Setting course for a translational pharmacology and a predictive toxicology based on the numerical probability of clinical relevance.

For a significant share of the chemicals, current bioassays mispredicted the outcomes in the reference methods they simulate. For any drug or chemical, and depending on the regulatory or corporate situation, three different approaches calculate the numerical probability by which agreement (or discrepancy) can be statistically expected between (1) the result of a predictive bioassay, and (2) the outcome on its reference method. If such concordance is expected with enough confidence based on a sufficient percentage probability, then specific results from that bioassay can be considered as correctly predictive.

Applying Bayesian forecasting to predictive toxicology: The probability of innate carcinogenicity to humans of colorants synthesized from benzidine.

The preclinical identification of health hazards relies on the performance (the historic concordance to the respective gold standard) of regulatorily recommended bioassays. However, any testing with less than 100% sensitivity (or 100% specificity) can deliver false results (outcomes discordant to the respective gold standard). Conversely, the predictive values approach (a.

The 2-year rodent bioassay in drug and chemical carcinogenicity testing: Performance, utility, and configuration for cancer hazard identification.

For several intended uses of chemicals, the 2-year rodent bioassay (RCB) has been the benchmark method to screen the carcinogenicity to humans of substances, according to the hazard identification sphere. Despite the ongoing controversy around this traditional testing, the RCB is in force and being used by stakeholders. After assembling the RCB's ability to forecast the carcinogenicity to humans of substances, the current review aimed to provide a discussion on the RCB's (1) sensitivity and specificity; (2) utility; (3) configuration, and (4) provisional role in the regulatory policy.

The numerical probability of carcinogenicity to humans of some antimicrobials: Nitro-monoaromatics (including 5-nitrofurans and 5-nitroimidazoles), quinoxaline-1,4-dioxides (including carbadox), and chloramphenicol.

Many substances are already tested in the long-term rodent bioassay (RCB). Nonetheless, statements such as the following are common in the regulatory literature: "the significance of the carcinogenicity findings in rodents relative to the therapeutic use of drugs in humans is unknown." (U.

The numerical probability of carcinogenicity to humans of some pharmaceutical drugs: Alkylating agents, topoisomerase inhibitors or poisons, and DNA intercalators.

The nonclinical branch of regulatory pharmacology has traditionally relied on the sensitivity and specificity of regulatorily recommended bioassays. Nonetheless, any predictive testing (eg, safety pharmacology) with less than 100% sensitivity or 100% specificity is prone to deliver false positive or negative results (namely, outcomes discordant to the clinical gold standard). It was recently suggested that the statistics-based and regulatory pertinent "predictive values approach" (PVA) might help to reach a more predictive use of preclinical testing data.

The 2-year rodent bioassay in drug and chemical carcinogenesis testing: Sensitivity, according to the framework of carcinogenic action.

The long-term rodent bioassay (RCB) has been the gold-standard for the pre-marketing prediction of chemical and drug carcinogenicity to humans. Nonetheless, the validity of this toxicity test has remained elusive for several decades. In the quest to uncover the performance of the RCB, its (SEN) was charted as the first step.

The predictivity of the -alert performance- functionality of the OECD QSAR-Toolbox (c/w further issues on the predictivity of nonclinical testing).

The OECD QSAR-Toolbox can be considered a milestone in predictive toxicology. Because of the reliability of its supporting institutions (OECD and ECHA), its broadness in terms of feeder databases, and its predictive capacity, the QSAR-Toolbox is called to have a major role in regulatory toxicology. Recently, a novel functionality was built for the QSAR-Toolbox: the alert performance (AP).

Drug excipients, food additives, and cosmetic ingredients probably not carcinogenic to humans reveal a functional specificity for the 2-year rodent bioassay.

Regarding carcinogenicity testing, the long-term rodent bioassay (RCB) has been the test required by most regulatory agencies across the world. Nonetheless, due to the lack of knowledge about its specificity, it has been argued that the RCB is unspecific or even invalid. Because of the substantial limitations of epidemiology to identify chemicals probably not carcinogenic to humans (PNCH), it has been very difficult to address the specificity of the RCB.

Vanadium: History, chemistry, interactions with α-amino acids and potential therapeutic applications.

In the last 30 years, since the discovery that vanadium is a cofactor found in certain enzymes of tunicates and possibly in mammals, different vanadium-based drugs have been developed targeting to treat different pathologies. So far, the studies of the insulin mimetic, antitumor and antiparasitic activity of certain compounds of vanadium have resulted in a great boom of its inorganic and bioinorganic chemistry. Chemical speciation studies of vanadium with amino acids under controlled conditions or, even in blood plasma, are essential for the understanding of the biotransformation of e.

Synthesis, β-hematin inhibition studies and antimalarial evaluation of new dehydroxy isoquine derivatives against Plasmodium berghei: A promising antimalarial agent.

Many people are affected by Malaria around the world, and the parasite is developing resistance against available drugs. Currently, isoquine and N-tert-butyl isoquine are some of the most promising antimalarial candidates that have already reached Phase I and II clinical trials, respectively. Nevertheless, pharmacodynamic studies have demonstrated that isoquine is highly sensitive to form O-glucuronide metabolite, which may affect its accumulation in tissues.

Design, synthesis, structure-activity relationship and mechanism of action studies of a series of 4-chloro-1-phthalazinyl hydrazones as a potent agent against Leishmania braziliensis.

With the aim to identify a potential drug candidate to treat cutaneous leishmaniasis, a series of 1-phthalazinyl hydrazones were synthesized and tested against Leishmania braziliensis parasite, one of the main responsible of this disease in the world. A structure-activity relationship permitted to identify two phthalazines containing nitroheterocyclic moiety 3l and 3m as promising new lead compounds. These compounds showed a significant antileishmanial activity against promastigote form of L.

Hypoglycemic activity of extracts and compounds from the leaves of Hintonia standleyana and H. latiflora: potential alternatives to the use of the stem bark of these species.

The CH(2)Cl(2)-MeOH (1:1) extract of the leaves of Hintonia standleyana and H. latiflora caused significant decrease in blood glucose levels in both normal and streptozotozin (STZ)-induced diabetic rats when compared with vehicle-treated groups (p < 0.05).