Consideraciones sobre el programa de Farmacología General en el plan de estudio D para la carrera de medicina / Considerations on the program of the General Pharmacology subject in the syllabus D for the medicine career

El plan de estudio, documento fundamental que establece la dirección general y el contenido principal de la preparación de los profesionales, se ha ido perfeccionamiento continuamente, en correspondencia con el desarrollo cientificotécnico alcanzado. El programa de la asignatura es el que refleja las características más importantes de esta, tiene validez científica y pedagógica y contribuye a la formación del médico general, según las demandas de la sociedad cubana actual. Teniendo en cuenta las consideraciones anteriores se realizó el presente estudio con el objetivo de analizar los elementos teóricos y metodológicos del programa de la asignatura Farmacología General en el plan de estudio D para la carrera de medicina.

The syllabus, fundamental document that establishes the general direction and the main content of the professionals training, has been continually improving, in correspondence with the scientific technical development achieved. The subject program is the one that reflects its most important characteristics; it has scientific and pedagogic validity and contributes to the general doctor training, according to the demands of the present Cuban society. Taking into account the previous considerations this study was carried out aimed at analyzing the theoretical and methodological elements of the General Pharmacology subject program in the syllabus D for the medicine career.

Randomized Controlled Trials Versus Real World Evidence: Neither Magic Nor Myth.

Compared with drugs from the blockbuster era, recently authorized drugs and those expected in the future present a heterogenous mix of chemicals, biologicals, and cell and gene therapies, a sizable fraction being for rare diseases, and even individualized treatments or individualized combinations. The shift in the nature of products entails secular trends for the definitions of "drugs" and "target population" and for clinical use and evidence generation. We discuss that the lessons learned from evidence generation for 20th century medicines may have limited relevance for 21st century medicines. We explain why the future is not about randomized controlled trials (RCTs) vs. real-world evidence (RWE) but RCTs and RWE-not just for the assessment of safety but also of effectiveness. Finally, we highlight that, in the era of precision medicine, we may not be able to reliably describe some small treatment effects-either by way of RCTs or RWE.

[Clinical pharmacology of cardio-oncology: a novel interdisciplinary platform for basic and translational research].

Advances in cancer treatment have led to dramatic increase in cancer survivors. In addition to cardiotoxicity resulting from anthracyclines and radiation therapy, the emergence of novel cancer treatment-related cardiovascular disease (CTRCD) with molecularly targeted therapies and immune checkpoint inhibitors has been recognized as an unmet medical need. Cardio-oncology is a new interdisciplinary research opportunity at the intersection of cardiovascular disease and cancer. Research priorities need to be identified for diagnosis, treatment, and prevention of previously unknown CTRCD(s), including (a) cardiac dysfunction and heart failure, (b) coronary artery disease, (c) valvular disease, (d) arrhythmias and QT-prolongation, (e) arterial hypertension, (f) thromboembolic disease, and (g) other cardiovascular disorders. In particular, understanding the fundamental mechanisms underlying CTRCD is essential for developing new methods. Applying more appropriate disease models and more effective methods for toxicity screening will help to better understand CTRCD. Although animal models have been used to predict potential problems, more advanced predictive models are also needed. Biobanks and other specimens with patient registries are expected to facilitate the validation of new biomarkers, genomic analysis, and imaging methods.

The key role of oncopharmacology in therapeutic management, from common to rare cancers: A literature review.

The therapeutic management of cancers has undergone considerable changes due to the emergence of genomics tools and tumor molecular deciphering. In this context, a dual pharmacological approach based on pharmacogenomic analyses and therapeutic drug monitoring is now part of the routine care in cancer management for personalized therapies. First, molecular and immune profiling of tumors allows the emergence of new pharmacological targets in common as well as in rare cancers. Second, pharmacogenomic analyses coupled to therapeutic drug monitoring guide the prescription by adjusting regimen and managing drug resistance.

Therapeutic targets of vitamin C on liver injury and associated biological mechanisms: A study of network pharmacology.

In our previous studies, vitamin C (VC) exerts potent pharmacological activities against liver injury (LI). Therefore, this report was designed to use network pharmacology-based strategy to predict therapeutic targets of VC against LI, and further to investigate the pharmacological molecular mechanisms. Pathological targets of LI were identified, followed by acquisition of verified targets of VC. After constructing target-functional protein interaction network of VC against LI, the core therapeutic targets of VC against LI were obtained. Further, biological function and pathway enrichment analyses were performed on core therapeutic targets to evaluate the biological processes and key signaling pathways of VC against LI. As revealed in network pharmacology assays, 6 key therapeutic targets for VC against LI were identified, showing tumor necrosis factor (TNF), nuclear factor-kappa-B p65 (RELA), nuclear factor-kappa-B p105 (NFKB1), TNF receptor-associated factor 2 (TRAF2), interleukin 6 (IL-6) and interleukin 1 beta (IL1B). On the basis of data analyses from DAVID database and omicshare cloud platform, bio-functional enrichment assays showed that the therapeutic effects of VC against LI were closely associated with regulating inflammatory reaction and apoptosis. Further, pathway enrichment analysis indicated the anti-LI benefits of VC were principally implicated in regulating the top 20 signaling pathways, such as inflammation-associated TNF signaling pathway, NF-κB signaling pathway. Taken together, the bioinformatics data elucidate that anti-LI pharmacological activities of VC may be predominantly related to inhibition of inflammatory stress, contributing to suppression of LI development. These resultant findings highlight the predicted therapeutic targets may be potential biomarkers for anti-LI.

Recent Advances and Challenges of mTOR Inhibitors Use in the Treatment of Patients with Tuberous Sclerosis Complex.

Tuberous sclerosis complex (TSC) is a genetic condition characterized by the presence of benign, noninvasive, and tumor-like lesions called hamartomas that can affect multiple organ systems and are responsible for the clinical features of the disease. In the majority of cases, TSC results from mutations in the TSC1 and TSC2 genes, leading to the overactivation of the mammalian target of rapamycin (mTOR) signalling pathway, which controls several cell functions, including cell growth, proliferation, and survival. The establishment of a connection between TSC and mTOR led to the clinical use of drugs known as mTOR inhibitors (like rapamycin, also known as sirolimus and everolimus), which are becoming an increasingly interesting tool in the management of TSC-associated features, such as subependymal giant cell astrocytomas, renal angiomyolipomas, and also epilepsy. However, the intrinsic characteristics of these drugs and their systemic effects in such a heterogeneous condition pose many challenges in clinical practice, so that some questions remain unanswered. This article provides an overview of the pharmacological aspects of mTOR inhibitors about the clinical trials leading to their approval in TSC-related conditions and exposes current challenges and future directions associated with this promising therapeutic line.

In the picture: disulfide-poor conopeptides, a class of pharmacologically interesting compounds

During evolution, nature has embraced different strategies for species to survive. One strategy, applied by predators as diverse as snakes, scorpions, sea anemones and cone snails, is using venom to immobilize or kill a prey. This venom offers a unique and extensive source of chemical diversity as it is driven by the evolutionary pressure to improve prey capture and/or to protect their species. Cone snail venom is an example of the remarkable diversity in pharmacologically active small peptides that venoms can consist of. These venom peptides, called conopeptides, are classified into two main groups based on the number of cysteine residues, namely disulfide-rich and disulfide-poor conopeptides. Since disulfide-poor conotoxins are minor components of this venom cocktail, the number of identified peptides and the characterization of these peptides is far outclassed by its cysteine-rich equivalents. This review provides an overview of 12 families of disulfide-poor peptides identified to date as well as the state of affairs.

International Union of Basic and Clinical Pharmacology. XCV. Recent advances in the understanding of the pharmacology and biological roles of relaxin family peptide receptors 1-4, the receptors for relaxin family peptides.

Relaxin, insulin-like peptide 3 (INSL3), relaxin-3, and INSL5 are the cognate ligands for the relaxin family peptide (RXFP) receptors 1-4, respectively. RXFP1 activates pleiotropic signaling pathways including the signalosome protein complex that facilitates high-sensitivity signaling; coupling to Gα(s), Gα(i), and Gα(o) proteins; interaction with glucocorticoid receptors; and the formation of hetero-oligomers with distinctive pharmacological properties. In addition to relaxin-related ligands, RXFP1 is activated by Clq-tumor necrosis factor-related protein 8 and by small-molecular-weight agonists, such as ML290 [2-isopropoxy-N-(2-(3-(trifluoromethylsulfonyl)phenylcarbamoyl)phenyl)benzamide], that act allosterically. RXFP2 activates only the Gα(s)- and Gα(o)-coupled pathways. Relaxin-3 is primarily a neuropeptide, and its cognate receptor RXFP3 is a target for the treatment of depression, anxiety, and autism. A variety of peptide agonists, antagonists, biased agonists, and an allosteric modulator target RXFP3. Both RXFP3 and the related RXFP4 couple to Gα(i)/Gα(o) proteins. INSL5 has the properties of an incretin; it is secreted from the gut and is orexigenic. The expression of RXFP4 in gut, adipose tissue, and ß-islets together with compromised glucose tolerance in INSL5 or RXFP4 knockout mice suggests a metabolic role. This review focuses on the many advances in our understanding of RXFP receptors in the last 5 years, their signal transduction mechanisms, the development of novel compounds that target RXFP1-4, the challenges facing the field, and current prospects for new therapeutics.

International Union of Basic and Clinical Pharmacology. XCIII. The parathyroid hormone receptors--family B G protein-coupled receptors.

The type-1 parathyroid hormone receptor (PTHR1) is a family B G protein-coupled receptor (GPCR) that mediates the actions of two polypeptide ligands; parathyroid hormone (PTH), an endocrine hormone that regulates the levels of calcium and inorganic phosphate in the blood by acting on bone and kidney, and PTH-related protein (PTHrP), a paracrine-factor that regulates cell differentiation and proliferation programs in developing bone and other tissues. The type-2 parathyroid hormone receptor (PTHR2) binds a peptide ligand, called tuberoinfundibular peptide-39 (TIP39), and while the biologic role of the PTHR2/TIP39 system is not as defined as that of the PTHR1, it likely plays a role in the central nervous system as well as in spermatogenesis. Mechanisms of action at these receptors have been explored through a variety of pharmacological and biochemical approaches, and the data obtained support a basic "two-site" mode of ligand binding now thought to be used by each of the family B peptide hormone GPCRs. Recent crystallographic studies on the family B GPCRs are providing new insights that help to further refine the specifics of the overall receptor architecture and modes of ligand docking. One intriguing pharmacological finding for the PTHR1 is that it can form surprisingly stable complexes with certain PTH/PTHrP ligand analogs and thereby mediate markedly prolonged cell signaling responses that persist even when the bulk of the complexes are found in internalized vesicles. The PTHR1 thus appears to be able to activate the Gα(s)/cAMP pathway not only from the plasma membrane but also from the endosomal domain. The cumulative findings could have an impact on efforts to develop new drug therapies for the PTH receptors.

International Union of Basic and Clinical Pharmacology. XCIV. Adhesion G protein-coupled receptors.

The Adhesion family forms a large branch of the pharmacologically important superfamily of G protein-coupled receptors (GPCRs). As Adhesion GPCRs increasingly receive attention from a wide spectrum of biomedical fields, the Adhesion GPCR Consortium, together with the International Union of Basic and Clinical Pharmacology Committee on Receptor Nomenclature and Drug Classification, proposes a unified nomenclature for Adhesion GPCRs. The new names have ADGR as common dominator followed by a letter and a number to denote each subfamily and subtype, respectively. The new names, with old and alternative names within parentheses, are: ADGRA1 (GPR123), ADGRA2 (GPR124), ADGRA3 (GPR125), ADGRB1 (BAI1), ADGRB2 (BAI2), ADGRB3 (BAI3), ADGRC1 (CELSR1), ADGRC2 (CELSR2), ADGRC3 (CELSR3), ADGRD1 (GPR133), ADGRD2 (GPR144), ADGRE1 (EMR1, F4/80), ADGRE2 (EMR2), ADGRE3 (EMR3), ADGRE4 (EMR4), ADGRE5 (CD97), ADGRF1 (GPR110), ADGRF2 (GPR111), ADGRF3 (GPR113), ADGRF4 (GPR115), ADGRF5 (GPR116, Ig-Hepta), ADGRG1 (GPR56), ADGRG2 (GPR64, HE6), ADGRG3 (GPR97), ADGRG4 (GPR112), ADGRG5 (GPR114), ADGRG6 (GPR126), ADGRG7 (GPR128), ADGRL1 (latrophilin-1, CIRL-1, CL1), ADGRL2 (latrophilin-2, CIRL-2, CL2), ADGRL3 (latrophilin-3, CIRL-3, CL3), ADGRL4 (ELTD1, ETL), and ADGRV1 (VLGR1, GPR98). This review covers all major biologic aspects of Adhesion GPCRs, including evolutionary origins, interaction partners, signaling, expression, physiologic functions, and therapeutic potential.

Biomarkers in pharmacology and drug discovery.

Biomarkers, quantitatively measurable indicators of biological or pathogenic processes, once validated play a critical role in disease diagnostics, the prediction of disease progression, and/or monitoring of the response to treatment. They may also represent drug targets. A number of different methods can be used for biomarker discovery and validation, including proteomics methods, metabolomics, imaging, and genome wide association studies (GWASs) and can be analysed using receiver operating characteristic (ROC) plots. The relative utility of single biomarkers compared to biomarker panels is discussed, along with paradigms for biomarker development, the latter in the context of three large-scale biomarker consortia, the Critical Path Predictive Safety Testing Consortium (PSTC), the NCI Early Detection Research Network (EDRN) and the Alzheimer's Disease Neuroimaging Initiative (ADNI). The importance of systematic optimization of many parameters in biomarker analysis, including validation, reproducibility, study design, statistical analysis and avoidance of bias are critical features used by these consortia. Problems including introduction of bias into study designs, data reporting or data analysis are also reviewed.

Structure-based drug design to overcome drug resistance: challenges and opportunities.

Drug resistance is a common concern for the development of novel antiviral, antimicrobial and anticancer therapies. To overcome this problem, several strategies have been developed, many of which involving the theme of this review, the use of structure-based drug design (SBDD) approaches. These include the successful design of new compounds that target resistant mutant proteins, as well as the development of drugs that target multiple proteins involved in specific biochemical pathways. Finally, drug resistance can also be considered in the early stages of drug discovery, through the use of strategies to delay the development of resistance. The purpose of this brief review is to underline the usefulness of SBDD approaches based on case studies, highlighting present challenges and opportunities in drug design.

Amylin and the regulation of appetite and adiposity: recent advances in receptor signaling, neurobiology and pharmacology.

PURPOSE OF REVIEW: This review focuses on recent advances in receptor signaling, neurobiology, and pharmacological interactions of amylin with nutritive status, as well as other metabolism-related regulatory signals. RECENT FINDINGS: Manipulation of components of the amylin receptor complex revealed important roles for the accessory proteins of amylin receptors in energy balance. In-vitro findings point to potential novel sites of action and postreceptor signaling pathways activated by amylin. Neurobiological studies elucidated how amylin activation of hindbrain neural circuitry modulates hypothalamic signaling and responsiveness to leptin. The notion of 'amylin resistance' was addressed in several models (drug or diet-induced hyper-amylinemia). Finally, progress in the design and delivery of amylinomimetics is briefly discussed. SUMMARY: Collectively, these mechanistic studies deepen our understanding of the role of endogenous amylin in the regulation of appetite and adiposity, and hopefully will help guide research efforts towards the development of more effective amylin-based therapies for metabolic diseases.

Natural products as sources of new drugs over the 30 years from 1981 to 2010.

This review is an updated and expanded version of the three prior reviews that were published in this journal in 1997, 2003, and 2007. In the case of all approved therapeutic agents, the time frame has been extended to cover the 30 years from January 1, 1981, to December 31, 2010, for all diseases worldwide, and from 1950 (earliest so far identified) to December 2010 for all approved antitumor drugs worldwide. We have continued to utilize our secondary subdivision of a "natural product mimic" or "NM" to join the original primary divisions and have added a new designation, "natural product botanical" or "NB", to cover those botanical "defined mixtures" that have now been recognized as drug entities by the FDA and similar organizations. From the data presented, the utility of natural products as sources of novel structures, but not necessarily the final drug entity, is still alive and well. Thus, in the area of cancer, over the time frame from around the 1940s to date, of the 175 small molecules, 131, or 74.8%, are other than "S" (synthetic), with 85, or 48.6%, actually being either natural products or directly derived therefrom. In other areas, the influence of natural product structures is quite marked, with, as expected from prior information, the anti-infective area being dependent on natural products and their structures. Although combinatorial chemistry techniques have succeeded as methods of optimizing structures and have been used very successfully in the optimization of many recently approved agents, we are able to identify only one de novo combinatorial compound approved as a drug in this 30-year time frame. We wish to draw the attention of readers to the rapidly evolving recognition that a significant number of natural product drugs/leads are actually produced by microbes and/or microbial interactions with the "host from whence it was isolated", and therefore we consider that this area of natural product research should be expanded significantly.

Timely recognition of cardiovascular toxicity by anticancer agents: a common objective of the pharmacologist, oncologist and cardiologist.

Both conventional and new anticancer drugs can frequently cause adverse cardiovascular effects, which can span from subclinical abnormalities to serious life-threatening and sometimes fatal events. This review examines the principal basic and clinical elements that may be of profit to identify, prevent and treat such toxicities. Clearly, the accomplishment of such objectives requires the strong commitment and cooperation of different professional figures including, but not limited to, pharmacologists, oncologists and cardiologists. The aspect of anticancer drug cardiotoxicity seems to be somehow underestimated, mainly due to inadequate reporting of adverse reactions from oncology drugs in the post-marketing setting. Thus, the implementation of pharmacovigilance is indispensable to rapidly and fully assess the safety of newer agents in real-life patients.

10th annual meeting of the Safety Pharmacology Society: an overview.

The 10th annual meeting of the Safety Pharmacology (SP) Society covered numerous topics of educational and practical research interest. Biopolymers - the theme of the keynote address - were presented as essential components of medical devices, diagnostic tools, biosensors, human tissue engineering and pharmaceutical formulations for optimized drug delivery. Toxicology and SP investigators - the topic of the Distinguished Service Award Lecture - were encouraged to collaborate in the development of SP technologies and protocols applicable to toxicology studies. Pharmaceutical companies, originally organizations bearing all risks for developing their portfolios, are increasingly moving towards fully integrated networks which outsource core activities (including SP studies) to large contract research organizations. Future nonclinical data are now expected to be of such high quality and predictability power that they may obviate the need for certain expensive and time-consuming clinical investigations. In this context, SP is called upon to extend its risk assessment purview to areas which currently are not systematically covered, such as drug-induced QRS interval prolongation, negative emotions and feelings (e.g., depression), and minor chronic cardiovascular and metabolic changes (e.g., as produced by drugs for type 2 diabetes) which can be responsible for delayed morbidity and mortality. The recently approved ICH S9 guidance relaxes the traditional regulatory SP package in order to accelerate the clinical access to anticancer drugs for patients with advanced malignancies. The novel FDA 'Animal Rule' guidance proposes that for clinical candidates with well-understood toxicities, marketing approval may be granted exclusively on efficacy data generated in animal studies as human clinical investigations for these types of drugs are either unfeasible or unethical. In conclusion, the core messages of this meeting are that SP should consistently operate according to the 'fit-for-purpose' principle and gradually integrate new mechanism-oriented safety paradigms into the traditional ones for ensuring more effectively the safety of drugs for any population of patients in need.