Current Clinical Pharmacology - Volume 9, Issue 3, 2014

Parasites are eukaryotic pathogens and largely include protozoa, helminths and arthropods that cause different diseases to human. Parasitic diseases have a significant impact on developing countries and it has raised the mortality rate to various millions per year. Despite the recent progress, no vaccines are presently available against any of the major parasitic infections of humans. Chemotherapy remains the only option for both clinical and control management. However, conventional drugs are present with features that limit their utility, such as high cost, poor compliance, drug resistance, low efficacy and poor safety. There is thus a clear need for new therapeutic agents against parasites infections.

Plants and their extracts have been used traditionally against different pathologies, and in some poor regions they are the only therapeutic source for treatments. Moreover, the identification of specific active secondary metabolites can be account for amelioration of clinical status of suffering individual. A series of ethnopharmacological surveys conducted in Brazil recorded the traditional use of plants against different pathologies and interestingly, some of them presented antileishmanial activity in vitro and in vivo, possibly due to their immunostimulatory, healing and microbicidal properties. Of note, Leishmania parasites can alter patient’s immunological status, leading to the development of extensive skin and/or visceral alterations. Therefore, the extracts or secondary metabolites presented in plants that might be capable of improving the pathological conditions can be attractive candidates in the development of new chemotherapeuticals against leishmaniosis.

Over 18 million people in tropical and subtropical America are afflicted by American trypanosomiasis or Chagas disease. In humans, symptoms of the disease include fever, swelling, and heart and brain damage, usually leading to death. There is currently no effective treatment for this disease. Plant products continue to be rich sources of clinically useful drugs, and the biodiversity of the Neotropics suggests great phytomedicinal potential. Screening programs have revealed numerous plant species and phytochemical agents that have shown in-vitro or in-vivo antitrypanosomal activity, but the biochemical targets of these phytochemicals are not known. In this work, we present a molecular docking analysis of Neotropical phytochemicals, which have already demonstrated antiparasitic activity against Trypanosoma cruzi, with potential druggable protein targets of the parasite. Several protein targets showed in-silico selectivity for trypanocidal phytochemicals, including trypanothione reductase, pteridine reductase 2, lipoamide dehydrogenase, glucokinase, dihydroorotate dehydrogenase, cruzain, dihydrofolate-reductase/thymidylate-synthase, and farnesyl diphosphate synthase. Some of the phytochemical ligands showed notable docking preference for trypanothione reductase, including flavonoids, fatty-acid-derived oxygenated hydrocarbons, geranylgeraniol and the lignans ganschisandrine and eupomatenoid-6.

The marine organisms are a rich source of varied natural products with unique functionality. A variety of natural products of new molecular structures with diverse biological activities have been reported from marine flora and fauna for treatment and/or prevention of human diseases. The present review briefly illustrates current status of marine products as antiprotozoal agents. The in vitro and in vivo studies of marine algae, invertebrates and micro-organism against different protozoa parasites are included. The marine products studied, according to international criterions for selection of more promisory products in the different models reported, demonstrated their potentialities as antiprozoal agents. Herein, the interest of scientific community to search new alternatives from marine environment has been demonstrated.

Crude methanol, pet. ether, ethyl acetate, n-hexane, dichloromethane and aqueous extracts of various species of medicinal plants have shown significant in-vivo and in-vitro pharmacological activities against ecto, endo and haemoparasites. The scientific evaluations of the use of the plants as antiparasitic agents were based on the claims of folklore drawn from traditional healers from various communities across the world. The pharmacological activities of these plants were associated with the presence of various bioactive compounds such as alkaloids, flavonoids, saponins, glycosides, allicinine, harmala, harmaline, harman, tetrahydroharman, ursolic acid, terapines, tannins, phenolic compounds, embelin and brucine. These compounds were either found in the leaves, seeds, bulbs, flowers, stem, root barks or entire plant. In the in-vivo studies, plant extracts were tested using animal models such as mice, sheep, goats, cattle and dogs. The in-vivo anthelmintic activities of the plants were assessed by faecal egg out puts and post-mortem worm counts which in most instances achieved 70-90% priori levels with some of the plants. For haemoparasitic infections, parasitaemia clearance levels were used, while larvae and adult deaths were used to measure the activity of the plants against ectoparasites. For in-vitro activities, inhibitory concentration IC50 values using the brine lethality test, micro dilution, flow cytometery and larval packet test were used to assess the efficacy of the plant extracts on the parasites in various cell cultures. Significant in-vitro activity of 99.8% at 3.1mg/ml was achieved with the ethanolic extract of Azadirachta indica. Many of the plants were found to be more potent and possessed similar mechanism of action as their novel synthetic drugs. Such breakthroughs have led to the development of less toxic, cheaper and readily available drugs. Worthy of note is the use of the fruit of the Thai plant Piper longum (PIPERACEAE) as part of a drug formulation used in India for the treatment of clinical giardiosis in human patients.

Trichomonas vaginalis infection is associated with important problems of public health, including the spreading of other sexual transmitted infections. The existence of clinical resistant isolates metronidazole and tinidazole, the drugs approved for the treatment of trichomoniasis, points to the necessity of continue searching for trichomonicidal substances. Here we optimize a colorimetric assay with MTT to assess trichomonas viability. The absence of ascorbic acid and cysteine in the culture medium was indispensable to perform the assay, as these compounds spontaneously reduce the MTT. Linearity of absorbance was verified versus trichomonas counts. Medium inhibitory concentration of metronidazole was determined using the sigmoidal Emax model, by comparing the absorbance of test cultures with controls. The obtained value was in the range of published data. The test would be used for the evaluation of trichomonicidal activity of chemical compounds and natural products.

Doxorubicin (DOX) is an effective and frequently used chemotherapeutic agent for various malignancies. However, its clinical use is hampered due to the development of cardiotoxicity. Investigations have proved that DOXinduced cardiotoxicity occurs through mechanisms other than those mediating its antitumor effect. This theory sheds light on the development of strategies for cardioprotection without altering therapeutic effectiveness of DOX. Bioactive plant constituents of dietary supplements, traditional herbs and foods with potential health benefits can play an important role in therapeutics. This manuscript is an exhaustive review and prospect of herbal and botanical agents against DOX-induced cardiotoxicity with their proposed mechanisms. The activity of herbs evaluated against DOX-induced cardiotoxicity has shown number of mechanisms including apoptosis, antioxidant potential, effect on mitochondria and calcium ion regulation etc. The manuscript reveals that most of the herbal drugs studied are effective through antioxidant mechanism and only few through other major pathways such as apoptosis and iron mediated pathways in DOX-induced cardiotoxicity. Only limited reports are available for the prevention of DOX-induced drug resistance using botanicals. Manuscript reports a number of constituents with evident potential in prevention of DOX cardiotoxicity e.g. proanthocyanidins, epigallocatechin-3-gallate, S-allylcysteine, reseveratrol, rutoside etc. In the present communication, several herbal drugs have also been discussed, which can act through mechanisms other than antioxidant and may be evaluated as a combination therapy for prevention of DOX-induced cardiotoxicity in future.

For many years the concept relating salt to blood pressure (BP) changes has been debated and the concept of natriuretic hormone eliminating excessive sodium by direct inhibition of Na/K-ATPase has raised controversy. However, a recently discovered Na/K-ATPase signaling function has been widely confirmed and provided a novel mechanism to explain the relationship between sodium and blood pressure. Recently, we have demonstrated that activation of this Na/KATPase signaling function regulates sodium reabsorption in renal proximal tubules (RPTs) to correct sodium retention related volume expansion and BP increase. This mechanism demonstrates that rather than contributing to development and maintenance of hypertension, a properly regulated RPT Na/K-ATPase signaling has a protective effect by stimulating renal sodium excretion. A clear understanding of molecular mechanisms whereby the Na/K-ATPase signaling axis counterbalance volume expansion would have major pathophysiological and therapeutic implications for volume expansion mediated hypertension. In this review, we will focus on the effect of the newly appreciated cardiotonic steroids (CTS)-Na/K-ATPase signaling on RPT-mediated sodium handling by coordinated regulation of the Na/K-ATPase and sodium/proton exchanger isoform 3 (NHE3).

The depot antipsychotics are synthesized by esterification of the active drug to a long chain fatty acid and the resultant compound is then dissolved in a vegetable oil, with the exception of some molecules of new generation characterized by microcrystalline technologies. The absorption rate constant is slower than the elimination rate constant and therefore, the depot antipsychotics exhibit 'flip-flop' kinetics where the time to steady-state is a function of the absorption rate, and the concentration at steady-state is a function of the elimination rate The pharmacokinetics of depot antipsychotic medications are such that an intramuscular injection given at intervals from 1 to 4 weeks will produce adequate plasma concentrations that are sufficient to prevent relapse over the dosage interval. Such medication is useful in patients who do not reliably take their oral medication. The pharmacokinetics and clinical actions of various depot formulations of antipsychotic drugs have been extensively studied. The clinical pharmacokinetics of the depot antipsychotics for which plasma level studies are available (i.e. fluphenazine enanthate and decanoate, haloperidol decanoate, bromperidol decanoate, clopenthixol decanoate, flupenthixol decanoate, perphenazine onanthat, pipotiazine undecylenate, pipotiazine palmitate, fluspirilene, Long-acting injectable risperidone, olanzapine pamoate, paliperidone palmitate, Long-acting iloperidone, Long-acting injectable aripiprazole) are reviewed. The proper study of these agents has been handicapped until recently by the necessity of accurately measuring subnanomolar concentrations in plasma. Their kinetic properties, the relationship of plasma concentrations to clinical effects, and conversion from oral to injectable therapy are discussed.