecting millions of people worldwide. A brief outline of the potential targets for rational drug design against these diseases are presented, with an emphasis placed on the enzyme trypanothione reductase. Trypanothione reductase was identified as unique to parasites and proposed to be an effective target against trypanosomiasis and leishmaniasis. The biochemical basis of selecting this enzyme as a target, with reference to the simile and contrast to human analogous enzyme glutathione reductase, and the structural aspects of its active site are presented. The process of designing selective inhibitors for the enzyme trypanothione reductase has been discussed. An overview of the different chemical classes of inhibitors of trypanothione reductase with their inhibitory activities against the parasites and their prospects as future chemotherapeutic agents are briefly revealed.Background and Aim Both thalassemia and carnitine deficiency represent independent causes of erythropoietin resistance, and thus anemia, in uremic patients. We evaluated the unknown long-term effects of L-carnitine administration in β-thalassemic on chronic hemodialysis. Methods We studied twelve subjects (M = 8; F = 4) affected by β-thalassemia minor (β-thal; HbA2 level = 6.6 ± 0.6%) and forty non-thalassemic subjects (M = 24; F = 16) as controls (C), on chronic hemodialysis treatment. Patients and controls were at target hemoglobin levels (11–12g/dl) prior to the study and underwent to i.v. L-carnitine administration for a one year period-time. Results Groups were comparable for age, gender, serum levels of hemoglobin (Hb), iron, ferritine, PTH and aluminum, transferrin saturation, and dialysis modalities. During the study both groups showed significant Hb increase and erythropoietin (EPO) decrease; as a difference, such changes emerged at the 3rd month in C but at the 8th month in β-thal. At start, during the dialysis session the erythrocyte MCV reduced in C but not in β-thal (65.3 ± 3.2 to 65.5 ± 3.2 fl; NS); along carnitine administration period, however, MCV during dialysis decreased also in β-thal, starting since the 9th month of treatment. Conclusion This study provides evidence of the lowering of EPO resistance in β-thalassemia patients on hemodialysis due to long-term carnitine administration. Thus, prolonged carnitine supplementation should be suggested to patients on dialysis affected by β-thalassemia with poorly responsive anemia, or requiring large doses of erythropoietin.The effect of cinnarizine, a drug used for the treatment of vertigo was assessed in animal models of visceral nociception, inflammation and gastric mucosal injury. Cinnarizine (1.25–20 mg/kg, s.c.) caused dose-dependent inhibition of the abdominal constrictions evoked by i.p. injection of acetic acid by 38.7–99.4%. This effect of cinnarizine (2.5 mg/kg) was unaffected by co-administration of the centrally acting dopamine D2 receptor antagonists, sulpiride, haloperidol or metoclopramide, the peripherally acting D2 receptor antagonist domperidone, but increased by the D2 receptor agonist bromocryptine and by the non-selective dopamine receptor antagonist chlorpromazine. The antinociception caused by cinnarizine was naloxone insenstive, but enhanced by propranolol, atropine and by yohimbine. The antinociceptive effect of cinnarizine was prevented by co-treatment with the adenosine receptor blocker theophylline or by the ATP-sensitive potassium channel (KATP) blocker glibenclamide. Cinnarizine at 2.5 mg/kg reversed the baclofen-induced antinociception. Cinnarizine at 2.5 mg/kg reduced immobility time in the Porsolt’s forced-swimming test by 24%. Cinnarizine inhibited the paw oedema response to carrageenan and reduced gastric mucosal lesions caused by indomethacin in rats. It is suggested that cinnarizine exerts anti-inflammatory, antinociceptive and gastric protective properties. The mechanism by which cinnarizine modulates pain transmission is likely to involve adenosine receptors and KATP channels.Brain tumor is associated with poor prognosis. The treatment option is severely limited for a patient with brain tumor, despite great advances in understanding the etiology and molecular biology of brain tumors that have lead to breakthroughs in developing pharmaceutical strategies, and ongoing NCI/Pharma-sponsored clinical trials. We reviewed the literature on molecular targeted agents in preclinical and clinical studies in brain tumor for the past decade, and observed that the molecular targeting in brain tumors is complex. This is because no single gene or protein can be affected by single molecular agent, requiring the use of combination molecular therapy with cytotoxic agents. In this review, we briefly discuss the potential molecular targets, and the challenges of targeted brain tumor treatment. For example, glial tumors are associated with over-expression of calcium-dependent potassium (KCa) channels, and high grade glioma express specific KCa channel gene (gBK) splice variants, and mutant epidermal growth factor receptors (EGFRvIII). These specific genes are promising targets for molecular targeted treatment in brain tumors. In addition, drugs like Avastin and Gleevec target the molecular targets such as vascular endothelial cell growth factor receptor, platelet-derived growth factor receptors, and BRC-ABL/Akt. Recent discovery of non-coding RNA, specifically microRNAs could be used as potential targeted drugs. Finally, we discuss the role of anti-cancer drug delivery to brain tumors by breaching the blood-brain tumor barrier. This non-invasive strategy is particularly useful as novel molecules and humanized monoclonal antibodies that target receptor tyrosine kinase receptors are rapidly being developed.The notorious biotechnological advance of the last few decades has allowed the development of experimental methods for understanding molecular mechanisms of genes and new therapeutic approaches. Gene therapy is maturing into a viable, practical method with the potential to cure a variety of human illnesses. Some nucleic-acid-based drugs are now available for controlling the progression of genetic diseases by inhibiting gene expression or the activity of their gene products. New therapeutic strategies employ a wide range of molecular tools such as bacterial plasmids containing transgenic inserts, RNA interference and aptamers. A nucleic-acid based constitution confers a lower immunogenic potential and as result of the high stringency selection of large molecular variety, these drugs have high affinity and selectivity for their targets. However, nucleic acids have poor biostability thus requiring chemical modifications and delivery systems to maintain their activity and ease their cellular internalization. This review discusses some of the mechanisms of action and the application of therapies based on nucleic acids such as aptamers and RNA interference as well as platforms for cellular uptake and intracellular delivery of therapeutic oligonucleotides and their trade-offs.Background Phospholipases A2 (PLA2) are aggressive enzymes that can destroy phospholipids of cell membranes. The resulting cell fragments trigger the kallikrein—mediated contact phase of coagulation. The aim of the present study was to expose citrated whole blood to PLA2 and to quantify thrombin generation in recalcified plasma. Methods Normal citrated blood was exposed to bovine pancreatic or snake PLA2, lipopolysaccharide (LPS), or zymosan A for 30–45 min (RT). After centrifugation the plasma samples were recalcified (10 + 1) with 250 mM CaCl2 in the recalcified coagulation activity assay (RECA). After 0–45 min coagulation reaction time (CRT at 37°C) 1.6 M arginine (final test concentration) was added to stop hemostasis activation and to depolymerize non-crosslinked fibrin. The generated thrombin activity was chromogenically determined. Results 100 ng/ml bovine pancreatic or snake PLA2 generates about 0.2–0.8 IU/ml thrombin after 15 min CRT. This thrombin generation is similar as that induced by 200 ng/ml LPS or 20 μg/ml zymosan A. Up to 60 ng/ml bovine pancreatic PLA2 the generated thrombin activity is proportional to the PLA2 activity used; 1 μg/ml PLA2 induces much less thrombin, but PLA2 at 10 μg/ml again results into thrombin generation of 0.1–3 IU/ml at 10–15 min CRT. As control, in pooled normal citrated plasma there is no significant change in thrombin generation when exposed to up to 10 μg/ml bovine pancreatic PLA2. Discussion Elevated plasmatic PLA2 activities (occurring e.g. in trauma, pancreatitis, or sepsis) activate the blood hemostasis system resulting in pathologic disseminated intravascular coagulation (PDIC). It is suggested to diagnose these life threatening states as early as possible, screening all patients for plasmatic thrombin activity.The targets for licensed drugs used for the treatment of human immunodeficiency virus type 1 (HIV-1) are confined to the viral reverse transcriptase (RT), protease (PR), and the gp41 transmembrane protein (TM). While currently approved drugs are effective in controlling HIV-1 infections, new drug targets and agents are needed due to the eventual emergence of drug resistant strains and drug toxicity. Our increased understanding of the virus life-cycle and how the virus interacts with the host cell has unveiled novel mechanisms for blocking HIV-1 replication. This review focuses on inhibitors that target the late stages of virus replication including the synthesis and trafficking of the viral polyproteins, viral assembly, maturation and budding. Novel approaches to blocking the oligomerization of viral enzymes and the interactions between viral proteins and host cell factors, including their feasibility as drug targets, are discussed.Sinomenine is one of the alkaloids extracted from Chinese medical plant, Sinomenium acutum Rehder et Wilson. Sinomenine has been used for Rheumatoid arthritis as an anti-inflammatory and immunomodulative drugs. We have so far been investigated the cardiovascular pharmacological actions of sinomenine. Sinomenine dilated NE (5 μM)-, KCl (60 mM)- and PDB (300 nM)-induced vasoconstrictions. The pretreatment with nicardipine (0.1 μM), staurosporine (30 nM), L-NMMA (100 μM), indomethacin (10 μM) or propranolol significantly attenuated the sinomenine-induced vasorelaxation. Therefore, these results indicate that sinomenine causes the vasorelaxation by the involvement with the inhibitions of Ca2+ current (ICa) and PK-C, β-adrenoceptor stimulation, and the activation of NO and PGI2 syntheses in endothelium. On the other hand, in the ventricular cardiomyocytes of guinea pig, sinomenine inhibits ICa and simultaneously decreases the delayed rectifier K+ current (IK), resulting in the prolongation of action potential duration. Sinomenine also suppresses the dysrhysmias induced by triggered activities under the Ca2+ overload condition. Therefore, sinomenine may be expected as one of effective therapeutic drugs for heart failure and dysrhythmias, and may maintain the cardiovascular functions due to modulation of cardiac ionic channels and blood vessels.Background The contact phase of coagulation is of physiologic/pathophysiologic importance, whenever unphysiologic polynegative substances such as cell fragments (microparticles) get in contact with blood. There are several clinically used inhibitors of intrinsic thrombin generation. Here the inhibitory concentrations 50% (IC50) of these anticoagulants are measured by the highly specific thrombin generation assay INCA. Methods Unfrozen pooled normal citrated plasma in polystyrole tubes was supplemented at 23°C in duplicate with 0–2 IU/ml low molecular weight heparin (dalteparin), 0–2 IU/ml unfractionated heparin, 0–500 KIU/ml aprotinin, or 0–40 mM arginine. 50 μl plasma or 1 IU/ml thrombin standard were pipetted into a polystyrole microtiter plate with flat bottom. 5 μl SiO2/CaCl2 - reagent (INCA activator) were added and after 0–30 min incubation at 37°C 100 μl 2.5 M arginine, pH 8.6, were added; arginine inhibits hemostasis activation and depolymerizes generated fibrin within 20 min at 23°C. The in the physiologic 37°C incubation phase generated thrombin was then chromogenically detected. The intra-assay CV values were < 5%. Results and Discussion The approximate IC50 were 0.01 IU/ml dalteparin, 0.02 IU/ml heparin, 25 KIU/ml aprotinin, and 12 mM arginine. The efficiency of any anticoagulant on intrinsic thrombin generation should be measured for each individual patient.Bone morphogenetic protein (BMP) appears to be one of the most promising cytokine and for clinical use in reconstructive surgery for bony defects and augmentation. To evaluate the effect of basic fibroblast growth factor (bFGF), FK506, elcatonin, and hyperbaric oxygenation (HBO) on osteoinduction by recombinant human bone morphogenetic protein-2 (rhBMP-2), 2 or 5 μg of rhBMP-2 was implanted into intramuscular sites of rats. At 21 days after implantation, the osteoinductive activity in the treatment group and control group was compared radiographically, biochemically, and histologically. The amount of new bone in the treatment group was significantly greater than that in the control group. The alkaline phosphatase activity and calcium content in the treatment group were significantly higher than those in the control group. These results suggest that bFGF, FK506, elcatonin, and HBO accelerated the activity and rate of osteoinduction by rhBMP2. These results may be useful when BMP is applied clinically in near future.Aromatic diamidines have been successfully used to combat a wide range of parasites that cause important human infections. Recently we reported that a N-phenyl-substituted analogue of furamidine (DB569) exerts a micromolar trypanocidal activity against Trypanosoma cruzi in vitro. Since DB569 also reduces the cardiac parasitism and increases the survival rates of T. cruzi-infected mice, our present aim was to analyze the potential protection of DB569 in the development of altered cardiac electrical conduction system during acute and chronic T. cruzi infection. In our experimental model of acute infection (Swiss mice inoculated with Y strain of T. cruzi), the prevailing disorder observed in electrocardiogram (ECG) analyses was sinus bradycardia. This ECG alteration was reverted in acutely infected mice treated with DB569. Interestingly, the DB569 treatment reduced significantly the numbers of CD8+ T cells in the cardiac infiltration. In addition, the noticed protection of DB569 in the ECG findings of acutely-infected animals was further extended to the chronic infection. Our data suggest that the reversion to and further maintenance of normal ECG profile in the DB569-treated infected animals may be associated with the reduced cardiac CD8+ lymphocyte infiltration and parasitism that might be ultimately contributing to their increased survival rates.Methamphetamine (METH) abuse is a serious health and social problem worldwide. At present, however, there are no effective medications for the treatment of METH abuse. Of the intracellular METH target proteins, monoamine oxidase (MAO) is involved in the regulation of monoaminergic tone in the brain, resulting in the modulation of METH-induced behavioral abnormalities in mammals. The METH-induced expression of increased motor activity, stereotypy, and sensitization is closely associated with monoaminergic transmission in the brain. Modification of MAO activity by MAO inhibitors can influence METH action. Of the MAO inhibitors, the propargylamine derivative clorgyline, an irreversible MAO-A inhibitor, effectively blocks METH-induced hyperlocomotion and behavioral sensitization in rodents. Analysis of the associated monoaminergic activity indicates an involvement of altered striatal serotonergic transmission as well as an increased dopaminergic tone. Some effects of MAO inhibitors on METH action appear to be independent of MAO, suggesting complex mechanisms of action of MAO inhibitors in METH abuse. This review describes current research to find effective treatment for METH abuse, using MAO inhibitors.Objective Anthroposophic medications (AMED) are widely used, but safety data on AMED from large prospective studies are sparse. The objective of this analysis was to determine the frequency of adverse drug reactions (ADR) to AMED in outpatients using AMED for acute respiratory and ear infections. Methods A prospective four-week observational cohort study was conducted in 21 primary care practices in Europe and the U.S.A. The cohort comprised 715 consecutive outpatients aged ≥1 month, treated by anthroposophic physicians for acute otitis and respiratory infections. Physicians’ prescription data and patient reports of adverse events were analyzed. Main outcome measures were use of AMED and ADR to AMED. Results Two patients had confirmed ADR to AMED: 1) swelling and redness at the injection site after subcutaneous injections of Prunus spinosa 5%, 2) sleeplessness after intake of Pneumodoron® 2 liquid. These ADR lasted one and two days respectively; both subsided after dose reduction; none were unexpected; none were serious. The frequency of confirmed ADR to AMED was 0.61% (2/327) of all different AMED used, 0.28% (2/715) of patients, and 0.004% (3/73,443) of applications. Conclusion In this prospective study, anthroposophic medications used by primary care patients with acute respiratory or ear infections were well tolerated.Cyclophilin (CyP) is a peptidyl prolyl cis/trans isomerase, catalyzing the cis-trans isomerization of proline residues in proteins. CyP plays key roles in several different aspects of cellular physiology including the immune response, transcription, mitochondrial function, cell death, and chemotaxis. In addition to these cellular events, a number of reports demonstrated that CyP plays a critical role in the life cycle of viruses, especially human immunodeficiency virus (HIV) and hepatitis C virus (HCV). These two viruses are significant causes of morbidity and mortality worldwide, but current therapies are often insufficient. CyP may provide a novel therapeutic target for the management and/or cure of these diseases, in particular HCV.Anti-angiogenic therapy is emerging as a valuable tool in the treatment of patients with cancer. As VEGF is a central target in anti-angiogenic therapy, its levels in the circulation might be relevant in selecting tumor types or patients likely to respond to this treatment. Additional VEGF has been recognized as a key factor in the pathogenesis of diabetic retinopathy. Recently anti-angiogenic therapy has been advocated in this situation. We measured VEGF levels in whole blood in 42 patients with high grade (n = 26) and low grade (n = 16) end stage cancer, and in 28 healthy controls and 37 patients with diabetes related vascular disease. Only 2/26 patients in the group of high grade cancer had significantly elevated VEGF levels, 1/16 in the low grade group and 1/28 in the healthy control group. In contrast, in 10/37 diabetic patients the mean VEGF levels were significantly elevated compared to the other groups. The mean level in these diabetic patients was significantly elevated compared to the other groups. These data indicate the limitation of the use of circulating VEGF levels as a potential selection criterion for anti-angiogenic therapy in cancer patients and suggest further studies into its application in the management of diabetic complications.Endothelial dysfunction is a pathological entity that multiply affects the health status. Erectile dysfunction is being recognized as a condition that is strongly interrelated with endothelial dysfunction, being a vascular event itself. Oral pharmacotherapy for erectile dysfunction has provided us with a new armamentarium on this condition. Phosphodiesterase 5 inhibitors have been investigated and proved useful in clinical practice for erectile dysfunction but in addition to this, the results seem promising of a beneficial effect on endothelial dysfunction, as well.The effect of the antiviral agent ribavirin given alone or in combination with silymarin on the development of liver injury induced in rats with carbon tetrachloride (CCl4; 2.8 ml/kg followed by 1.4 ml/kg after one week) was studied. Ribavirin at three dose levels (30, 60 or 90 mg/kg), silymarin (25 mg/kg) or combination of ribavirin (60 mg/kg) and silymarin (25 mg/kg) was administered once daily orally for 14 days, starting at time of administration of CCl4. The administration of ribavirin decreased the elevations in serum alanine aminotransferase (ALT) by 78.5, 82.1, 75.1%, aspartate aminotransferase (AST) 47.5, 37.4, 38.8%, and alkaline phosphatase (ALP) by 23.4, 16, 21.6%, respectively and also pre-vented the development of hepatic necrosis caused by CCl4. In comparison, the elevated serum ALT, AST and ALP levels decreased to 43.3%, 46%, and 37.5% of controls, respectively by silymarin. When silymarin was combined with ribavirin, the serum activities of AST and ALP were further decreased, indicating a beneficial additive effect. Morphometric analysis indicated significant reduction in the area of necrosis and fibrosis on ribavirin treatment and this was further reduced after the addition of silymarin. Metabolic pertuberations caused by CCl4 as reflected in a decrease in intracellular protein content in hepatocytes were improved by ribavirin monotherapy and to higher extent by combined silymarin and ribavirin therapy. Proliferating cell nuclear antigen was reduced in nuclei of hepatocytes by ribavirin montherapy or the combination of ribavirin and silymarin compared with CCl4-control group. The study demonstrates that ribavirin treatment in the model of CCl4-induced liver injury results in less liver damage. Results also indicate that the combined application of ribavirin and sily-marin is likely to be a useful additive in reducing liver injury.Although the oral route of drug administration is the most acceptable way of self-medication with a high degree of patient compliance, the intestinal absorption of many drugs is severely hampered by different biological barriers. These barriers comprise of biochemical and physical components. The biochemical barrier includes enzymatic degradation in the gastrointestinal lumen, brush border and in the cytoplasm of the epithelial cells as well as efflux transporters that pump drug molecules from inside the epithelial cell back to the gastrointestinal lumen. The physical barrier consists of the epithelial cell membranes, tight junctions and mucus layer. Different strategies have been applied to improve the absorption of drugs after oral administration, which range from chemical modification of drug molecules and formulation technologies to the targeting of receptors, transporters and specialized cells such as the gut-associated lymphoid tissues. This review focuses specifically on the targeting of receptor-mediated endocytosis, transporters and the absorption-site as methods of optimizing intestinal drug absorption. Intestinal epithelial cells express several nutrient transporters that can be targeted by modifying the drug molecule in such a way that it is recognized as a substrate. Receptor-mediated endocytosis is a transport mechanism that can be targeted for instance by linking a receptor substrate to the drug molecule of interest. Many formulation strategies exist for enhancing drug absorption of which one is to deliver drugs at a specific site in the gastrointestinal tract where optimum drug absorption takes place.It has been shown that melanoma cells do not express argininosuccinate synthetase (ASS) and therefore are unable to synthesize arginine from citrulline. Depleting arginine using pegylated arginine deiminase (ADI-PEG20) results in cell death in melanoma but not normal cells. This concept was translated into clinical trial and responses were seen. However, induction of ASS expression does occur which results in resistance to ADI-PEG20. We have used 4 melanoma cell lines to study factors which may govern ASS expression. Although these 4 melanoma cell lines do not express ASS protein or mRNA as detected by both immunoblot and northernblot analysis, ASS protein can be induced after these cells are grown in the presence of ADI-PEG20, but again repressed after replenishing arginine in the media. The levels of induction are different and one cell line could not be induced. Interestingly, a melanoma cell line with the highest level of induction could also be made resistant to ADI-PEG20. This resistant line possesses high levels of ASS mRNA and protein expression which cannot be repressed with arginine. Our study indicates that ASS expression in melanoma cells is complex and governed by biochemical parameters which are different among melanoma cells.The recent evidence that neurogenesis occurs throughout adulthood and neural stem cells (NSCs) reside in the adult central nervous system (CNS) suggests that the CNS has the potential for self-repair. Beside this potential, the function of newly generated neuronal cells in the adult brain remains the focus of intense research. The hippocampus of patients with depression show signs of atrophy and neuronal loss. This suggests that adult neurogenesis may contribute to the biology of depression. The observations that antidepressants, like fluoxetine, increase neurogenesis in the dentate gyrus (DG) and neurogenesis is required for the behavioral effect of antidepressants, lead to a new theory for depression and the design of new strategies and drugs for the treatment of depression. However, the role of adult neurogenesis in the etiology of depression remains the source of controversies and debates.Alzheimer’s disease (AD) is a neurodegenerative disease, characterized in the brain by amyloid plaque deposits and neurofibrillary tangles. It is the most common form of dementia among older people. There is at present no cure for AD, and current treatments consist mainly in drug therapy. Potential therapies for AD involve gene and cellular therapy. The recent confirmation that neurogenesis occurs in the adult brain and neural stem cells (NSCs) reside in the adult central nervous system (CNS) provide new opportunities for cellular therapy in the CNS, particularly for AD, and to better understand brain physiopathology. Hence, researchers have aimed at characterizing neurogenesis in patients with AD. Studies show that neurogenesis is increased in these patients, and in animal models of AD. The effect of drugs used to treat AD on neurogenesis is currently being investigated, to identify whether neurogenesis contributes to their therapeutic activities.Background For enhancement of drug effectiveness and reduction of drug toxicity, liposomal drugs have been studied in laboratories and clinics for decades. Although the results obtained from in vitro are encouraging, but the results from in vivo tests were not satisfactory. The main reasons for this situation were that we do not have enough information about the way how liposomal particles penetrating into solid tumor tissue, and what happening to the liposome particles after they got into the tumor tissue. In this paper, we are going to report the results from our observations on the way folic acid targeted and non-targeted PEGyl-DSPC liposomal doxorubicin particles penetrate into solid tumor tissue. Methods Subcutaneous transplanted murine L1210JF solid tumors in mice were used as a model. PEGyl liposomal doxorubicins were injected through tail venue, and tumor tissue samples were collected at special time points. Cryosections were cut and dried by a flowing of air after mounted on the slides right away. Then the dried cryosections were stained in water systems; the blood vessel cells were stained with green fluorescent FITC labeled antibody against CD31 antigen; the nuclei of the living cells were stained with a blue fluorescent dye DAPI. Since the whole procedure was carried out in aquatic system, the red color fluorescent liposomal doxorubicin particles remain visible under fluorescence microscope. Results Both folate conjugated and non-conjugated PEGyl-DSPC liposomal doxorubicin particles were only leaking out from the broken holes of blood vessels with a special direction and spread out for a limited distance, which was similar to the results showed before, in that observation a latex microsphere sample was used as a model.Some systemic rheumatic diseases and disorders, especially fibrotic and vascular disorders, are often refractory to corticosteroid therapy. Recently, ever accumulating evidence suggests that platelet-derived growth factor (PDGF) is involved in those refractory diseases. Imatinib mesylate inhibits the activation of PDGF receptor as well as c-Abl, Bcr-Abl and c-Kit tyrosine kinases. It has therefore been widely used for the treatment of chronic myeloid leukemia and gastrointestinal stromal tumors. Imatinib effectively suppresses the activation and proliferation of fibroblasts, mesangial cells and smooth muscle cells both in vitro and in vivo. Additionally, it has recently been reported that some patients with rheumatoid arthritis or idiopathic pulmonary arterial hypertension demonstrated a good clinical response to imatinib therapy. Imatinib may therefore overcome the limitations of current therapeutic strategy with corticosteroids and immunosuppressive agents for refractory diseases, such as systemic sclerosis and interstitial lung diseases, without clinical intolerability.Our understanding of the physiology of digestion, absorption, secretion, and motility in the gastrointestinal tract has improved immensely. Today it is well established that the gross functions of the gastrointestinal tract depend on the coordination between the muscles, nerves and hormones. The enteric nervous system (ENS) is involved in most of the physiological and pathophysiological processes in the gastrointestinal tract. Therefore, clinical and experimental studies on the ENS provide the basis for a better understanding of the mechanisms involved in gastrointestinal disorders and promote the development of therapeutic options. This review outlines some of the current views on the role of the ENS and its related hormones in gastrointestinal motility.

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.

Adaptogens: Tonic Herbs for Fatigue and Stress

T he history of the herbal substances known as adaptogens appears to begin with Order No 4654-p of the People’s Commissars Council of the Union of Soviet Socialist Republ ics, dated March 4, 1943 and concerning research work “with the purpose of finding. . .tonic substances” for both soldiers and persons working in the Russian defense industry during the Second World War.1 Both the term “adaptogens” and the concept of these herbal substances as compounds that would increase “th e sta te o f non -spe c i f ic resistance” under conditions of stress were formalized in Russia between 1950 and 1960.2,3 As originally defined,4 an adaptogen was a substance that had to: (1) show some nonspecific effect, such as increasing bodily resistance to physically, chemically, or biologically noxious agents or factors; (2) have a normalizing influence on a pathologic state, independent of the nature of that state; and (3) be innocuous and not disturb body function at a normal level.4 Thus defined, adaptogens constitute a new class of metabolic regulators that increase the ability to adapt to and avoid damage by environmental factors. Since 1997, the term “adaptog e n” ha s be en u sed a s a f unc t i o n a l t e rm by Ru s s i a n health-regulatory authorities, and in 1998 this term was allowed as a functional claim for certain products by the U.S. Food and Drug Administration. Too often, however, the term “adaptogen” is carelessly used, without sufficient experimental evidence to support the criteria for the formal definition of such a substance. To date, few of the substances called adaptogens comply fully with the formal definition. Empirically, some plants used in traditional medicine, such as Eleutherococcus senticosus, Rhodiola rosea, Schisandra chinensis, and Bryonia alba4–12 appear to meet the criteria of being adaptogens on the basis of the ability to increase nonspecific resistance to stress. Table 1 lists the plants most often described as adaptogens. Despite major differences between various effects of adaptogens and CNS-active drugs (Table 2),13 some manuals and handbooks—even in Russia, where adaptogens have been recognized as a distinct group of substances—continue to classify them as a group of CNS stimulants or other drugs.14 Recent History of Adaptogens

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.