History Of Drug Development Research Articles

As Pílulas Rosadas do Dr. Williams: o que um medicamento para anemia pode nos indicar sobre racismo e sexismo?

The history of drug development can be understood from different nuances and perspectives, with undeniable links between the pharmaceutical industry, economics and scientific development. This article analyzes the ads for the drug Dr. Williams Pink Pills, announced in a Journal of Ceará state in the beginning of the 20th century. The analysis provides us with evidence of the processes by which racist and sexist representations that discriminated against aspects of beauty and morality were fundamental aspects in determining the medication's clientele.

Primary Sulfonamide Synthesis Using the Sulfinylamine Reagent N-Sulfinyl-O-(tert-butyl)hydroxylamine, t-BuONSO.

Sulfonamides have played a defining role in the history of drug development and continue to be prevalent today. In particular, primary sulfonamides are common in marketed drugs. Here we describe the direct synthesis of these valuable compounds from organometallic reagents and a novel sulfinylamine reagent, t-BuONSO. A variety of (hetero)aryl and alkyl Grignard and organolithium reagents perform well in the reaction, providing primary sulfonamides in good to excellent yields in a convenient one-step process.

Meeting Proceedings of the “Phase I: Where Science Becomes Medicine” Conference, Manchester, UK

Meeting Proceedings of the “Phase I: Where Science Becomes Medicine” Conference, Manchester, UK

Too Many Avoidable Suicides Occur Worldwide in Young Patients.

United States (US) and European Union (EU) laws attempt to counterbalance the presumed discrimination of children in drug treatment and drug development. The US Food and Drug Administration (FDA)-rewarded pediatric studies with antidepressants triggered in 2004 an FDA black-box warning of suicidality in young patients. Fewer antidepressants were prescribed, and the number of completed suicides of young persons increased. The dilemma between this warning and the need to adequately treat young depressed patients remains unsolved. We analyzed the history of drug development, the evolving view of diseases in young patients, US/EU pediatric laws, and pediatric studies triggered by FDA/European Medicines Agency (EMA) in depression and other diseases on the background of developmental pharmacology; financial, institutional, and other interests; and the literature. The FDA/EMA define children administratively, not physiologically, as <17 (FDA)/<18 years old (EMA). But young persons mature physiologically well before their 17th/18th birthday. Depression occurs in young persons, has special characteristics, but is not fundamentally different from adult depression. Young persons are not another species. Regulatory requirements for “pediatric” studies focus on “pediatric” labels. Many “pediatric” studies, including those in depression, lacked and lack medical sense and harm patients by placebo treatment although effective drugs exist. The FDA has partially abandoned separate “pediatric” efficacy studies, but not in psychiatry. Clinicians, parents, institutional review boards, and ethics committees should become aware of questionable “pediatric” studies, should re-evaluate ongoing ones, consider to suspend them, and to reject new ones. The concept of separate “pediatric” drug approval needs to be abandoned.

Salinomycin and its derivatives – A new class of multiple-targeted “magic bullets”

The history of drug development clearly shows the scale of painstaking effort leading to a finished product – a highly biologically active agent that would be at the same time no or little toxic to human organism. Moreover, the aim of modern drug discovery can move from “one-molecule one-target” concept to more promising “one-molecule multiple-targets” one, particularly in the context of effective fight against cancer and other complex diseases. Gratifyingly, natural compounds are excellent source of potential drug leads. One of such promising naturally-occurring drug candidates is a polyether ionophore – salinomycin (SAL). This compound should be identified as multi-target agent for two reasons. Firstly, SAL combines a broad spectrum of bioactivity, including antibacterial, antifungal, antiviral, antiparasitic and anticancer activity, with high selectivity of action, proving its significant therapeutic potential. Secondly, the multimodal mechanism of action of SAL has been shown to be related to its interactions with multiple molecular targets and signalling pathways that are synergistic for achieving a therapeutic anticancer effect. On the other hand, according to the Paul Ehrlich's “magic bullet” concept, invariably inspiring the scientists working on design of novel target-selective molecules, a very interesting direction of research is rational chemical modification of SAL. Importantly, many of SAL derivatives have been found to be more promising as chemotherapeutics than the native structure. This concise review article is focused both on the possible role of SAL and its selected analogues in future antimicrobial and/or cancer therapy, and on the potential use of SAL as a new class of multiple-targeted “magic bullet” because of its multimodal mechanism of action.

Can public financing of the private sector defeat antimicrobial resistance?

Public financing to incentivise private sector innovation in antimicrobial pharmaceuticals is believed by many to be necessary to defeat growing threats from antimicrobial resistance. Large cash incentives from the public sector are said to be essential to stimulate 'normal' market forces capable of unleashing much-needed innovation. However, there is little evidence to suggest that lack of innovation in drug development is peculiar to antimicrobials or that current deficits in the supply of antimicrobials is due to unique inefficiencies in the antimicrobial market. Neither the history of drug development in general nor of antimicrobial innovation in particular supports economic interventions intended to stimulate private sector supply of new antimicrobials. On the contrary, public underwriting of the private sector, which by definition is compelled to prioritise profit, risks dire consequences for future global health.

Why Has a Run-In Period Been a Design Element in Most Landmark Clinical Trials? Analysis of the Critical Role of Run-In Periods in Drug Development

Prior exposure to one of the randomized treatments has been a routine design element of large-scale trials in patients at high cardiovascular risk. A run-in feature has allowed our trials to be more realistic; it has strengthened their ability to estimate the true treatment effect; and it has never undermined the validity of a trial's findings. Those who suggest that run-in periods distort the results of large-scale trials should become more familiar with our history of drug development and our standards of clinical practice. Physicians use run-in periods every day in real life, and trialists have used run-in periods for decades to reliably establish the role of new cardiovascular drugs. Those who reflexively criticize the trials because of their inclusion of a run-in period need to carefully reexamine how medicine is practiced and how it advances.

An assessment of the phytochemicals and antibacterial activity on pathogenic clinical isolates On extract ofphyllanthusniruri.

Throughout the history of drug development, natural products have provided a fundamental source of drugs for fighting infections. In this study, the phytochemical constituents present in the leaf extract of Phyllanthus niruri (Keela Nelli) were screened and their antibacterial properties in vitro were determined using the agar diffusion plate method on selected human pathogens, namely Vibrio cholera 01ogawa, V. cholera 0139, V. parahaemolyticusVP81; O3:K6, Vibrio fluvialis, Salmonella enteritidis-A11, Shigella dysenteriae type 5, Enterotoxigenic E. coli, Bacillus cereus and Pseudomonas sp. The solvent extracts revealed a good concentration dependent antibacterial activity against the test organisms similar to that of the standard antibiotic discs, such as Penicillin, Streptomycin, Kanamycin, Ampicillin, Amoxycillin and Rifampicin. The antioxidant activity was evaluated by free radical scavenging power against 1, 1diphenyl-2-picrylhydrazyl (DPPH) free radical. The IC50 values of the methanolic extract of P. niruri was 49.2 µg/ml and that of control i.e. ascorbic acid was 39.1 µg/ml. Results of phytochemical components of the leaf extracts of Phyllanthus niruri were rich in the alkaloids, terpenoids, tannins, flavonoids and saponins, which might be responsible for its various bioactivities. Qualitative estimation was also done by FT-IR and GCMS analyses for the determination of major functional groups. The outcome of this study could therefore justify the ethno medicinal uses of P. niruri and the antibacterial and antioxidant activities of P. niruri against human pathogens.

A history of drug development in four acts

• The future of pharmaceutical discovery is unclear in light of unique trends in marketing and R&D allocations.

Phytomedicines as potential inhibitors of β amyloid aggregation: significance to Alzheimer's disease

Throughout the history of drug development, plants have been an important source for the discovery of novel therapeutically active compounds for many diseases. The ethnopharmacological approach has provided several leads to identify potential new drugs from plant sources, including those for memory disorders. For the treatment of Alzheimer's disease the drug discovery focus shifted from cholinesterase inhibitors, to other targets primarily based on two key neuropathological hallmarks, namely the hyperphosphorylation of the tau protein resulting in the formation of neurofibrillary tangles (NFTs), and the increased formation and aggregation of amyloid-beta peptide (Aβ) derived from amyloid precursor protein (APP). The present article aims to provide a comprehensive literature survey of plants and their constituents that have been tested for Aβ aggregation, thus possibly relieving several features of Alzheimer's disease (AD).

Targeting of histone deacetylases in brain tumors.

Histone deacetylase inhibitors (HDACis) have fascinated researchers in almost all fields of oncology for many years owing to their pleiotropic effects on nearly every aspect of cancer biology. Since the approval of the first HDACi vorinostat for the treatment of cutaneous T-cell leukemia in 2006, more than a hundred clinical trials have been initiated with a HDACi as a single agent or in combination therapy. Although a number of epigenetic and nonepigenetic molecular mechanisms of action have been proposed, biomarkers for response prediction and patient selection are still lacking. One of the inherent problems in the field of HDACis is their 'reverse' history of drug development: these compounds reached clinical application at an early stage, before the biology of their targets, HDAC1-11, was sufficiently understood. This review summarizes the current knowledge on the human family of HDACs as drug targets in pediatric and adult brain tumors, the efficacy and molecular action of HDACis in preclinical models, as well as the current status of the clinical development of these compounds in the field of neuro-oncology.

Farmacologia no século XX: a ciência dos medicamentos a partir da análise do livro de Goodman e Gilman

This article analyzes the presentation of pharmacology as a science in the textbook by Louis Goodman and Alfred Gilman, updated and reprinted many times between 1941 and 2006. In the first editions, pharmacology was characterized as the science of drugs and related to other areas of knowledge; the history of drug development, the role of this science in its social context and its relationship with industry were stressed. In the following editions, these aspects were minimized, almost disappearing in the 11th (2006). The treatment of historical aspects may contribute to understanding the development of pharmacology, as well as the material on relationships with industry and society is important when reflecting on the criteria for using drugs.

Why is theNew York TimesWriting so Much about Alzheimer's Disease Therapies?

Can we go back to proving that drugs work in preventing, postponing, and ameliorating familial Alzheimer's disease (ad)? Ad is so devastating that there is a great public interest in the drug discovery process as evinced by the sheer number of articles in the serious popular press. The presently available, yet poorly performing, drugs have been approved despite their multiple peripheral side effects. The research on disease-modifying agents for the treatment of ad is largely focused on reducing amyloid plaques. However, it is now clear that companies and researchers alike are losing hope in finding an efficacious therapy rapidly that works in ad patients who are already cognitively impaired, and that people who staked their scientific and professional career on finding a cure for ad based on the amyloid hypothesis are shaken by the series of failed clinical trials within a short period of time. It is emerging that we may start to treat ad far too late to be able to make any significant slowing of the disease or postponing the onset of the symptoms of the disease. The history of drug development for other diseases should encourage us to focus on patients in whom we can identify the genetic markers associated with familial ad. Then when we have an efficacious and very safe drug, we will be able to establish its efficacy on, most importantly, cognition, but also at the level of plaques. This will provide the pharmacological evidence needed to show that it is worth fighting amyloidosis because it saves memory. We have a successful and lucrative history of preventive medicine on a large scale, all we need now is the foresight and will to switch strategy and no longer look for a magic bullet to fix ad, but to discover drugs that will delay and prevent the onset of ad, drugs that may be safely taken by symptom-free patients who are vulnerable and susceptible to ad. The initial population that might be preventatively treated against ad would indeed be those with genetic predisposition. While prevention trials are long and expensive as emphasized by the industry, the market for a safe and effective drug would be extended to the large number of patients susceptible to sporadic ad. Since the highest risk factor for sporadic ad is age, this would be an extraordinarily large market.

KEGG for representation and analysis of molecular networks involving diseases and drugs

Most human diseases are complex multi-factorial diseases resulting from the combination of various genetic and environmental factors. In the KEGG database resource (http://www.genome.jp/kegg/), diseases are viewed as perturbed states of the molecular system, and drugs as perturbants to the molecular system. Disease information is computerized in two forms: pathway maps and gene/molecule lists. The KEGG PATHWAY database contains pathway maps for the molecular systems in both normal and perturbed states. In the KEGG DISEASE database, each disease is represented by a list of known disease genes, any known environmental factors at the molecular level, diagnostic markers and therapeutic drugs, which may reflect the underlying molecular system. The KEGG DRUG database contains chemical structures and/or chemical components of all drugs in Japan, including crude drugs and TCM (Traditional Chinese Medicine) formulas, and drugs in the USA and Europe. This database also captures knowledge about two types of molecular networks: the interaction network with target molecules, metabolizing enzymes, other drugs, etc. and the chemical structure transformation network in the history of drug development. The new disease/drug information resource named KEGG MEDICUS can be used as a reference knowledge base for computational analysis of molecular networks, especially, by integrating large-scale experimental datasets.

Extraction and Analysis of Chemical Modification Patterns in Drug Development

Most drugs have been continuously modified from prototypic compounds in the drug development process. Such chemical modifications in the history of drug development are expected to contain a wealth of medicinal chemists' knowledge, and the KEGG DRUG structure maps have been compiled to capture this knowledge. Here we attempted to extract the information on the chemical modification patterns from 3745 approved drugs in the KEGG DRUG database and 255 drug pairs in the KEGG DRUG structure maps. We first identified 236 core structures and 506 peripheral fragments from the KEGG DRUG database using bit-represented fingerprints and hierarchical clustering of similar structures. We then examined position-dependent relationships between core structures and peripheral fragments, which revealed the tendency of specific fragments connected to specific modification sites on the core structures. Next we converted the drug pairs into 204 peripheral fragment changes at the modification sites. Each change was represented by the transformation profile defined as a difference of fingerprint bit patterns, and the hierarchical clustering of similar transformation profiles was performed. We thus identified 125 chemical modification patterns that characterize the KEGG DRUG structure maps. These patterns were further applied to the reconstruction of a new structure map. The approach presented here may be applicable to systematic in silico drug modifications.

Packaging BCG: Standardizing an Anti-Tuberculosis Vaccine in Interwar Europe

Using the example of the anti-tuberculosis vaccine BCG during the 1920s and 1930s, this article asks how a labile laboratory-modified bacteria was transformed into a genuine standard vaccine packaged and commercialized as a pharmaceutical product. At the center of the analysis lies the notion of standardization inquiring why and how a local laboratory process with standard operating procedures (SOPs) reached its limits and was transformed when the product faced international distribution. Moving from Paul Ehrlich's initial technological notion of Wertbestimmung referring to a practice physiologically testing the effects of ill-defined antitoxins, the concept of standardization is extended to pharmaceutical and economical meanings implying quality control for biological therapeutic agents produced by a variety of industrial entrepreneurs. Following the request for product uniformity, two ways to maintain levels of compatibility and commonality are depicted opposing SOPs and end-product control. Furthermore, standardization is understood as a spiral, never ending process where progressive transformation of the vaccine in its production and medical uses periodically recreated the necessity of standardization. Developments analyzed are thus understood as a stabilization process aligning laboratory settings, products, and practices with medical theories and practices through technical, bureaucratic, and organizational systems. A paradox of the analysis is that standardization as a historical phenomenon and moment in the history of drug development was initially linked to a problem of under-determination of what was to be standardized and to a knowledge gap before it could become a central concept for quality control.

Natural Products as a Robust Source of New Drugs and Drug Leads: Past Successes and Present Day Issues

The history of drug development has its foundation firmly set in the study of natural remedies used to treat human disease over centuries. Analysis of medicinal plants, bioactive cultures, and increased understanding of micronutrients in the food chain opened the door to the development of purified and defined chemical compounds as dose-controlled medicines. Thus, with the early discovery of cardiotonics in foxglove, salicylic acid in willow bark, morphine in poppies, and penicillin in mold, the pharmaceutical industry was launched. Such natural small molecules served as treatments for disease and ultimately, as pharmacologic tools to enable the understanding of the biochemical pathways and mechanisms of disease. In contrast, modern drug discovery technologies coupled with the powerful tools of biotechnology have prompted drug discovery organizations to focus on target-driven drug discovery at the molecular level by launching high-throughput screening programs using artificial biochemical assays. At a time when the pharmaceutical industry has come under scrutiny for high rates of drug development failure, it is interesting to see that natural products drug discovery has been marginalized in favor of this high-throughput biochemical screening paradigm. If modern drug development is once again to benefit from natural products as a source, then the limitations of artificial biochemical assays as applied to the screening of natural extracts must be realized in order to capitalize on the vast natural molecular diversity and rich ethnobotanic data that has emerged worldwide. Natural compounds can again become central players in the treatment of disease and in the understanding of disease mechanisms.

The Single Controlled Trial: Industry Survey Indicates that Implementation is Still a Work in Progress

The Food and Drug Administration Modernization Act of 1997 amended the standard of approval for effectiveness by providing that under certain circumstances, one adequate and well-controlled clinical investigation and confirmatory evidence would be sufficient. The standard of effectiveness has been a point of contention throughout the modern history of drug development and remains so today. With the imminent need to consider the reauthorization of the Prescription Drug User Fee Act, the implementation of the Food and Drug Administration Modernization Act of 1997 will also be open to discussion. In anticipation of the upcoming Congressional and public debate surrounding these laws, the Tufts Center for the Study of Drug Development conducted a survey of nearly 50 of the leading pharmaceutical and biotechnology firms in order to assess the level and manner of utilization of the single controlled trial at the outset of the Food and Drug Administration Modernization Act of 1997 to serve as a frame of reference for these discussions.

Discovery of New Drug Therapies Based on the Study of Adverse Reactions

The term adverse drug reaction (ADR) describes any adverse event associated with the use of a drug in humans. The generalized use of the adjective adverse when describing drug reactions that were not sought after may be inappropriate when these reactions are beneficial to certain subpopulations of patients with other underlying illnesses. Some ADRs may provide invaluable leads to the development of new therapies. There is a well-established history of drug development based upon the serendipitous appreciation of ADRs. A concerted effort to foster the study of ADRs and ADR databases could augment this process.