Drug development

Repurposing has the objective of targeting existing drugs and failed, abandoned, or yet-to-be-pursued clinical candidates to new disease areas. The open-source model permits for the sharing of data, resources, compounds, clinical molecules, small libraries, and screening platforms to cost-effectively advance old drugs and/or candidates into clinical re-development. Clearly, at the core of drug-repurposing activities is collaboration, in many cases progressing beyond the open sharing of resources, technology, and intellectual property, to the sharing of facilities and joint program development to foster drug-repurposing human-capacity development. A variety of initiatives under way for drug repurposing, including those targeting rare and neglected diseases, are discussed in this review and provide insight into the stakeholders engaged in drug-repurposing discovery, the models of collaboration used, the intellectual property-management policies crafted, and human capacity developed. In the case of neglected tropical diseases, it is suggested that the development of human capital be a central aspect of drug-repurposing programs. Open-source models can support human-capital development through collaborative data generation, open compound access, open and collaborative screening, preclinical and possibly clinical studies. Given the urgency of drug development for neglected tropical diseases, the review suggests elements from current repurposing programs be extended to the neglected tropical diseases arena.

Unlike traditional biological research that focuses on a small set of components, systems biology studies the complex interactions among a large number of genes, proteins, and other elements of biological networks and systems. Host-pathogen systems biology examines the interactions between the components of two distinct organisms: a microbial or viral pathogen and its animal host. With the availability of complete genomic sequences of a variety of hosts and pathogens, together with breakthroughs in proteomics, metabolomics, and other experimental areas, the investigation of host-pathogen systems on a multitude of levels of detail has come within reach. This chapter introduces methods and approaches for the analysis of host-pathogen systems. We will particularly emphasize the role of biochemical networks for the study of complex relationships across species boundaries. Although the research area of host-pathogen systems biology spans multiple spatial and temporal scales, we will focus on the molecular and cellular aspects of pathogen-host interactions. We will cover the construction of biochemical networks, the identification of functional response sub-networks, and their comparative network analysis. These methods find application in the identification of host markers and drug targets for further drug development and therapeutic interventions. We will also provide a brief review of other modeling techniques and applications within host-pathogen systems biology, including rule-based modeling of signal transduction pathways, immune system models, and physiological top-down approaches.

The pharmaceutical industry has produced many drugs that have benefited man. Political frameworks designed to govern the industry must maintain these benefits. However, regulation needs to be sufficiently robust to protect public health from drugs that are unsafe, ineffective, or unnecessary. The extent of industry influence over drug regulation, at the expense of other interested parties, suggests that the current system could be more robust. The many ways in which the pharmaceutical industry can influence governments and regulatory agencies are discussed, and methods by which this influence can be curbed are suggested.

PET is a technique with a strong potential for use in drug evaluation and development. In particular, the distribution and pharmacokinetics of locally administered drugs may be advantageously explored noninvasively using labeled compounds. This pilot study was performed to demonstrate the effectiveness of PET for drug development and to determine the human biodistribution and kinetics of triamcinolone acetonide, labeled with 11C, formulated and nasally administered as Nasacort AQ nasal inhalant. Carbon-11-labeled triamcinolone acetonide was formulated as the commercial product, and PET scans of the heads of four volunteers were performed in a vertical orientation. Region-of-interest analysis with MRI coregistration was used to analyze the distribution and kinetics in nasal tissues. Deposition of the majority of the dose on target tissues was immediate. Penetration into sinuses was observed. There was moderate redistribution and slow migration of the drug through nasal passages to th...

Check the properties attributed to medicinal plants is of vital importance as an alternative in the medical therapy and as a source of development of new drugs. Medicinal plants offer a path with great possibilities, an encouraging alternative for the control of various diseases in man. Mangroves are a resource of great significance for Cuba and the world, mangrove vegetation is represented in this country for four tree species, where Rhizophora mangle L. also known as red mangrove, is now the dominant species. Due to the pharmacological results found in this species as healing, antiseptic, antimicrobial, anti-ulcer, treatment of open wounds, anti-inflammatory, antioxidant, antidiarrheal, insecticide, larvicide among others; it could be an important source of new products aimed at solving health problems of great current relevance, but using this species for drug development has been limited by the damage it can cause to the ecosystem over-exploitation of mangroves. The objective of...

The pharmacokinetics of a single oral dose of 3H-astemizole (AST) of 1 mg/kg was studied in Beagle dogs and compared with that of a tracer dose superposed at the end of a subchronic experiment. Single and superposed doses were equally well absorbed, and elimination half-lives of AST and of its metabolites were similar at both occasions (t1/2ß = 3–5 d). Steady-state was reached after 2–3 weeks of daily dosing. AST and its metabolite desmethylastemizole (DES-AST) were extensively distributed, mainly to well perfused tissues but only poorly to brain, muscle, and fat. All tissue levels were many times higher than the corresponding plasma concentrations. The superposed tracer dose was well stirred in the tissue compartments and showed instantaneous equilibrium with pretreatment levels. Tissue/plasma level ratios of AST and DES-AST remained constant with time, indicating that the elimination from tissues proceeded at a similar rate to that from plasma. The extensive distribution of AST and DES-AST is explained by a strong, but reversible tissue binding that appears to be rate-limiting for the elimination from the body.

Prostate cancer chemoprevention represents a relatively new and promising strategy for reducing the immense public health burden of this devastating cancer of men in the United States and Western societies. Chemoprevention is defined as the administration of agents (drugs, biologics, and natural products) that modulate (inhibit) one or more steps in the multistage carcinogenesis process culminating in invasive adenocarcinoma of the prostate. In 2000, there were an estimated 170,000 new cases of prostate cancer and 31,000 deaths in the United States. During the past decade, the National Cancer Institute (NCI) organized the chemoprevention research program and began testing the first generation of promising agents (eg, 4-(hydroxy)-fenretinide [4-HPR], difluoromethylornithine [DFMO], antiandrogens) in high-risk cohorts and launched the first-large scale US phase 3 primary prevention trial, known as Prostate Cancer Prevention Trial (PCPT-1), in 18,000 average-risk men (age more than 55 years and prostate-specific antigen [PSA] less than 3 ng/mL) treated for 7 years with finasteride or placebo. In the summer of 1998, the NCI Prostate Cancer Progress Review Group (PRG) Report to the director of NCI was published in response to the leadership of the prostate cancer advocacy community in conjunction with Congress. To further elucidate and address critical issues identified in this report and to develop a research agenda for the newly created Prostate and Urologic Cancer Research Group in the Division of Cancer Prevention at NCI, the NCI organized the workshop "New Clinical Trial Strategies for Prostate Cancer Chemoprevention." The major objectives were to promote understanding and cooperation among the NCI, US Food and Drug Administration (FDA), academia, pharmaceutical industry, and the public regarding new opportunities for clinical prevention trials for prostate cancer. The workshop was divided into three concurrent breakout panels and a fourth joint integrative panel. The workshop addressed multiple key areas identified in the PRG report in the following panels: (1) Molecular Targets and Promising Agents in Clinical Development; (2) Intermediate Endpoint Biomarkers for Prevention Trials; (3) High-Risk Study Populations for Prevention Trials, and (4) Preventive Clinical Trial Designs and Regulatory Issues. Expert panelists were drawn from leading academic, pharmaceutical, and government scientists in basic research and clinical investigation. Key pharmaceutical, biotechnology, academic, and National Institutes of Health scientists presented overviews of their new agents and products in clinical development (representing the next generation of promising agents). Senior FDA physicians from the Center for Drugs and Center for Biologics presented on current standards for new drug and biologic approval for chemoprevention efficacy. Some of the key topics included recent advances in the state of knowledge of promising agents in the clinic based on molecular targets as well as bottlenecks in drug development for pharmaceutical sponsors; strategic modulable biomarkers that can serve as primary endpoints in phase 1/2 trials to assess preventive efficacy; high-risk cohorts with precancer (high-grade prostatic intraepithelial neoplasia) and representative clinical trial designs that are ready for immediate translation into efficient prevention trials, such as Bayesian sequential monitoring for early assessment of biologic activity and factorial designs for assessment of multiagent combinations. Finally, each expert panel generated recommendations for areas of future research emphasizing opportunities and infrastructure needs.

Aviscumine is an Escherichia coli-derived recombinant type II ribosome-inactivating protein with potent antitumor activity in vitro and in vivo. It is the recombinant counterpart of natural mistletoe lectin-I. The current study was performed to determine the safety profile, dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) of the intravenous (i.v.) administration of aviscumine in cancer patients. Translational research included the evaluation of pharmacokinetics and monitoring of plasma cytokine and anti-aviscumine antibody induction after administration of the drug. Aviscumine was given twice weekly as a 1 h central i.v. infusion in patients with advanced, refractory progressive, solid malignant tumors who had not been previously exposed to natural mistletoe preparations. They had histologically or cytologically verified disease, were > or =18 years old, had an Eastern Cooperative Oncology Group performance status < or =2 and adequate bone marrow, liver and renal ...

Cysteine proteases (falcipains), a papain-family of enzymes of Plasmodium falciparum, are responsible for haemoglobin degradation and thus necessary for its survival during asexual life cycle phase inside the human red blood cells while remaining non-functional for the human body. Therefore, these can act as potential targets for designing antimalarial drugs. The P. falciparum cysteine proteases, falcipain-II and falcipain- III are the enzymes which initiate the haemoglobin degradation, therefore, have been selected as targets. In the present study, we have designed new leupeptin analogues and subjected to virtual screening using Glide at the active site cavity of falcipain-II and falcipain-III to select the best docked analogues on the basis of Glide score and also compare with the result of AutoDock. The proposed analogues can be synthesized and tested in vivo as future potent antimalarial drugs. Protein falcipain-II and falcipain-III together with bounds inhibitors epoxysuccinate...

Enabled by their size and supramolecular structures, nanoparticles (that is, particles of approximately 10 to 100 nanometers) promise to be particularly capable agents in the detection, diagnosis, and treatment of cancer. When loaded with chemotherapeutic agents, nanoparticle delivery to cancerous tissues relative to healthy tissues may be favorably biased by size and through the attachment of targeting ligands to the surface of the particle. Nanoparticles may be made from a variety of materials, and in addition to chemotherapeutic payloads, nanoparticles can incorporate non-bioactive elements useful as diagnostic and device agents. For example, the inclusion of iron oxide colloids enables nanoparticle use as magnetic resonance imaging (MRI) contrast agents, and also, through the application of an alternating magnetic field (AMF), enables the particle to generate enough heat to be used for hyperthermic therapeutic applications. In this report, we also introduce novel Magnetic Nanoparticle Hydro-Gel (MagNaGelTM) materials comprised of chemotherapeutic agents, iron oxide colloids, and targeting ligands. MagNaGel particles were fabricated in the 20- to 40-nm size range with very narrow size dispersion. These particles demonstrate high (>10 wt %) chemotherapeutic loading, tumor-associated biomolecular binding, good magnetic susceptibility, and attractive toxicity and circulation profiles in mouse models. Looking forward, the convergence of drug and device on the nano-scale promises treatment modalities that cannot be practiced through traditionally distinct drug and device combinations. MagNaGel nanoparticles are drug-device hybrids that, when used in conjunction with diagnostic MRI and inductive heating, may play a key role in new and powerful cancer treatment regimens. Drug Dev. Res. 67:70–93, 2006. © 2006 Wiley-Liss, Inc.

-----ÖZET: Bugün, farklı farmasötik sınıflardan çeşitli antidepresif ajanlar klinik depresyon tedavisinde başarıyla kullanılmaktadır. Ne var ki Türkçe tıp literatüründe bu ilaçların güncel klinik kullanım ve sonuçlarına dair bol miktarda yayın bulunmasına karşın, bunların tarihi klinik gelişim sürecini kökenlere inerek, teferruatla bildiren çalışmalar çok azdır. Bu araştırmada, literatürdeki bu boşluğun dolduruluşuna katkıda bulunmak amaçlanmıştır. Araştırmada, antidepresif ajanların kısmen etki mekanizmalarına kısmen de kimyasal yapılarına göre düzenlenmiş olan klasik tasnifi izlenmiştir. PubMed ve ScienceDirect gibi veri tabanlarının ve çeşitli bilimsel dergilerin arşivlerinin retrospektif taranışı ile her bir farmasötik alt sınıfın başlangıcını teşkil eden prototipik antidepresanın keşfi; tarihi olay örgüsüne, ilgili tıbbi figürlere ve orijinal klinik araştırma sonuçlarına dair ilk elden bilimsel yayınlar üzerinden işlenmiştir. Antidepresif psikofarmakoterapi tarihindeki dönüm noktaları üzerinde durulmuş, başlıca ilaç sınıfları (monoamin oksidaz inhibitörleri, trisiklik ve tetrasiklik ajanlar ve monoaminerjik geri alım inhibitörleri) arasında bağlantılar kurulmuş ve yerine göre analojiler yapılmış ya da farklılıklar vurgulanmıştır. Varılan başlıca bir sonuç, antidepresif psikofarmakoterapi tarihinde tesadüfi gözlem eseri ("ilk kuşak/klasik") ajanlardan rasyonel dizaynla ilaç üretimine ("ikinci kuşak" antidepresanlara) geçişin interdisipliner iş birliğine borçlu olunan gelişmelerle mümkün olmuş olduğudur: Çeşitli bilimsel branşlardan kişilerce monoaminerjik konsantrasyon hipotezinin ortaya atılışı, monoamin oksidaz-A ve-B enzimlerinin keşfi, floresans mikroskopiye dayanan histokimyasal görüntüleme yönteminin geliştirilişi, antidepresif ajanların etki mekanizmalarının sistematik in vitro ve in vivo tetkikatla aydınlatılışı ve de antihistaminikler gibi mevcut kimyasalların ya da yeni maddelerin klinik çalışmalarla antidepresif potansiyelleri bakımından sınanışı gibi aşamalardan geçilerek, sonunda bugün majör depresif bozukluk tedavisinde başvurulan birincil ilaçlar olan monoaminerjik geri alım inhibitörlerine ulaşılmıştır.

-----ABSTRACT: Various antidepressive agents from different pharmaceutical classes are used successfully to treat depression today. Despite their well-documented clinical use and outcomes, however, the Turkish medical literature appears to lack studies dilating upon their historical development with reference to the origins and key events. Aimed at contributing to filling this gap, this study was built on the classical classification of antidepres-sive agents based partly on mechanism of action and chemical structure. PubMed, ScienceDirect, and various journal archives were reviewed retrospectively concerning the discovery of each agent that prototyped the pharmaceutical subclass investigated, with a focus on the timeline events, medical figures, and original clinical research results. The milestones in the history of antidepressive psychopharmacotherapy were highlighted, with connection and comparison between the main drug classes (monoamine oxidase inhibitors, tricyclics and tetracyclics, and monoaminergic reuptake inhibitors) through analogies and distinctions identified when appropriate. A main conclusion was that the consequential transition from the serendipitously obtained ("first-generation/classical") agents to rationally designed drug production (the "second-generation" antidepressants) was achieved by developments brought about by interdisciplinary collaboration. Production of the MRIs, pharmaceutics used primarily in treating major depressive disorder today, was processed through various stages by various scientific contributors propounding the monoaminergic concentration hypothesis, discovering the monoamine oxidase-A and-B enzymes, developing the histochemical visualization methodology by fluorescence microscopy, elucidating mechanisms of action of antidepressive agents through in vitro and in vivo investigation, and testing the existing chemicals such as antihistamines or new derivatives in clinical studies for their antidepressive potentials.

Background: Hyperhidrosis is a chronic disease characterized by increased sweat production. Local injections of botulinum toxin A (BTX-A) have been extensively used for treatment of primary hyperhidrosis (idiopathic).

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Non-narcotic opioids and cannabinoids as potential analgesic agents. It is known that cannabinoids and opioids have a central analgesic effect. it is also known that they are active and with local application. For example, ointments based on marijuana are active as well as ointment on the basis of rapidly degrading endogenous endorphins and enkephalins. Such drugs alleviate pain in inflammatory processes, chronic pain, and hypothetically can be effective in cases of injury. But for the full activity of these forms of drugs are not sufficiently active. Overcoming chronic pain is an unresolved issue, despite the development of numerous drugs, various groups and types of actions and other efforts. In this paper, it is proposed to consider in more detail the possibilities of the drug design in this area, with examples of opioids and cannabinoids, in order to achieve new results at a new level of quality and safety: Local application provides a precise influence on the process, standard application affects the entire chain of passage of the pain signal, from the point of origin to the point of recognition and perception. If we use drugs that do not cross the blood-brain barrier, but are active opiates or cannabinoids, we can probably get something in between. The brain and spinal cord will not receive even one-hundredth of the drugs, but the peripheral nervous system is almost open to substances that do not pass through the lipid barrier. In this case, we do not need to worry about the drug not to defund into the bloodstream, for fear of a narcotic effect. We can increase the dose, make a subcutaneous injection, inject the drug intravenously or orally as a tablet form. Without fear of narcotic effects, addiction. Tolerance and dependence can manifest at the peripheral level, but this is in no way compared to the syndrome of drug opiate withdrawal. Nature has many examples of substances that somehow do not pass the barriers of bioavailability. These are biolabile substances, surface-active substances, substances not absorbed by the digestive system, quaternary ammonium salts that do not cross the blood-brain barrier. There are few natural cannabinoids and opiates among such substances, these are exclusively endogenous cannabinoids and opioids, they are biolabile, and this is a small window of opportunity. But chemical compounds of a similar nature are also scarce, these are topical preparations such as Loperamide (which is not absorbed in the digestive tract) and Quaternary bases of morphine derivatives (acting as laxatives, because they are alkylated in the responsible part of the molecule). The figure shows examples of a fundamentally new approach to drug design of quaternary bases from this area. These are quaternary bases which probably retain their functionality and activity, but when transformed into tertiary or secondary bases, they are inactivated. For these examples of substances, activity is possible only in the form of quaternary bases. This is a very important quality. because it eliminates the narcotic activity of catabolites. Also, such substances are characterized by high safety against overdose. As the drug is known, the design of opiates requires a very high-quality and subtle approach; otherwise, overdose and respiratory arrest are possible, even at medium dosages. But substances that do not pass through the blood-brain barrier do not require this complex adjustment during design, this requirement is absent, since even metabolites are not narcotic.