Drug development

Van Leemput, L., W. Meuldermans, R. Woestenborghs, J. Hendrickx, R. Hendriks, and J. Heykants: Post-harvest treatment of apples with imazilil: Fate of the fungicide during fruit storage and juice production. Drug Dev. Res. 8:333-339, 1986. Golden Delicious apples were dip-treated with 14C-labeled or unlabeled imazalil (500 mgl liter) and subsequently kept in controlled-atmosphere storage for up to 7 months. Virtually all the residue was restricted to the peel of the fruit. Although the extraction recovery declined with storage time due to formation of "bound-residue," more than 80% of the total imazalil-derived residue was recovered at the end of storage. The levels of imazalil on the I4C-treated apples decreased with a first-order rate constant of 3.45 x lO-*/month. The presence of an O-dealkylation product (R 14 821) and the formation of "boundresidue" was prominent from the 4-month sampling on. Apples that had undergone imazalil treatment (375 mglliter) on a commercial scale were processed to single-strength juice after 5.5 months of cold storage. The wet pomace contained 66-71% (3.7-4.2 pglg) of the whole-fruit residue, and the single-strength juice 1.3-3.5% (0.07-0.12 pglml). In the filtration cake 6.0-8.3% (5.4-5.8 pglg) of the original residue was found. Detectable (z 0.05 pg/g) levels of R 14 821 were found in the filtration cake only.

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.

Drug development performance is examined using data on clinical research projects of 10 pharmaceutical companies. In contrast to previous work on the discovery phase of pharmaceutical R&D we find a strong correlation between the diversity of firms' development efforts and the success probability of individual projects, but no effect of scale per se. Large firms' superior performance in drug development appears to be driven by returns to scope rather than returns to scale. Scope is confounded with firm fixed effects, however, suggesting an important role for inter-firm differences in the organization and management of the development function.

Drugs with antihistamine action are among the most commonly prescribed medicines in pediatrics. According to the International Medical Statistics (IMS), almost two million antihistamine units (in solution) for pediatric use were sold in Spain during 2006-at a cost of nearly 6 million euros. Of this amount, 34% corresponded to fi rst-generation (or sedating) antihistamines. The diffi culties inherent to research for drug development increase considerably when the pediatric age range is involved. The use of any medication in this age group must adhere to the strictest safety criteria, and must offer the maximum guarantees of effi cacy. For this reason, detailed knowledge of the best scientifi c evidence available in relation to these aspects is essential for warranting drug use. The fi rst-generation antihistamines have never been adequately studied for pediatric age groups, though they are still widely used in application to such patients. In contrast, studies in children have been made with the second-generation antihistamines, allowing us to know their safety profi le, and such medicines are available at pediatric dosages that have been well documented from the pharmacological perspective. The present review affords an update to our most recent knowledge on antihistamine use in children, based on the best scientifi c evidence available.

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.

The aim of this study was to determine whether lamotrigine can be reintroduced safely and with a benefit in young people who previously had a mild rash associated with the first introduction of this drug. In the first 150 young people (5-19 years old) treated with lamotrigine in a special centre for epilepsy, seven developed a mild rash soon after starting the drug. In none of these cases was the rash severe, nor was there any mucous membrane involvement. The lamotrigine was stopped immediately when the rash was identified and was subsequently reintroduced , using a special very-low-dose-escalation regime, starting with 0.1 mg/day total daily dose, after periods ranging from 47 to 236 days. It was possible to reintroduce the lamotrigine without recurrence of persistent rash and without any adverse effects in all seven cases. The re-introduction of lamotrigine was associated with improvement in five of the seven cases. It is recommended that lamotrigine is stopped as soon as any rash attributable to the drug develops but it may be possible to reintroduce the drug after mild rash using a very-slow-dose-escalation regime, with a benefit in at least some cases.

Pharmacogenomics is the study of the myriad interactions between genes and pharmacotherapy. Developments in pharmacogenomics have changed and will affect pharmaceutical research, drug development and the practice of medicine in a significant way. In this article, we make an inventory of the ethical implications that might arise as a result of possible developments in pharmacogenomics and investigate whether the present ethical framework will be able to adequately answer arising questions. We think that many of the questions related to the consequences of pharmacogenomics are answerable along the lines of present ethical thinking. We also believe, however, that many 'changes of degree' may result in a 'change of kind.' We therefore think that pharmacogenomics may potentially have such a profound influence on scientific research and the pharmaceutical industry, the practice of medicine and society at large, that this will generate its own unique dynamic, which will require new ethical research. We suggest that the notion of 'responsibility' will be a major focus of such research.

Based on reinforced urn process introduced by Muliere, Secchi and Walker we propose a Bayesian nonparametric approach to analyse a design determining the maximum tolerated dose in Phase I clinical trials for new drug development when intrapatient dose escalation is allowed. A predictive distribution of maximum tolerated dose is obtained and its point estimation may consist in the corresponding expected value.

Peptide sub-libraries and omission sub-libraries derived from parent peptide libraries synthesized with the portioning-mixing method are defined. They can be distinguished by their order, i.e., the number of non-varied positions or omission positions in the molecules. The number of types of sub-libraries as well as the number of their components depend on both the order and the number of residues. Sub-libraries belonging to a given residue number and a given order altogether form a kit. The paper outlines the potential use of sub-libraries and other kinds of partial libraries in identification of the bioactive components of peptide and other kinds of biooligomer libraries.

High-throughput applications on time-lapse microscopy allows us to follow the in vitro temporal and spatial evolution of cell populations; analysis on those kind of data will reveal cell motion parameters such as average speed, persistence and directionality, important informations for many research and therapeutic applications such as drug development or wound healing. The large quantity of frames usually acquired containing multiple cells require automated analysis methods dealing with a cell tracking process. In this work an either semi-or fully automated cell tracking system is proposed, developed to deal especially with time-lapse phase-contrast microscopy of fibroblasts, which are difficult to follow cells in some cases also for a human expert. Fig. 1: An example frame of phase-contrast microscopy of in vitro MEF fibroblasts.

The brain is a delicate organ, and nature has very efficiently protected it. The brain is shielded against potentially toxic substances by the presence of two barrier systems: the blood brain barrier (BBB) and the blood cerebrospinal fluid barrier (BCSFB). Unfortunately, the same mechanisms that protect it against intrusive chemicals can also frustrate therapeutic interventions. Despite aggressive research, patients suffering from fatal and/or debilitating central nervous system (CNS) diseases, such as brain tumours, HIV encephalopathy, epilepsy, cerebrovascular diseases and neurodegenerative disorders, far outnumber those dying of all types of systemic cancers or heart diseases. The abysmally low number of potential therapeutics reaching commercial success is primarily due to the complexity of the CNS drug development. The clinical failure of many probable candidates is often, ascribable to poor delivery methods which do not pervade the unyielding BBB. It restricts the passive diffusion of many drugs into the brain and constitutes a significant obstacle in the pharmacological treatment of central nervous system (CNS) disorders. General methods that can enhance drug delivery to the brain are, therefore, of great pharmaceutical interest. Various strategies like non-invasive methods, including drug manipulation encompassing transformation into lipophilic analogues, prodrugs, chemical drug delivery, carrier-mediated drug delivery, receptor/vector mediated drug delivery and intranasal drug delivery, which exploits the olfactory and trigeminal neuronal pathways to deliver drugs to the brain, are widely used. On the other hand the invasive methods which primarily rely on disruption of the BBB integrity by osmotic or biochemical means, or direct intracranial drug delivery by intracerebroventricular, intracerebral or intrathecal administration after creating reversible openings in the head, are recognised. Extensive review pertaining specifically, to the patents relating to drug delivery across the CNS is currently available. However, many patents e.g. US63722506, US2002183683 etc., have been mentioned in a few articles. It is the objective of this article to expansively review drug delivery systems for CNS by discussing the recent patents available.

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 in vitro dissolution of albendazole from three different commercially available products (200 mg tablets) was studied using U.S. Pharmacopeia (USP) Apparatus 2 and USP Apparatus 4 in order to compare the release performance of the drug in two essentially different dissolution systems. For both cases, 0.1 N HCl was used as dissolution medium. Only the reference product and one of the generic products studied met the 80% USP 24 specification for albendazole dissolved at 30 min, using USP Apparatus 2. Although the reference product reached 80% of albendazole dissolved at 30 min when Apparatus 4 was used, the generic products' dissolution performance was markedly reduced in this system. Though dissolution rate was slower using Apparatus 4, the total quantity of albendazole dissolved from the reference product, represented by area under the dissolution profile, was practically the same regardless of the system used. Dissolution kinetics of albendazole was adequately described by Weibull's function for all the products. The dissolution time (t d ) derived from data fitting to this function showed significant differences among the products studied. Data analysis based on analysis of variance (ANOVA) showed nonequivalence among the dissolution profiles of generic products compared with the reference product either with the dissolution vessel system or the flow-through cell, as well as nonequivalence among the dissolution profiles using both apparatuses with the same product. Though differences in the dissolution profiles for generic products against the reference product in both systems were found, USP Apparatus 4 showed higher discriminative capacity in differentiating the release characteristics of the products tested.

This review highlights the many roles mass spectrometry plays in the discovery and development of new therapeutics by both the pharmaceutical and the biotechnology industries. Innovations in mass spectrometer source design, improvements to mass accuracy, and implementation of computer-controlled automation have accelerated the purification and characterization of compounds derived from combinatorial libraries, as well as the throughput of pharmacokinetics studies. The use of accelerator mass spectrometry, chemical reaction interface-mass spectrometry and continuous flow-isotope ratio mass spectrometry are promising alternatives for conducting mass balance studies in man. To meet the technical challenges of proteomics, discovery groups in biotechnology companies have led the way to development of instruments with greater sensitivity and mass accuracy (e.g., MALDI-TOF, ESI-Q-TOF, Ion Trap), the miniaturization of separation techniques and ion sources (e.g., capillary HPLC and nanospray), and the utilization of bioinformatics. Affinity-based methods coupled to mass spectrometry are allowing rapid and selective identification of both synthetic and biological molecules. With decreasing instrument cost and size and increasing reliability, mass spectrometers are penetrating both the manufacturing and the quality control arenas. The next generation of technologies to simplify the investigation of the complex fate of novel pharmaceutical entities in vitro and in vivo will be chip-based approaches coupled with mass spectrometry.

Accurate predictions of human pharmacokinetic and pharmacodynamic (PK/PD) profiles are critical in early drug development, as safe, efficacious, and "developable" dosing regimens of promising compounds have to be identified. While advantages of successful integration of preclinical PK/PD data in the "anticipation" of human doses (AHD) have been recognized, pharmaceutical scientists have faced difficulties with practical implementation, especially for PK/PD profile projections of compounds with challenging absorption, distribution, metabolism, excretion and formulation properties. In this article, practical projection approaches for formulation-dependent human PK/PD parameters and profiles of Biopharmaceutics Classification System classes I-IV drugs based on preclinical data are described. Case examples for "AHD" demonstrate the utility of preclinical and clinical PK/PD modeling for formulation risk identification, lead candidate differentiation, and prediction of clinical outcome. The application of allometric scaling methods and physiologically based pharmacokinetic approaches for clearance or volume of distribution projections is described using GastroPlus™. Methods to enhance prediction confidence such as in vitro-in vivo extrapolations in clearance predictions using in vitro microsomal data are discussed. Examples for integration of clinical PK/PD and formulation data from frontrunner compounds via "reverse pharmacology strategies" that minimize uncertainty with PK/PD predictions are included. The use of integrated softwares such as GastroPlus™ in combination with established PK projection methods allow the projection of formulation-dependent preclinical and human PK/PD profiles required for compound differentiation and development risk assessments.

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.

Many flaviviruses are significant human pathogens. The plus-strand RNA genome of a flavivirus contains a 5′ terminal cap 1 structure (m 7 GpppAmG). The flavivirus encodes one methyltransferase (MTase), located at the N-terminal portion of the NS5 RNA-dependent RNA polymerase (RdRp). Here we review recent advances in our understanding of flaviviral capping machinery and the implications for drug development. The NS5 MTase catalyzes both guanine N7 and ribose 2′-OH methylations during viral cap formation. Representative flavivirus MTases, from dengue, yellow fever, and West Nile virus (WNV), sequentially generate GpppA → m 7 GpppA → m 7 GpppAm. Despite the existence of two distinct methylation activities, the crystal structures of flavivirus MTases showed a single binding site for S-adenosyl-L-methionine (SAM), the methyl donor. This finding indicates that the substrate GpppA-RNA must be repositioned to accept the N7 and 2′-O methyl groups from SAM during the sequential reactions. Further studies demonstrated that distinct RNA elements are required for the methylations of guanine N7 on the cap and of ribose 2′-OH on the first transcribed nucleotide. Mutant enzymes with different methylation defects can trans complement one another in vitro, demonstrating that separate molecules of the enzyme can independently catalyze the two cap methylations in vitro. In the context of the infectious virus, defects in both methylations, or a defect in the N7 methylation alone, are lethal to WNV. However, viruses defective solely in 2′-O methylation are attenuated and can protect mice from later wild-type WNV challenge. The results demonstrate that the N7 methylation activity is essential for the WNV life cycle and, thus, methyltransferase represents a novel and promising target for flavivirus therapy.

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.

A major challenge in the field of functional genomics is the development of computational techniques for organizing and interpreting large amounts of gene expression data. These methods will be critical for the discovery of new therapeutic drug targets. Here, we present a simple method for determining the most likely drug target candidates from temporal gene expression patterns assayed with reverse-transcription polymerase chain reaction (RT-PCR) and DNA microarrays.

The performance of general pharmacology procedures on new drug candidates supports both drug discovery and safety assessment activities; however, the potential contribution of general pharmacology to safety assessment has had less attention than other aspects of nonclinical testing. Pharmaceutical companies are divided as to whether or not general pharmacology is integrated with the rest of toxicology testing or carried out as part of the discovery program, and, recently, discussions have taken place within Europe as to whether or not these studies should be subject to Good Laboratory Practice (CLP) conditions. All three regions (the United States, Europe, and Japan) require data on the pharmacological properties of new drugs to be included in a marketing application. This should cover primary and secondary pharmacological effects, and should provide information concerning potential adverse reactions. In addition, Europe and the United States request non-clinical data on potential drug interactions. However, the most detailed requirements are described in the Japanese guidelines. This paper reviews the current regulatory environment in the European Community (EC), Japan, and the United States, highlighting some general features of the three regulatory systems which are relevant to general pharmacology, and summarising the specific guidelines for these studies in the three regions. Although there are significant differences between the detailed Japanese general pharmacology requirements and the more flexible Western approach, it i s not clear that it i s appropriate to include general pharmacology within the international harmonization discussions. Rather, deregulation in this area i s a desirable goal for the future. c IOY-I hiIey-Liss, i n i . A d d r r s i reprint reque5k to Cynthia t Lumley, Centre for Medicines Reiearc h, Wooclrnansterne Road, Carbhalton, surrey, U K SM54DS This article i s based on J presentation at the inaugural meeting of the General Pharm~~cology/Safetv Ph<irrnacology Uiscuwon

Selegiline and rasagiline are selective and irreversible monoamine oxidase-B inhibitors that exert neuroprotective effects in various preclinical models. The aim of the present study was to examine the effect of selegiline and its major metabolite, L-methamphetamine in comparison to rasagiline and its major metabolite, 1-R-aminoindan on oxygen -glucose deprivation induced cell death in nerve growth factor (NGF)-differentiated pheochromocytoma (PC12) cells. Our results show that selegiline reduces oxygen -glucose deprivation induced cell death by 30%. When the cultures were treated with rasagiline at similar concentrations, cell death induced by oxygen -glucose deprivation was reduced by 45 -55%. L-methamphetamine, a major selegiline metabolite, but not 1-R-aminoindan, the major rasagiline metabolite, enhanced oxygen -glucose deprivation-induced cell death by 70%. Under normoxic conditions, both metabolites lack neurotoxicity. Concomitant exposure of the cultures under oxygen -glucose deprivation, to a combination of either selegiline and L-methamphetamine or rasagiline and 1-R-aminoindan, indicated that L-methamphetamine, but not 1-R-aminoindan, blocked the neuroprotective effect of the parental drug. These results suggest there may be a neuroprotective advantage of rasagiline over selegiline. D

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 &gt; or =18 years old, had an Eastern Cooperative Oncology Group performance status &lt; 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...

A "microdose clinical trial" (microdosing) is one kind of early phase exploratory clinical trial, administering the compound at doses estimated to have no pharmacological or toxicological effects, aimed at screening candidates for further clinical development. This article's objective is to clarify the ethical, legal, and social implications (ELSI) of such an exploratory minimum-risk human trial. The definition and non-clinical study requirements for microdosing have been harmonized among the European Union (EU), United States (US), and Japan. Being conducted according to these regulations, microdosing seems to be ethically well justified in terms of respect for persons, beneficence, justice, human dignity, and animal welfare. Three big projects have been demonstrating the predictability of therapeutic dose pharmacokinetics from microdosing. The article offers suggestions as how microdosing can become a more useful and socially accepted strategy.

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.

Claudin-18 isoform 2 (CLDN18.2) is one of the few members of the human claudin family of tight junction molecules with strict restriction to one cell lineage. The objective of the current study was to compare molecular structure and tissue distribution of this gastrocyte specific molecule in mammals. We show here that the CLDN18.2 protein sequence is highly conserved, in particular with regard to functionally relevant domains in mouse, rat, rabbit, dog, monkey and human and also in lizards. Moreover, promoter regions of orthologs are highly homologous, including the binding site of the transcription factor cyclic AMP-responsive element binding protein (CREB), which is known to regulate activation of human CLDN18.2. Employing RT-PCR and immunohistochemistry, we found that, analogous to the human gene, all orthologous CLDN18.2 transcripts and proteins are exclusively expressed in differentiated gastric cells. Gene structure, promoter elements and RNA expression pattern of the lung-tissue specific Claudin-18 isoform 1 (CLDN18.1) as well, are homologous across species. These findings exemplify phylogenetic conservation of lineage-specific members of a multigene family. Given that CLDN18.2 is a novel drug target candidate, our data is also relevant for drug development as it reveals all six investigated mammalian species as suitable models for testing safety of CLDN18.2 targeting regimen.

-----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.

Recent advances in the developmental biology, genetics and cell biology of the inner ear are guiding research to novel therapeutic modalities -a market currently estimated to be at least US$10 billion. This article highlights prospects to manipulate the mammalian hearing organ with gene and stem cell delivery to the inner ear to protect, repair or regenerate the hair cells, supporting cells and associated nerves. IUBMB Life, 58: 525-530, 2006

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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Recent advances in studies of nicotinic agents in humans have begun to more carefully define cognitive operations that can be influenced by nicotinic stimulation and/or blockade. Careful separation of the cognitive domains affected by nicotinic stimulation has identified attentional performance as the most likely candidate to be positively influenced by nicotinic receptor activation. Studies of the effects of nicotinic systems and/or nicotinic receptor stimulation in pathological disease states such as Alzheimer's disease, Parkinson's disease, attention deficit/ hyperactivity disorder and schizophrenia show the potential for therapeutic utility of nicotinic drugs. In contrast to studies in pathological states, studies of nicotine in normal-non-smokers tend to show deleterious effects. This contradiction can be resolved by consideration of cognitive and biological baseline dependency differences between study populations in terms of the relationship of optimal cognitive performance to nicotinic receptor activity. Although normal individuals are unlikely to show cognitive benefits after nicotinic stimulation except under extreme task conditions, individuals with a variety of disease states can benefit from nicotinic drugs. Attentional function/ dysfunction may serve as an endophenotypic therapeutic target for nicotinic drug development.

Cancer leads to approximately 25% of all mortalities, making it the second leading cause of death in the United States. Early and accurate detection of cancer is critical to the well being of patients. Analysis of gene expression data leads to cancer identification and classification, which will facilitate proper treatment selection and drug development. Gene expression data sets for ovarian, prostate, and lung cancer were analyzed in this research. An integrated gene-search algorithm for genetic expression data analysis was proposed. This integrated algorithm involves a genetic algorithm and correlation-based heuristics for data preprocessing (on partitioned data sets) and data mining (decision tree and support vector machines algorithms) for making predictions. Knowledge derived by the proposed algorithm has high classification accuracy with the ability to identify the most significant genes. Bagging and stacking algorithms were applied to further enhance the classification accuracy. The results were compared with that reported in the literature. Mapping of genotype information to the phenotype parameters will ultimately reduce the cost and complexity of cancer detection and classification. ᭧

Radiopharmaceuticals have a long tradition of clinical and research applications. Current legislation of developed Countries includes these compounds in the regulatory environment of medicinal products. Products used under a marketing authorisation license and investigational radiopharmaceuticals are then part of the clinical practice and scientific programs. Positron Emission Tomography has induced a strong increase in the number of potentially available radiopharmaceuticals and, beside being a breakthrough in diagnostic nuclear medicine, has demostrated its value as research tool. Drug Development Research is searching new tools for reducing attrition and increasing efficiency in the identification and development of new medicines. Molecular Imaging, PET in particular seems to have important answers to this demand. The regulatory environment in Europe is hence revised in the perspective of utilisation of nuclear molecular imaging as a supporting tool for DDR. Relevant documents from European regulatory Agency (EMEA) as well as their essential impact on radiopharmaceuticals have been summarised and discussed.

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.

Biomolecular interaction analysis (BIA) is now utilised increasingly in drug development to kinetically characterise binding events of relevant components. BIA thereby covers a broad range of applications in early ADME (adsorption, distribution, metabolism and excretion), secondary screens, functional and metabolic assays and in assay development.This versatile technology allows measurements in real time without the need of labelling. A wide range of affinities can be characterised in a nearnative state, with high reproducibility, high sensitivity and low sample consumption. However, limitations due to experimental design, and limitations in sample throughput, may occur. Future developments of BIA aim at parallelisation and automatisation and at coupling to platform technologies already established in the drug development process.