Metalloid compounds as drugs.

The six elements commonly known as metalloids are boron, silicon, germanium, arsenic, antimony, and tellurium. Metalloid containing compounds have been used as antiprotozoal drugs. Boron-based drugs, the benzoxaboroles have been exploited as potential treatments for neglected tropical diseases. Arsenic has been used as a medicinal agent and arsphenamine was the main drug used to treat syphilis. Arsenic trioxide has been approved for the treatment of acute promyelocytic leukemia. Pentavalent antimonials have been the recommended drug for visceral leishmaniasis and cutaneous leishmaniasis. Tellurium (IV) compounds may have important roles in thiol redox biological activity in the human body, and ammonium trichloro (dioxoethylene-O, O'-)tellurate (AS101) may be a promising agent for the treatment of Parkinson's disease. Organosilicon compounds have been shown to be effective in vitro multidrug-resistance reverting agents.

Pharmaceutical co-crystals - a review

Co-crystallization alters the molecular interactions and composition of pharmaceutical materials, and is considered better alternatives to optimize drug properties. Co-crystals consists of API and a stoichiometric amount of a pharmaceutically acceptable co-crystal former. Pharmaceutical co-crystals are nonionic supramolecular complexes and can be used to address physical property issues such as solubility, stability and bioavailability in pharmaceutical development without changing the chemical composition of the API. Co-crystals can be constructed through several types of interaction, including hydrogen bonding, pi-stacking, and van der Waals forces. Co-crystals High Throughput provides information on relationship between formation and chemical structure of the API and conformer. Factors affecting co-crystal stability are reported and a co-crystal is only expected to form if it is thermodynamically more stable than the crystals of its components. Phase transformations induced during processing/storage affects the mechanisms of conversion of crystalline drugs to co-crystals. Pharmaceutical co-crystals could play a major part in the future of API formulation and can be employed for chiral resolution(AU)

Increase in brain nitric oxide synthase activity in daunorubicin-treated rats.

Anthracyclines such as daunorubicin are very effective anticancer agents. These drugs are known to cause side effects including cardiotoxicity. Anthracyclines are neurotoxic to laboratory animals. Nitric oxide is a novel and very important chemical messenger in the brain. However, at higher levels, nitric oxide causes well defined neurotoxicity. Therefore, we determined nitric oxide synthase activity in rat brain after daunorubicin treatment in an effort to explain the neurotoxicity produced by anthracyclines. Male Sprague-Dawley rats were treated with different subcutaneous doses of daunorubicin (0.1-4.0 mg/kg/week for five weeks) while control animals were injected with phosphate buffered saline. There was a significant increase (80%) of nitric oxide synthase activity in daunorubicin-treated animals as compared to controls. This activity was inhibited by N-monomethyl-L-arginine (NMMA), nitroarginine, N-6-aminohexyl-5-chloro-1-napthalene sulfonamide (W-7), a calmodulin antagonist, suggesting that the nitric oxide synthase activity is calmodulin dependent. Further, our in vitro studies demonstrated that daunorubicin interacted with calmodulin as measured by N-phenyl-1-napthylamine (NPN) fluorescence. These results indicate that daunorubicin increases nitric oxide synthase activity in rat brain which may increase the levels of nitric oxide. The increased levels of nitric oxide may cause neurotoxicity. Our results further indicate that daunorubicin interacts with calmodulin and enhances nitric oxide synthase activity which is dependent on calmodulin.

Effect of carbon tetrachloride on inositol 1,4,5-trisphosphate dependent and independent regulation of rat brain microsomal Ca2+ flux.

Carbon tetrachloride (CCl4) is a highly toxic industrial solvent with pronounced effects on the liver and brain. CCl4 is enzymatically cleaved to produce free radicals which attack membrane components, including proteins. Earlier reports indicated that CCl4 affects Ca(2+)-regulated events in the brain. Hence, the present study was initiated to determine whether CCl4 affects inositol 1,4,5-trisphosphate (IP3) receptor binding, free-Ca2+ movements across the microsomal membrane and protein kinase C (PKC) activity in rat brain, since IP3, Ca2+ and PKC are known to be involved in signal transduction. [3H]IP3 binding, free-Ca2+ movements and 45Ca2+ uptake were determined using rat brain microsomes and PKC activity was determined in the cytosolic fraction. CCl4 in vitro decreased [3H]IP3 binding to microsomes. IP3 mediated Ca2+ release from microsomes was inhibited and also the reuptake of IP3-released Ca2+ into microsomes was decreased in the presence of CCl4. CCl4 at concentrations < 2 microM independently released Ca2+ from microsomes. Uptake of total Ca2+ into microsomes was inhibited by CCl4 as observed with 45Ca(2+)-uptake studies. CCl4 at 1 microM inhibited PKC activity by 50%. Thus, perturbations in the binding of IP3 to its receptor sites, changes in the Ca2+ flux across the microsomal membrane and modulation of PKC activity by CCl4 in vitro suggested that CCl4 may exert neurotoxicity by altering signal transduction pathways.

Combined effects of carbon tetrachloride and chlordecone on calmodulin activity in gerbil brain.

The potentiation of carbon tetrachloride (CCl4) toxicity by chlordecone (CD) pretreatment in different animal models is well established. However, these studies have only dealt with hepatotoxicity. The present study was initiated to determine whether CD preexposure potentiates CCl4 neurotoxicity in gerbils. Gerbils were chosen for the reason that the metabolism of CD in gerbil is similar to that of humans. Gerbils (50-80 g), fed on diet without or with CD (10 ppm) for 15 d, were challenged with a single dose of CCl4 (15 microliters, ip). Ca(2+)-ATPase and calmodulin (CaM) activities were determined in gerbil brain P2 fraction and cytosol, respectively, at intervals of 0.5, 2, 6, 12, and 24 h after CCl4 administration. Ca(2+)-ATPase and CaM activities were decreased at 0.5 and 2 h in both CD-preexposed and CCl4-treated gerbils. However, CaM activity returned to normal levels after 6 h and Ca(2+)-ATPase activity showed 80% recovery after 2 h. In vitro experiments showed that CCl4 alone at 5 microM concentration inhibited Ca(2+)-ATPase activity up to 50%. Combination of CD (0.5 microM) and CCl4 (1 and 5 microM) on Ca(2+)-ATPase activity showed no additive effect in vitro. Interaction between CCl4 and CaM was studied in the presence and absence of CD by monitoring NPN fluorescence. The decrease in NPN fluorescence observed with CCl4 was not potentiated by CD preincubation. These data suggest that CD does not enhance CCl4-induced alterations of Ca(2+)-ATPase and CaM activities in gerbil brain.