Drug development

The treatment of schizophrenia has evolved over the past half century primarily in the context of antipsychotic drug development. Although there has been significant progress resulting in the availability and use of numerous medications, these reflect three basic classes of medications (conventional (typical), atypical and dopamine partial agonist antipsychotics) all of which, despite working by varying mechanisms of actions, act principally on dopamine systems. Many of the second-generation (atypical and dopamine partial agonist) antipsychotics are believed to offer advantages over first-generation agents in the treatment for schizophrenia. However, the pharmacological properties that confer the different therapeutic effects of the new generation of antipsychotic drugs have remained elusive, and certain side effects can still impact patient health and quality of life. Moreover, the efficacy of antipsychotic drugs is limited prompting the clinical use of adjunctive pharmacy to augme...

In the last three decades the discovery of metabolites with biological activities from macroalgae has increased significantly. However, despite the intense research effort by academic and corporate institutions, very few products with real potential have been identified or developed. Based on Silverplatter MEDLINE and Aquatic Biology, Aquaculture & Fisheries Resources databases, the literature was searched for natural products from marine macroalgae in the Rhodophyta, Phaeophyta and Chlorophyta with biological and pharmacological activity. Substances that currently receive most attention from pharmaceutical companies for use in drug development, or from researchers in the field of medicine-related research include: sulphated polysaccharides as antiviral substances, halogenated furanones from Delisea pulchra as antifouling compounds, and kahalalide F from a species of Bryopsis as a possible treatment of lung cancer, tumours and AIDS. Other substances such as macroalgal lectins, fucoidans, kainoids and aplysiatoxins are routinely used in biomedical research and a multitude of other substances have known biological activities. The potential pharmaceutical, medicinal and research applications of these compounds are discussed.

Urolithiasis is a common worldwide problem with high recurrence. This review covers forty four (44) families starting from alphabet A to L and includes Bignoniaceae (05) Juglandaceae (01) plant used globally in different countries. The plants of three families Asteraceae, Fabaceae and Lamiaceae are revisited to provide updated information. This review will not only be useful for the general public but also attract the scientific world for antiurolithiatic drug discovery.

Targeting specific sites in vivo for the delivery of therapeutic compounds presents a major obstacle to the treatment of many diseases. One targeted delivery technique that has gained prominence in recent years is the use of magnetic nanoparticles. In these systems, therapeutic compounds are attached to biocompatible magnetic nanoparticles and magnetic fields generated outside the body are focused on specific targets in vivo. The fields capture the particle complex resulting in enhanced delivery to the target site. This review will focus on technical aspects of magnetic targeting as well as nanoparticle design and animal and clinical trials. Drug Dev. Res. 67:55-60, 2006.

A number of new molecular entities (NMEs) selected for full-scale development based on their safety and pharmacological data suffer from undesirable physicochemical and biopharmaceutical properties, which lead to poor pharmacokinetics and distribution after in vivo administration. An optimization of the preformulation studies to develop a dosage form with proper drug delivery system to achieve desirable pharmacokinetic and toxicological properties can aid in the accelerated development of these NMEs into therapies. Nanoparticulate drug delivery systems show a promising approach to obtain desirable druglike properties by altering the biopharmaceutics and pharmacokinetics properties of the molecule. Apart from the advantages of enhancing potential for systemic administration, nanoparticulate drug delivery systems can also be used for site-specific delivery, thus alleviating unwanted toxicity due to nonspecific distribution, improve patient compliance, and provide favorable clinical outcomes. This review summarizes some of the parameters and approaches that can be used to evaluate nanoparticulate drug delivery systems in early stages of formulation development. ß

Poor water solubility a b s t r a c t Drug absorption, sufficient and reproducible bioavailability and/or pharmacokinetic profile in humans are recognized today as one of the major challenges in oral delivery of new drug substances. The issue arose especially when drug discovery and medicinal chemistry moved from wet chemistry to combinatorial chemistry and high throughput screening in the mid-1990s. Taking into account the drug product development times of 8-12 years, the apparent R&D productivity gap as determined by the number of products in late stage clinical development today, is the result of the drug discovery and formulation development in the late 1990s, which were the early and enthusiastic times of the combinatorial chemistry and high throughput screening. In parallel to implementation of these new technologies, tremendous knowledge has been accumulated on biological factors like transporters, metabolizing enzymes and efflux systems as well as on the physicochemical characteristics of the drug substances like crystal structures and salt formation impacting oral bioavailability. Research tools and technologies have been, are and will be developed to assess the impact of these factors on drug absorption for the new chemical entities.

The selective serotonin reuptake inhibitors (SSRIs) have emerged as a major therapeutic advance in psychopharmacology. As a result, the discovery of these agents marks a milestone in neuropsychopharmacology and rational drug design, and has launched a new era in psychotropic drug development. Prior to the SSRIs, all psychotropic medications were the result of chance observation. In an attempt to develop a SSRI, researchers discovered a number of nontricyclic agents with amine-uptake inhibitory properties, acting on both noradrenergic and serotonergic neurons with considerable differences in potency. A given drug may affect one or more sites over its clinically relevant dosing range and may produce multiple and different clinical effects. The enhanced safety profile includes a reduced likelihood of pharmacodynamically mediated adverse drug -drug interactions by avoiding affects on sites that are not essential to the intended outcome. SSRIs were developed for inhibition of the neuronal uptake pump for serotonin (5-HT), a property shared with the TCAs, but without affecting the other various neuroreceptors or fast sodium channels. The therapeutic mechanism of action of SSRIs involves alteration in the 5-HT system. The plethora of biological substrates, receptors and pathways for 5-HT are candidates to mediate not only the therapeutic actions of SSRIs, but also their side effects. A hypothesis to explain these immediate side effects is that 5-HT is increased at specific 5-HT receptor subtypes in discrete regions of the body where the relevant physiologic processes are regulated. Marked differences exist between the SSRIs with regard to effects on specific cytochrome P450 (CYP) enzymes, and thus the likelihood of clinically important pharmacokinetic drugdrug interactions. Although no clear relationship exists between the clinical efficacy, plasma concentration of SSRIs, nor any threshold that defines toxic concentrations, but therapeutic drug monitoring (TDM) may be useful in special populations, such as in elderly patients, poor metabolizers (PM) of sparteine (CYP2D6) or mephenytoin (CYP2C19), and patients with liver and kidney impairment. Several metaanalyses have reviewed the comparative efficacy of TCAs and SSRIs, and concluded that both TCAs and SSRIs have similar efficacy in the treatment of depression. SSRIs have demonstrated better efficacy and tolerability in the treatment of obsessive compulsive disorder (OCD). They have also been found to be effective in the treatment for social anxiety disorder both in reducing total levels of social anxiety and in improving overall clinical condition. The benefit of SSRIs in anorexia nervosa (AN) is apparently short-term unless medication is given in the context of nutritional or behavioral therapy. No single antidepressant can ever be recommended for every patient, but in a vast majority of patients, SSRIs should be considered as one of the first-line drugs in the treatment of depression. D 0278-5846/02/$ -see front matter D 2002 Elsevier Science Inc. All rights reserved. PII: S 0 2 7 8 -5 8 4 6 ( 0 2 ) 0 0 3 3 8 -X

-----ÖZET: Doğal droglarla binlerce yıldır ilaç üretilmekteyse de, doğadan izole etmek veya laboratuvarda sentezlemek yoluyla antikanser ajanlar elde etmeye yönelik sistematik ve kapsamlı çalışmalara yirminci yüzyılda girişilmiştir. Aynı dönemde in vitro çalışmalara ek olarak, kimyasalların antikanser potansiyellerini test için in vivo preklinik deneylerin gerçekleştirilebileceği hayvan modelleri geliştirilmiştir. Modern kanser kemoterapisi çağı 1940'larda ilk klasik kemoterapötik ajanların elde edilişiyle başlamıştır; 1940'ların başlarında ilk alkilleyici ajanlar, sonlarında ise ilk antimetabolitler üretilmiştir. 1950'lerde laboratuvarın dışına çıkılarak, antikanser droglar keşfetmek amacıyla doğa araştırmalarına başlanmıştır. Mikroorganizmalar, sabit konumlu bitkiler ve deniz omurgasızları, çok çeşitli kimyasal savunma mekanizmaları geliştirerek evrildiğinden, bunlar arasından kimi maddelerin antikanser etkinlik gösterebileceği düşünülmüştür. Başta ABD tarafından, bu canlılardan sağlanan on binlerce drog 1950'lerden itibaren antikanser etkinlik yönünden taranmıştır. 1960'larda vinka alkaloitleri, 1970'lerde antikanser antibiyotikler ve 1990'larda taksanlar, doğa araştırmalarının meyvelerindendir. Bugün bu terapötik ajanların kullanıldığı kanser kemoterapisi, hastalığın tedavisinde cerrahi ve radyoterapi gibi lokal müdahalelere ilaveten, sistemik bir modalite olarak tıbbın hizmetindedir.

-----ABSTRACT: Although medicines have been obtained from natural products for millennia, extensive systematic studies to obtain anticancer agents through isolation from natural sources or through synthesis in the laboratory were attempted in the twentieth century. The same period also saw the development of animal models through which in vivo preclinical research could be conducted to examine the anticancer potential of chemicals, in addition to in vitro research. In the 1940s the era of modern cancer chemotherapy started with the introduction of the first classical chemotherapeutics; the first alkylating agents were obtained in the early 1940s and the first antimetabolites toward the end of the decade. In the 1950s scientists ventured out of the laboratory to discover natural products with anticancer potential. Since microorganisms, sessile terrestrial plants and marine invertebrates have evolved a large number of chemical defense mechanisms, it has been argued that some substances out of these might show anticancer activity. Tens of thousands of natural products derived from these organisms have been screened for anticancer activity primarily by the US since the 1950s. Vinca alkaloids introduced in the 1960s, anticancer antibiotics in the 1970s and taxanes in the 1990s are examples of the encouraging outcomes. In addition to local interventions such as surgery and radiotherapy, cancer chemotherapy based upon these therapeutic agents is available in medicine today as a systemic modality in the treatment of the disease.

It is not commonly understood that one of the largest components of the overall cost of bringing a new drug to the market is the cost of product development. Cost of product development can account for as much as 30% to 35% of the total cost of bringing a new drug to the market. Quality of product development also affects time to market and the quality of manufacturing and therefore cost of manufacturing. Investment in basic research in the science of product development and manufacturing will pay for itself through savings achievable in the cost of new drug development and in the cost of goods sold (COGS) of pharmaceutical products. In order for us to arrive at good estimates of the saving potential, one first needs to have credible estimates of the cost of new drug development and the overall COGS for pharmaceutical products.

Despite major advances in modern drug discovery and development, the number of new drug approvals has not kept pace with the increased cost of their development. Increasingly, innovative uses of biomarkers are employed in an attempt to speed new drugs to market. Still, widespread adoption of biomarkers is impeded by limited experience interpreting biomarker data and an unclear regulatory climate. Key differences preclude the direct application of existing validation paradigms for drug analysis to biomarker research. Following the AAPS 2003 Biomarker Workshop (J. W. Lee, R. S. Weiner, J. M. Sailstad, et al. Method validation and measurement of biomarkers in nonclinical and clinical samples in drug development. A conference report. Pharm Res 22:499Y511, 2005)

Biodiversity of natural resources has served not only for the primary human needs but also for health care, since time immemorial. The Indian subcontinent, with the history of one of the oldest civilization, harbors many traditional health care systems. Their development was supported by the diverse biodiversity in flora and fauna due to variations in geographical landscaping. Ayurveda, whose history goes back to 5000 b.c., is one of the ancient health care systems. The Ayurveda was developed through daily life experiences with the mutual relationship between mankind and nature. The ancient text of Ayurveda reports more than 2000 plant species for their therapeutic potentials. Besides Ayurveda, other traditional and folklore systems of health care were developed in the different time periods in Indian subcontinent, where more than 7500 plant species were used. According to a WHO estimate, about 80% of the world population relies on traditional systems of medicines for primary health care, where plants form the dominant component over other natural resources. Renewed interest of developing as well as developed countries in the natural resources has opened new horizons for the exploration of natural sources with the perspectives of safety and efficacy. The development of these traditional systems of medicines with the perspectives of safety, efficacy and quality will help not only to preserve this traditional heritage but also to rationalize the use of natural products in the health care. Until recent past, the nature was considered as a compendium for templates of new chemical entities (NCEs). The plant species mentioned in the ancient texts of these Ayurveda and other Indian systems of medicines may be explored with the modern scientific approaches for better leads in the health care.

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The advent of high through-put screening in the drug discovery process has resulted in compounds with high lipophilicity and poor solubility. Increasing the solubility of such compounds poses a major challenge to formulation scientists. Various approaches have been adopted to address this including preparation of solid dispersions and solid solutions. Hot-melt extrusion is an efficient technology for producing solid molecular dispersions with considerable advantages over solvent-based processes such as spray drying and co-precipitation. Hot-melt extrusion has been demonstrated to provide sustained, modified, and targeted drug delivery. Improvements in bioavailability utilizing the hot-melt extrusion technique demonstrate the value of the technology as a potential drug delivery processing tool. The interest in hot-melt extrusion technology for pharmaceutical applications is evident from the increasing number of patents and publications in the scientific literature. Part II of this article reviews the myriad of hot-melt extrusion applications for pharmaceutical dosage forms including granules, pellets, tablets, implants, transmucosal, and transdermal systems.

Experimenta naturae, like the glucose-6-phosphate dehydrogenase deficiency, indicate that malaria parasites are highly susceptible to alterations in the redox equilibrium. This offers a great potential for the development of urgently required novel chemotherapeutic strategies. However, the relationship between the redox status of malarial parasites and that of their host is complex. In this review article we summarise the presently available knowledge on sources and detoxification pathways of reactive oxygen species in malaria parasite-infected red cells, on clinical aspects of redox metabolism and redox-related mechanisms of drug action as well as future prospects for drug development. As delineated below, alterations in redox status contribute to disease manifestation including sequestration, cerebral pathology, anaemia, respiratory distress, and placental malaria. Studying haemoglobinopathies, like thalassemias and sickle cell disease, and other red cell defects that provide protection against malaria allows insights into this fine balance of redox interactions. The host immune response to malaria involves phagocytosis as well as the production of nitric oxide and oxygen radicals that form part of the host defence system and also contribute to the pathology of the disease. Haemoglobin degradation by the malarial parasite produces the redox active by-products, free haem and H 2 O 2 , conferring oxidative insult on the host cell. However, the parasite also supplies antioxidant moieties to the host and possesses an efficient enzymatic antioxidant defence system including glutathione-and thioredoxin-dependent proteins. Mechanistic and structural work on these enzymes might provide a basis for targeting the parasite. Indeed, a number of currently used drugs, especially the endoperoxide antimalarials, appear to act by increasing oxidant stress, and novel drugs such as peroxidic compounds and anthroquinones are being developed. q

The advent of high through-put screening in the drug discovery process has resulted in compounds with high lipophilicity and poor solubility. Increasing the solubility of such compounds poses a major challenge to formulation scientists. Various approaches have been adopted to address this including preparation of solid dispersions and solid solutions. Hot-melt extrusion is an efficient technology for producing solid molecular dispersions with considerable advantages over solvent-based processes such as spray drying and co-precipitation. Hot-melt extrusion has been demonstrated to provide sustained, modified, and targeted drug delivery. Improvements in bioavailability utilizing the hot-melt extrusion technique demonstrate the value of the technology as a potential drug delivery processing tool. The interest in hot-melt extrusion technology for pharmaceutical applications is evident from the increasing number of patents and publications in the scientific literature. Part II of this article reviews the myriad of hot-melt extrusion applications for pharmaceutical dosage forms including granules, pellets, tablets, implants, transmucosal, and transdermal systems.

The development of new acaricides is a long and very expensive process. Worryingly, there is increasing resistance to available acaricides worldwide leading to the real possibility that our dwindling supply of effective acaricides will be exhausted unless action is taken to increase the number of new acaricidal products and reduce the rate of resistance development. In 1995, eight major animal health pharmaceutical companies formed the Veterinary Parasite Resistance Group (VPRG) to act as an expert consultative group to guide the FAO in resistance management and collaborate in the prudent use of acaricides. In this paper, members of the VPRG discuss the problems and processes in acaricide development, resistance in the field to commonly used acaricides and the different considerations when targeting the cattle and pet market, and give their view of the future for tick control from the perspective of the animal health industry.

Echinacea, better known as purple coneflower, has received a global attention because of its increasing medicinal value. There is enormous potential for the discovery of new medicinal compounds in this species and an immediate need for techniques to facilitate the production of high quality, chemically consistent plant material for drug development and clinical trials. In vitro tissue culture of Echinacea can play a vital role in the development of novel germplasm, rapid multiplication, and genetic modifications for an enhanced phytochemical production. Recent establishment of liquid culture techniques, large-scale bioreactors, and Agrobacterium-mediated transformation are changing the production parameters of the Echinacea species. This review provides an overview of the recent developments in in vitro technologies and challenges that remain in the Echinacea biotechnology.

objective: To check the occurrence of extrapyramidal side effects in patients receiving neuroleptic drugs, how these effects are treated, and to observe the occurrence of hallucinations caused by treatment of extrapyramidal symptoms. Methods: The present study analyzed ...

Flow cytometry-based assays serve as valuable tools for various aspects of the drug development process ranging from target discovery and characterization to evaluation of responses in a clinical setting. The integrity of the samples and the appropriate selection and characterization of the reagents used in these assays are in themselves challenging. These concerns taken together with the flow-based technology makes the validation of flow cytometry assays a challenging effort. Therefore, apart from summarizing the role of flow cytometry technology in various stages of drug development, this manuscript focuses on recommendations for the validation of methods applying flow cytometry. Information is also provided on the relevant validation parameters for different types of flow cytometry assays to guide the users of this platform. Together, the recommendations and the information on regulatory guidelines provided in this manuscript represent the consensus of all the authors and can assist the flow cytometry user in implementing the appropriate method validation strategies.

The use of chemotherapy to treat cancer began at the start of the 20th century with attempts to narrow the universe of chemicals that might affect the disease by developing methods to screen chemicals using transplantable tumors in rodents. It was, however, four World War II-related programs, and the effects of drugs that evolved from them, that provided the impetus

... 2346–2353. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (355). [7] S. Sharma, N. Ahmad, A. Prakash, VN Singh, KA Ghosh and BR Mehta, Mater Sci Appl 1 (2010), pp. 1–7. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (0). ...

Despite extensive research, the current theories on serotonergic dysfunctions and cortisol hypersecretion do not provide sufficient explanations for the nature of depression. Rational treatments aimed at causal factors of depression are not available yet. With the currently available antidepressant drugs, which mainly target serotonin, less than two thirds of depressed patients achieve remission. There is now evidence that inflammatory and neurodegenerative (I&ND) processes play an important role in depression and that enhanced neurodegeneration in depression may–at least partly–be caused by inflammatory processes. Multiple inflammatory-cytokines, oxygen radical damage, tryptophan catabolites–and neurodegenerative biomarkers have been established in patients with depression and these findings are corroborated by animal models of depression. A number of vulnerability factors may predispose towards depression by enhancing inflammatory reactions, e.g. lower peptidase activities (dipeptidyl-peptidase IV, DPP IV), lower omega-3 polyunsaturated levels and an increased gut permeability (leaky gut). The cytokine hypothesis considers that external, e.g. psychosocial stressors, and internal stressors, e.g. organic inflammatory disorders or conditions, such as the postpartum period, may trigger depression via inflammatory processes. Most if not all antidepressants have specific anti-inflammatory effects, while restoration of decreased neurogenesis, which may be induced by inflammatory processes, may be related to the therapeutic efficacy of antidepressant treatments. Future research to disentangle the complex etiology of depression calls for a powerful paradigm shift, i.e. by means of a high throughput-high quality screening, including functional genetics and genotyping microarrays; established and novel animal and ex vivo–in vitro models for depression, such as new transgenic mouse models and endophenotype-based animal models, specific cell lines, in vivo and ex vivo electroporation, and organotypic brain slice culture models. This screening will allow to: 1) discover new I&ND biomarkers, both at the level of gene expression and the phenotype; and elucidate the underlying molecular I&ND pathways causing depression; and 2) identify new therapeutic targets in the I&ND pathways; develop new anti-I&ND drugs for these targets; select existing anti-I&ND drugs or substances that could augment the efficacy of antidepressants; and predict therapeutic response by genetic I&ND profiles.

Based on the long history of medicinal plant use, users of traditional medicines accept that they are safe for human consumption. However, the absence of regulation of the medicinal plant trade in aspects such as collection, processing and storage provides no such guarantee. Environmental pollution, misidentification and adulteration provides further grounds for concern. The potential adverse effects of South African traditional medicines are not well documented. There are only a few investigations of mutagenic properties and heavy metal contamination. In the absence of regulatory controls, the safety and quality of medicinal plants vary considerably. The current comprehension and future challenges regarding quality, safety and efficacy of South African traditional medicine are discussed.

Although used in academic research for several decades, 3D culture models have long been regarded expensive, cumbersome and unnecessary in drug development processes. Technical advances, coupled with recent observations showing that gene expression in 3D is much closer to clinical expression profiles than those seen in 2D, have renewed attention and generated hope in the feasibility of maturing organotypic 3D systems to therapy test platforms with greater power to predict clinical efficacies. Here we describe a standardized setup for reproducible, easy-handling culture, treatment and routine analysis of multicellular spheroids, the classical 3D culture system resembling many aspects of the pathophysiological situation in human tumor tissue. We discuss essential conceptual and practical considerations for an adequate establishment and use of spheroid-based drug screening platforms and also provide a list of human carcinoma cell lines, partly on the basis of the NCI-DTP 60-cell line screen, that produce treatable spheroids under identical culture conditions. In contrast to many other settings with which to achieve similar results, the protocol is particularly useful to be integrated into standardized large-scale drug test routines as it requires a minimum number of defined spheroids and a limited amount of drug. The estimated time to run the complete screening protocol described herein-including spheroid initiation, drug treatment and determination of the analytical end points (spheroid integrity, and cell survival through the acid phosphatase assay)-is about 170 h. Monitoring of spheroid growth kinetics to determine growth delay and regrowth, respectively, after drug treatment requires long-term culturing (Z14 d).

The plant Momordica balsamina Linn. belongs to family Cucurbitaceae and found in Punjab, Rajasthan and Saurashtra. The African people use the fruit of Momordica balsamina Linn. as a medicine for a variety of ailments. Since no reports are available on the pharmacognostical and phytochemical evaluation regarding the fruits of Momordica balsamina Linn., so present study was devoted to study macroscopy, microscopical, physiochemical and phytochemical properties of the fruit. From the study we have found that Immature fruit is green, ovoid, 2.5-7.5 cm long, narrow to both ends, rostrate, fleshy, smooth or muricate and bitter in taste. Mature fruit is red, berry type of fruit and tuberculate in shape. Seeds are ash coloured, ellipsoid, compressed, rugulose on the flat faces and with a grooved margin which is tuberculate on edges. Microscopically, fruits show epidermis with stomata, Uniseriate and multicellular glandular trichomes, hypodermis, prismatic crystals of calcium oxalates, mesoc...

Addiction to drugs, such as heroin, cocaine and alcohol, exacts great human and financial costs on society, but the development of pharmacotherapies for addiction has been largely neglected by the pharmaceutical industry. With advances in our understanding of the underlying biology of addictions now opening the door for the development of novel pharmacotherapies, it could be time for a reassessment

Computational tools for predicting toxicity have been envisaged for their potential to considerably impact the attrition rate of compounds in drug discovery and development. In silico techniques like knowledge-based expert systems (quantitative) structure activity relationship tools and modeling approaches may therefore help to significantly reduce drug development costs by succeeding in predicting adverse drug reactions in preclinical studies. It has been shown that commercial as well as proprietary systems can be successfully applied in the pharmaceutical industry. As the prediction has been exhaustively optimized for early safety-relevant endpoints like genotoxicity, future activities will now be directed to prevent the occurrence of undesired toxicity in patients by making these tools more relevant to human disease.

Cannabinoids and their derivatives are group of more than 60 biologically active chemical agents, which have been used in natural medicine for centuries. The major agent of exogenous cannabinoids is D 9 -tetrahydrocannabinol (D 9 -THC), natural psychoactive ingredient of marijuana. However, psychoactive properties of these substances limited their use as approved medicines. Recent discoveries of endogenous cannabinoids (e.g. arachidonoylethanolamide, 2-arachidonoylglycerol or palmithyloethanolamide) and their receptors initiated discussion on the role of cannabinoid system in physiological conditions as well as in various diseases. Based on the current knowledge, it could be stated that cannabinoids are important mediators in the skin, however their role have not been well elucidated yet. In our review, we summarized the current knowledge about the significant role of the cannabinoid system in the cutaneous physiology and pathology, pointing out possible future therapeutic targets.

It is not commonly understood that one of the largest components of the overall cost of bringing a new drug to the market is the cost of product development. Cost of product development can account for as much as 30% to 35% of the total cost of bringing a new drug to the market. Quality of product development also affects time to market and the quality of manufacturing and therefore cost of manufacturing. Investment in basic research in the science of product development and manufacturing will pay for itself through savings achievable in the cost of new drug development and in the cost of goods sold (COGS) of pharmaceutical products. In order for us to arrive at good estimates of the saving potential, one first needs to have credible estimates of the cost of new drug development and the overall COGS for pharmaceutical products.

Alzheimer's disease (AD), the most common form of dementia among the elderly, is a progressive, degenerative disorder of the brain with a loss of memory and cognition. A defining characteristic of AD is the deposition of amyloid fibrils and neurofibrillary tangles in the brain of afflicted individuals. Biochemically, they are mainly composed of β-amyloid protein (Aβ) and phosphorylated tau proteins, respectively. There is also a loss of the presynaptic markers of the cholinergic system, such as acetylcholine, in the brain areas related to memory and learning. The biochemical pathways leading to AD are presently unknown and are a subject of intensive study with current theories favoring a hypothesis where Aβ aggregates to toxic forms that induce tau phosphorylation and aggregation. It is believed that this ultimately leads to dysfunction and death of cholinergic neurons, and compensation for this loss had been the primary focus of first generation therapeutic agents. The amyloid and tau hypotheses have lead to a focus on amyloid and tau as therapeutic targets. The current therapeutic goals are to reduce amyloid levels, prevention of amyloid aggregation/toxicity and tau phosphorylation/aggregation. AD has a heterogeneous etiology with a large percentage termed sporadic AD arising from unknown causes and a smaller fraction of early onset familial AD (FAD) caused by mutations in several genes, such as the β-amyloid precursor protein (APP) and presenilins (PS1, PS2). Other genes, such as apolipoprotein E (APOE), are considered to be risk factors for AD. Several proteins, such as APP, APOE, BACE (β-amyloid cleaving enzyme), PS1/2, secretases, and tau play important roles in the pathology of AD. Therefore, attempts are being made to develop new inhibitors for BACE, PS-1 and γ-secretase for treatment of AD. There is also a significant advancement in understanding the function of cholinesterase (ChE) in the brain and the use of ChE inhibitors in AD. The mechanism of a new generation of acetyl- and butyrylChE inhibitors is being studied and tested in human clinical trials for AD. Other strategies, such as vaccination, anti-inflammatory agents, cholesterol-lowering agents, anti-oxidants and hormone therapy, are also being studied for treating or slowing the progression of AD. Developments of early diagnostic tools based on quantitative biochemical markers will be useful to better follow the course of the disease and to evaluate different therapeutic strategies. In the present review, we attempt to critically examine recent trends in AD research from neurochemical to clinical areas. We analyze various neurobiological mechanisms that provide the basis of new targets for AD drug development. These current research efforts should lead to a deeper understanding of the pathobiochemical processes that occur in the AD brain to effectively diagnose and prevent their occurrence. Drug Dev. Res. 56:267–281, 2002. © 2002 Wiley-Liss, Inc.

Structure-based design has emerged as a new tool in medicinal chemistry. A prerequisite for this new approach is an understanding of the principles of molecular recognition in protein-ligand complexes. If the three-dimensional structure of a given protein is known, this information can be directly exploited for the retrieval and design of new ligands. Structure-based ligand design is an iterative approach. First of all, it requires the crystal structure or a model derived from the crystal structure of a closely related homolog of the target protein, preferentially complexed with a ligand. This complex unravels the binding mode and conformation of a ligand under investigation and indicates the essential aspects determining its binding affinity. It is then used to generate new ideas about ways of improving an existing ligand or of developing new alternative bonding skele-tons. Computational methods supplemented by molecular graphics are applied to assist this step of hypothesis generation. The features of the protein binding pocket can be translated into queries used for virtual computer screening of large compound libraries or to design novel ligands de novo. These initial proposals must be confirmed experimentally. Subsequently they are optimized toward higher affinity and better selectivity. The latter aspect is of utmost importance in defining and controlling the pharmacological profile of a ligand. A prerequisite to tailoring selectivity by rational design is a detailed understanding of molecular parameters determining selectivity. Taking examples from current drug development programs (HIV proteinase, t-RNA transglycosylase, thymidylate synthase, thrombin and, related serine proteinases), we describe recent advances in lead discovery via computer screening, iterative design, and understanding of selectivity discrimination.

The botanical collections of early explorers and the later ethnobotany have played important roles in the development of new drugs for many centuries. In the middle of the last century interest in this approach had declined dramatically, but has risen again during its last decade, and new foci have developed. The systematic evaluation of indigenous pharmacopoeias in order to contribute to improved health care in marginalized regions has been placed on the agenda of international and national organizations and of NGOs. In this paper the results of various projects on Mexican Indian ethnobotany and some of the subsequent pharmacological and phytochemical studies are summarized. Medicinal plants are an important element of indigenous medical systems in Mexico. This study uses the medicinal plants in four indigenous groups of Mexican Indians-Maya, Nahua, Zapotec and Mixe-as an example. The relative importance of a medicinal plant within a culture is documented using a quantitative method and the data are compared intra-and interculturally. While the species used by the indigenous groups vary, the data indicate that there exist well-defined criteria specific for each culture, which lead to the selection of a plant as a medicine. For example, a large number of species are used for gastrointestinal illnesses by two or more of the indigenous groups. At least in this case, the multiple transfers of species and their uses within Mexico seems to be an important reason for the widespread use of a species.

Urolithiasis is a common worldwide problem with high recurrence. This review covers thirty six (36) families starting from alphabet M to R. It includes Rubiaceae (17); Phyllanthaceae and Rutaceae (09); Polygonaceae (08); Pinaceae and Piperaceae (06) (01) plant used globally in different countries. Hopefully, this review will not only be useful for the general public but also attract the scientific world for antiurolithiatic drug discovery.

A general method was developed to select the optimal salt form for BMS-180431, a novel HMG-CoA reductase inhibitor and a candidate for oral dosage form development, in an expeditious manner at the onset of the drug development process. The physicochemical properties such as hygroscopicity. physical stability of crystal forms at different humidity conditions, aqueous solubility, and chemical stability of seven salts, e.g., sodium, potassium, calcium, zinc, magnesium, arginine and lysine, were studied using a multi-tier approach. The progression of studies among different tiers was such that the least time-consuming experiments were conducted earlier, thus saving time and effort. A 'go/ no go' decision was made after each tier of testing the salts, thus avoiding generation of extensive data on all available salt forms. The hygroscopicities of all BMS-180431 salts were evaluated at tier 1 and four salts (sodium, potassium, calcium and zinc) were dropped from consideration due to excessive moisture uptake within the expected humidity range of pharmaceutical manufacturing plants (30-500/c R.H. at ambient tempcraturc). The remaining three salts were subjected to the tier 2 evaluation for any change in their crystal structures with respect to humidity and the determination of their aqueous solubilities in the gastrointestinal pH range. The magnesium salt was dropped from further consideration due to humidity-dependent changes in its crystal structure and low solubility in water (3.7 mg/ml at room temperature). Arginine and lysine salts, which were resistant to any change in their crystalline structures under extremes of humidity conditions (6 and 75% R.H.) and had high aqueous solubilities ( > 200 mg/ml), were elevated to tier 3 for the determination of their chemical stability. Based on solid state stability of these two salts under accelerated conditions (temperature, humidity, and prcsencc of cxcipicnts), consideration of ease of synthesis, ease of analysis, potential impurities, etc., and input from the marketing group with respect to its preference of counter ion species, the arginine salt was selected for further devclopmcnt. The number of tiers necessary to reach a decision on the optimal salt form of a compound may depend on the physicochemical properties studied and the number of salts available. This salt selection process can be completed within 4-6 weeks and be easily adopted in the drug development program,

The anthelmintic activity of Calotropis (C.) procera flowers in comparison with levamisole was evaluated through in vitro and in vivo studies. In vitro studies revealed anthelmintic effects (P < 0.05) of crude aqueous (CAE) and crude methanolic extracts (CME) of Calotropis procera flowers on live Haemonchus (H.) contortus as evident from their mortality or temporary paralysis. For in vivo studies, Calotropis procera flowers were administered as crude powder (CP), CAE and CME to sheep naturally infected with mixed species of gastrointestinal nematodes. Egg count percent reduction (ECR) was recorded as 88.4 and 77.8% in sheep treated with CAE and CP at 3 g kg −1 body weight on day 7 and 10 post-treatment (PT), respectively. CME was least effective resulting in 20.9% reduction in ECR on day 7 PT. It was found that Calotropis procera flowers possess good anthelmintic activity against nematodes, yet it was lower than that exhibited by levamisole (97.8-100%). It is suggested that further research on large scale be carried out involving a large number of animals, doses higher than those used in the current study, identification of active principles, and standardization of dose and toxicity studies for drug development.

Tissue engineered constructs have the potential to function as in vitro pre-clinical models of normal tissue function and disease pathogenesis for drug screening and toxicity assessment. Effective high throughput assays demand minimal systems with clearly defined performance parameters. These systems must accurately model the structure and function of the human organs and their physiological response to different stimuli. Musculoskeletal tissues present unique challenges in this respect, as they are load-bearing, matrix-rich tissues whose functionality is intimately connected to the extracellular matrix and its organization. Of particular clinical importance is the osteochondral junction, the target tissue affected in degenerative joint diseases, such as osteoarthritis (OA), which consists of hyaline articular cartilage in close interaction with subchondral bone. In this review, we present an overview of currently available in vitro three-dimensional systems for bone and cartilage tissue engineering that mimic native physiology, and the utility and limitations of these systems. Specifically, we address the need to combine bone, cartilage and other tissues to form an interactive microphysiological system (MPS) to fully capture the biological complexity and mechanical functions of the osteochondral junction of the articular joint. The potential applications of three-dimensional MPSs for musculoskeletal biology and medicine are highlighted