Jones, Juanita; And Others
This handbook, written in a conversational tone, is to help the teacher of very young children work effectively with the child who evidences a high risk for a learning disability. Based upon the theories of child development of Gesell, Piaget, and Kephart, this manual attempts to provide prescriptive activities for specific learning problems in…
This article describes the lengthy background and debate leading up to the passage of the Medicare Prescription Drug, Improvement and Modernization Act of 2003 (MMA). Full implementation of the prescription drug aspect of the law will not be completed for some time, and final assessment of its impact awaits a history yet to be written. Instead, this article summarizes the efforts of supporters until they finally managed to succeed after being stymied so many times in the preceding four decades. PMID:17290634
Caraci, Filippo; Castellano, Sabrina; Salomone, Salvatore; Drago, Filippo; Bosco, Paolo; Di Nuovo, Santo
Drug discovery efforts in Alzheimer's disease (AD) have been directed in the last ten years to develop "disease-modifying drugs" able to exert neuroprotective effects in an early phase of AD pathogenesis. Unfortunately several candidate disease-modifying drugs have failed in Phase III clinical trials conducted in mild to moderate AD for different methodological difficulties, such as the time course of treatment in relation to development of disease as well as the appropriate use of validated biological and neuropsychological markers. Mild cognitive impairment (MCI) has been considered a precursor of AD. Much effort is now directed to identify the most appropriate and sensitive markers which can predict the progression from MCI to AD, such as neuroimaging markers (e.g. hippocampal atrophy and amyloid positron emission tomography imaging), cerebrospinal fluid markers (i.e. association of elevated tau with low levels of amyloid β -peptide(1-42) and neuropsychological markers (i.e. episodic memory deficits and executive dysfunction). Recent studies demonstrate that the combination of these different biomarkers significantly increases the chance to predict the conversion into AD within 24 months. These biomarkers will be essential in the future to analyze clinical efficacy of disease-modifying drugs in MCI patients at high risk to develop AD. In the present review we analyze recent evidence on the combination of neuropsychological and biological markers in AD as a new tool to track disease progression in early AD as well as the response to disease-modifying drugs.
Aikin, Kathryn J; Sullivan, Helen W; Betts, Kevin R
Direct-to-consumer (DTC) prescription drug advertisements sometimes include information about the disease condition in addition to information about the advertised product. Although the intent of such information is to educate about the disease condition, in some cases consumers may mistakenly assume that the drug will address all of the potential consequences of the condition mentioned in the ad. We investigated the effects of adding disease information to DTC prescription drug print ads on consumer product perceptions and understanding. Participants (4,064 adults) viewed 1 of 15 DTC print ads for fictitious prescription drugs indicated to treat chronic obstructive pulmonary disease, anemia, or lymphoma that varied in disease information presence, type, and format. Participants answered questions that assessed risk and benefit memory, perception, and behavioral intention. Results indicate that exposure to disease information as part of DTC prescription drug ads can promote the impression that the drug addresses consequences of the condition that are not part of the drug's indication.
of Child 1971 6.7 0 Health and Human Development Caries National Institute of Dental 1971 0.6 0 ( tooth decay ) Research Sickle cell National Heart...industry was marketed in the late 1960s. The caries ( tooth decay ) drug development program was started in 1971 by the National Institute of Dental...Malaria/tropical diseases 280,000 Vaccines 60 Epilepsy 4,400 Antivirals 50 Contraceptives 2,800 Caries ( tooth decay ) 300 Sickle cell anemia 25 Narcotic
Alzheimer's disease, the most common cause of dementia, is characterized by two major pathological hallmarks: amyloid plaques and neurofibrillary tangles. Based on these two indicators, an amyloid cascade hypothesis was proposed, and accordingly, most current therapeutic approaches are now focused on the removal of β-amyloid peptides (Aβ from the brain. Additionally, strategies for blocking tau hyperphosphorylation and aggregation have been suggested, including the development of drugs that can block the formation of tangles. However, there are no true disease-modifying drugs in the current market, though many drugs based on theories other than Aβ and tau pathology are under development. The purpose of this review was to provide information on the current development of AD drugs and to discuss the issues related to drug development. PMID:22110351
Stephenson, Michael T; Quick, Brian L
The National Youth Anti-Drug Media Campaign aims not only to reduce drug use by teens and preteens, but also to arm parents with knowledge about specific parenting practices known to reduce the risk of teen drug use. Among the documented successes of the campaign to date was a small, but direct effect on some parenting practices, including parent-child discussions about drug use. To reach a deeper understanding about the substance of the parental ads, we content analyzed the message strategies employed in the campaign's parent ads over the inaugural 5 years of the campaign. Each ad was coded for its major theme, minor subtheme, and featured drug. Among seven possible major themes, the parental anti-drug ads largely featured four: enhance the risk of their child's drug use, encourage monitoring practices, promote parent-child discussions about drug use, or advocate positive involvement behaviors. Moreover, most parental messages addressed marijuana use or addressed drug use in general. Marijuana and inhalant ads largely were risk based, while general drug messages focused on monitoring, parent-child discussions or positive involvement practices.
Carocci, Alessia; Catalano, Alessia; Sinicropi, Maria Stefania
Melatonin (N-acetyl-5-methoxytryptamine) is widely known as “the darkness hormone”. It is a major chronobiological regulator involved in circadian phasing and sleep-wake cycle in humans. Numerous other functions, including cyto/neuroprotection, immune modulation, and energy metabolism have been ascribed to melatonin. A variety of studies have revealed a role for melatonin and its receptors in different pathophysiological conditions. However, the suitability of melatonin as a drug is limited because of its short half-life, poor oral bioavailability, and ubiquitous action. Due to the therapeutic potential of melatonin in a wide variety of clinical conditions, the development of new agents able to interact selectively with melatonin receptors has become an area of great interest during the last decade. Therefore, the field of melatonergic receptor agonists comprises a great number of structurally different chemical entities, which range from indolic to nonindolic compounds. Melatonergic agonists are suitable for sleep disturbances, neuropsychiatric disorders related to circadian dysphasing, and metabolic diseases associated with insulin resistance. The results of preclinical studies on animal models show that melatonin receptor agonists can be considered promising agents for the treatment of central nervous system-related pathologies. An overview of recent advances in the field of investigational melatonergic drugs will be presented in this review. PMID:25258560
Carocci, Alessia; Catalano, Alessia; Sinicropi, Maria Stefania
Melatonin (N-acetyl-5-methoxytryptamine) is widely known as "the darkness hormone". It is a major chronobiological regulator involved in circadian phasing and sleep-wake cycle in humans. Numerous other functions, including cyto/neuroprotection, immune modulation, and energy metabolism have been ascribed to melatonin. A variety of studies have revealed a role for melatonin and its receptors in different pathophysiological conditions. However, the suitability of melatonin as a drug is limited because of its short half-life, poor oral bioavailability, and ubiquitous action. Due to the therapeutic potential of melatonin in a wide variety of clinical conditions, the development of new agents able to interact selectively with melatonin receptors has become an area of great interest during the last decade. Therefore, the field of melatonergic receptor agonists comprises a great number of structurally different chemical entities, which range from indolic to nonindolic compounds. Melatonergic agonists are suitable for sleep disturbances, neuropsychiatric disorders related to circadian dysphasing, and metabolic diseases associated with insulin resistance. The results of preclinical studies on animal models show that melatonin receptor agonists can be considered promising agents for the treatment of central nervous system-related pathologies. An overview of recent advances in the field of investigational melatonergic drugs will be presented in this review.
An, Soontae; Muturi, Nancy
Older adults are increasingly the intended target of direct-to-consumer (DTC) prescription drug ads, but limited evidence exists as to how they assess the educational value of DTC ads and, more importantly, whether their assessment depends on their level of health literacy. In-person interviews of 170 older adults revealed that those with low subjective health literacy evaluated the educational value of DTC ads significantly lower than did those with high subjective health literacy. The results prompt us to pay more scholarly attention to determining how effectively DTC ads convey useful medical information, particularly to those with limited health literacy.
Peyrot, M; Alperstein, N M; Van Doren, D; Poli, L G
This study examines the impact of direct-to-consumer (DTC) pharmaceutical advertising on prescription drug knowledge and the requesting behavior of consumers. The authors developed and tested a conceptual model of prescription drug knowledge and requests. Consumers' belief that drug advertising can educate them was associated with a greater amount of drug knowledge, and the belief they would upset physicians by asking for specific drugs was associated with less knowledge. The belief that drug advertising reduces prices was associated with greater probability of drug requests, and the belief that physicians should be the sole source of drug information was associated with lesser probability of request. Preference for generic drugs was associated with a lesser likelihood of requesting a specific drug. Media exposure and drug advertising awareness were associated with higher drug knowledge and a greater probability of drug requesting.
... approve it. More Information Step 5 FDA Post-Market Safety Monitoring FDA Post-Market Safety Monitoring FDA monitors all drug and device ... Step 4: FDA Review Step 5: FDA Post-Market Safety Monitoring Page Last Updated: 06/24/2015 ...
Warner, Benjamin P.; McCleskey, T. Mark; Burrell, Anthony K.
X-ray fluorescence (XRF) spectrometry has been used for detecting binding events and measuring binding selectivities between chemicals and receptors. XRF may also be used for estimating the therapeutic index of a chemical, for estimating the binding selectivity of a chemical versus chemical analogs, for measuring post-translational modifications of proteins, and for drug manufacturing.
Pardridge, William M.
Alzheimer's disease (AD) drug development is limited by the presence of the blood-brain barrier (BBB). More than 98% of all small molecule drugs, and ∼100% of all large molecule drugs, do not cross the BBB. Despite the fact that the vast majority of AD drug candidates do not cross the BBB, the present-day AD drug development effort is characterized by an imbalance, whereby >99% of the drug development effort is devoted to CNS drug discovery, and <1% of drug development is devoted to CNS drug delivery. Future AD drug development needs a concerted effort to incorporate the BBB sciences early in the CNS drug discovery process. This can be accomplished by a reallocation of resources, and an expansion of the effort in the pure science of BBB biology and the applied science of brain drug targeting technology. PMID:19751922
Lockhart, Michelle Marie; Babar, Zaheer-Ud-Din; Carswell, Christopher; Garg, Sanjay
The pharmaceutical industry's profitability depends on identifying and successfully developing new drug candidates while trying to contain the increasing costs of drug development. It is actively searching for new sources of innovative compounds and for mechanisms to reduce the enormous costs of developing new drug candidates. There is an opportunity for academia to further develop as a source of drug discovery. The rising levels of industry outsourcing also provide prospects for organisations that can reduce the costs of drug development. We explored the potential returns to New Zealand (NZ) from its drug discovery expertise by assuming a drug development candidate is out-licensed without clinical data and has anticipated peak global sales of $350 million. We also estimated the revenue from NZ's clinical research industry based on a standard per participant payment to study sites and the number of industry-sponsored clinical trials approved each year. Our analyses found that NZ's clinical research industry has generated increasing foreign revenue and appropriate policy support could ensure that this continues to grow. In addition the probability-based revenue from the out-licensing of a drug development candidate could be important for NZ if provided with appropriate policy and financial support.
Limbu, Yam; Torres, Ivonne M
This article examines consumers' attitudes toward Direct-to-Consumer (DTC) advertising of prescription drugs that are influenced by the use different types of DTC ads and product involvement. Our findings suggest that product involvement and the type of DTC ad are significant predictors of consumers' attitudinal responses toward DTC advertising. High involvement consumers have more favorable attitudes toward the drug's price, DTC ad and brand name, and a higher intention to ask a doctor about the advertised drug than low involvement consumers. In contrast to Informational and Reminder DTC ads, Persuasive ads have more favorable effects on consumers' reactions to DTC prescription drug advertising.
Nairne, James; Iveson, Peter B; Meijer, Andreas
Imaging has played an important part in the diagnosis of disease and development of the understanding of the underlying disease mechanisms and is now poised to make an impact in the development of new pharmaceuticals. This chapter discusses the underlying technologies that make the field ready for this challenge. In particular, the potentials of magnetic resonance imaging and functional magnetic resonance imaging are outlined, including the new methods developed to provide additional information from the scans carried out. The field of nuclear medicine has seen a rapid increase in interest as advances in radiochemistry have enabled a wide range of new radiotracers to be synthesised.
Membrane transporters can be major determinants of the pharmacokinetic, safety and efficacy profiles of drugs. This presents several key questions for drug development, including which transporters are clinically important in drug absorption and disposition, and which in vitro methods are suitable for studying drug interactions with these transporters. In addition, what criteria should trigger follow-up clinical studies, and which clinical studies should be conducted if needed. In this article, we provide the recommendations of the International Transporter Consortium on these issues, and present decision trees that are intended to help guide clinical studies on the currently recognized most important drug transporter interactions. The recommendations are generally intended to support clinical development and filing of a new drug application. Overall, it is advised that the timing of transporter investigations should be driven by efficacy, safety and clinical trial enrolment questions (for example, exclusion and inclusion criteria), as well as a need for further understanding of the absorption, distribution, metabolism and excretion properties of the drug molecule, and information required for drug labeling. PMID:20190787
Monzote, Lianet; Siddiq, Afshan
The diseases caused by protozoan parasite are responsible for considerable mortality and morbidity, affecting more than 500 million of people in the world. The epidemiological control of protozoan is unsatisfactory due to difficulties of vector and reservoir control; while the progress in the development of vaccine tends to be slow and arduous. Currently, the chemotherapy remains essential component of both clinical management and disease control programmer in endemic areas. The drugs in use as anti-protozoan agents were discovered over 50 years and a number of factors limit their utility such as: high cost, poor compliance, drug resistance, low efficacy and poor safety. In the recent years, the searches about the development of new drugs against protozoa parasite have been increased. This special issue of The Open Medicinal Chemistry Journal will present some of developments in this field with the aim to shown the significant advances in the discovery of new anti-protozoan drugs.
In the last years, a sharp rise in the morbidity due to lung cancer is observed, especially in the male population. Despite the intensive, multidirectional development of oncology, early detection and effective treatment of lung cancer is still limited. Its detection is delayed because of the lack of characteristic early signs. Especially poor in prognosis are patients with small cell lung cancer (SCLC), who usually die in consequence of distant metastases. This may result due to coating of the surface of circulating neoplastic cells with thrombocytes and clots. Platelets aggregates on the surface of neoplastic cells may have a protective action in relation to cytostatic drugs. This is why neoplastic cells that persist through this phase, implant themselves into various organs giving rise to metastases. The aim of the 1st part of the paper was to evaluate the influence of antiplatelet drugs (AD) on the haemostatic system of patients with SCLC. There is data in literature indicating a ameliorating influence of AD on time of survival of patients with certain neoplasms. The study was performed in 87 male patients aged 35-73 years with SCLC, limited to half of the chest (limited disease). After 2 i.v. chemotherapy series in 3 week intervals (VAC scheme according Greco): --Adriamycin (ADR) 40 mg on 1sq.m of body surface; --Vincristin (VCR) 1 mg; on 1sq.m of body surface; --Cyclophosfamid (CTX) 1000 mg on 1sq.m of body surface; radiation was also applied--40 Gy during 20 days on the tumor and mediastinum. The described treatment was performed in 22 patients from controls (Group I). Patients from Group II (n = 22) received additionally Defibrotide, Group III (n = 22) Ticlide and Group IV (n = 21) Aspirin. To evaluate of the influence of AD on the haemostatic system--every 3 months during the consecutive 27 weeks, the following tests were performed: bleeding time, clotting time, platelet aggregation, platelets aggregation ratio, euglobulin clot lysis time (ECLT
Chapman, Robert M.; Porsteinsson, Anton P.; Gardner, Margaret N.; Mapstone, Mark; McCrary, John W.; Sandoval, Tiffany C.; Guillily, Maria D.; Reilly, Lindsey A.; DeGrush, Elizabeth
This paper investigates how commonly prescribed pharmacologic treatments for Alzheimer’s disease (AD) affect Event-Related Potential (ERP) biomarkers as tools for predicting AD conversion in individuals with Mild Cognitive Impairment (MCI). We gathered baseline ERP data from two MCI groups (those taking AD medications and those not) and later determined which subjects developed AD (Convert->AD) and which subjects remained cognitively stable (Stable). We utilized a previously developed and validated multivariate system of ERP components to measure medication effects among these four subgroups. Discriminant analysis produced classification scores for each individual as a measure of similarity to each clinical group (Convert->AD, Stable), and we found a large significant main Group effect but no main AD Medications effect and no Group by Medications interaction. This suggested AD medications have negligible influence on this set of ERP components as weighted markers of disease progression. These results provide practical information to those using ERP measures as a biomarker to identify and track AD in individuals in a clinical or research setting. PMID:23905997
Wang, Chen; Huang, Sui
While combinational diagnostic and treatment strategies over the past decades have significantly improved the overall survival of cancer patients, metastatic cancer remains a leading cause of death in developed countries. The lack of successful treatment strategies for the disease is in large part due to the complexity of the metastatic transformation, which embodies extensive cellular and extracellular alterations, enabling metastatic cancer cells to reach and colonize other organs. The mode of action for the majority of anti-cancer drugs used in clinics today is primarily tumor growth inhibition. While they are effective in destroying cancer cells, they fall short in blocking metastasis. Here we discuss the evolution of past and current anti-cancer drug development, the limits of current strategies, and possible alternative approaches for future drug development against metastatic cancers. PMID:28356899
Huansuriya, Thipnapa; Siegel, Jason T; Crano, William D
The authors combined the 2-step flow of communication model and the theory of planned behavior to create a framework to evaluate the effectiveness of a set of advertisements from the National Youth Anti-Drug Media Campaign promoting parent-child drug communication. The sample consisted of 1,349 pairs of parents and children who responded to the first and second annual rounds of the National Survey of Parents and Youth, and 1,276 pairs from Rounds 3 and 4. Parents' exposure to the campaign reported at Round 1 was indirectly associated with youth's lowered intentions to use marijuana at Round 2. Ad exposure was associated with positive changes in parental attitudes toward drug communication and perceived social approval of antidrug communications. These two beliefs, along with perceived behavioral control, predicted parents' intentions to discuss drugs with their children. Parental intentions to discuss drugs reported at Round 1 were associated with youth's report of actual drug communication with their parents at Round 2. Frequency and breadth of the topics in parent-child drug communication were associated with less positive attitudes toward marijuana use among youth who spoke with their parents. Together, the child's attitudes toward marijuana use and perceived ability to refuse marijuana use predicted youth's intentions to use marijuana. The proposed model fit well with the data and was replicated in a parallel analysis of the data from Rounds 3 and 4. Implications for future antidrug media campaign efforts are discussed.
Winters, Ken C.; Arria, Amelia
Research now suggests that the human brain is still maturing during adolescence. The developing brain may help explain why adolescents sometimes make decisions that are risky and can lead to safety or health concerns, including unique vulnerabilities to drug abuse. This article explores how this new science may be put to use in our prevention and…
Trame, Mirjam N; Biliouris, Konstantinos; Lesko, Lawrence J; Mettetal, Jerome T
Ensuring that drugs are safe and effective is a very high priority for drug development and the US Food and Drug Administration review process. This is especially true today because of faster approval times and smaller clinical trials, especially in oncology and rare diseases. In light of these trends, systems pharmacology is seen as an essential strategy to understand and predict adverse drug events during drug development by analyzing interactions between drugs and multiple targets rather than the traditional "one-drug-one-target" approach. This commentary offers an overview of the current trends and challenges of using systems pharmacology to reduce the risks of unintended adverse events.
Bates, Susan E; Amiri-Kordestani, Laleh; Giaccone, Giuseppe
A British humorist said, "There is much to be said for failure. It is much more interesting than success." This CCR Focus section is aimed at identifying lessons to be learned from difficulties encountered in recent years during development of anticancer agents. Clearly, we have not found a silver bullet tyrosine kinase inhibitor against solid tumors comparable with imatinib in chronic myelogenous leukemia. Although vemurafenib for B-Raf-mutated melanoma and crizotinib for non-small cell lung cancers with echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) rearrangements were developed rapidly and offer hope for individualized targeted therapies, the development of agents targeting a number of other pathways has been slower and less successful. These agents include drugs for blocking the insulin-like growth factor I/insulin receptor pathways, mitotic kinase inhibitors, and Hsp90 antagonists. Several potentially useful, if not groundbreaking, agents have had setbacks in clinical development, including trastuzumab emtansine, gemtuzumab ozogamicin, and satraplatin. From experience, we have learned the following: (i) not every altered protein or pathway is a valid anticancer target; (ii) drugs must effectively engage the target; (iii) the biology of the systems we use must be very well understood; and (iv) clinical trials must be designed to assess whether the drug reached and impaired the target. It is also important that we improve the drug development enterprise to enhance enrollment, streamline clinical trials, reduce financial risk, and encourage the development of agents for niche indications. Such enormous challenges are offset by potentially tremendous gains in our understanding and treatment of cancer.
Cacabelos, Ramón; Cacabelos, Pablo; Torrellas, Clara; Tellado, Iván; Carril, Juan C
Alzheimer's disease (AD) is a major problem of health and disability, with a relevant economic impact on our society. Despite important advances in pathogenesis, diagnosis, and treatment, its primary causes still remain elusive, accurate biomarkers are not well characterized, and the available pharmacological treatments are not cost-effective. As a complex disorder, AD is a polygenic and multifactorial clinical entity in which hundreds of defective genes distributed across the human genome may contribute to its pathogenesis. Diverse environmental factors, cerebrovascular dysfunction, and epigenetic phenomena, together with structural and functional genomic dysfunctions, lead to amyloid deposition, neurofibrillary tangle formation, and premature neuronal death, the major neuropathological hallmarks of AD. Future perspectives for the global management of AD predict that genomics and proteomics may help in the search for reliable biomarkers. In practical terms, the therapeutic response to conventional drugs (cholinesterase inhibitors, multifactorial strategies) is genotype-specific. Genomic factors potentially involved in AD pharmacogenomics include at least five categories of gene clusters: (1) genes associated with disease pathogenesis; (2) genes associated with the mechanism of action of drugs; (3) genes associated with drug metabolism (phase I and II reactions); (4) genes associated with drug transporters; and (5) pleiotropic genes involved in multifaceted cascades and metabolic reactions. The implementation of pharmacogenomic strategies will contribute to optimize drug development and therapeutics in AD and related disorders.
Ikonomidou, Chrysanthy; Turski, Lechoslaw
Epilepsy, the most common neurological disorder in young humans, has its highest incidence during the first year of life. Antiepileptic drugs (AEDs) which are used to treat seizures in infants, children and pregnant women target ion channels, neurotransmitters and second messenger systems in the brain. The same targets regulate brain processes essential both for propagation of seizures and for brain development, learning, memory and emotional behavior. Here we review adverse effects of AEDs in the developing mammalian brain. In addition, we discuss mechanisms explaining adverse effects of AEDs in the developing mammalian brain including interference with cell proliferation and migration, neurogenesis, axonal arborization, synaptogenesis, synaptic plasticity and physiological apoptotic cell death.
Pereira, Richard Van Vleck; Siler, Julie D.; Bicalho, Rodrigo Carvalho; Warnick, Lorin D.
Antimicrobial resistance represents a major global threat to modern medicine. In vitro studies have shown that very low concentrations of drugs, as frequently identified in the environment, and in foods and water for human and animal consumption, can select for resistant bacteria. However, limited information is currently available on the in vivo impact of ingested drug residues. The objective of our study was to evaluate the effect of feeding preweaned calves milk containing antimicrobial drug residues (below the minimum inhibitory concentration), similar to concentrations detected in milk commonly fed to dairy calves, on selection of resistant fecal E. coli in calves from birth to weaning. At birth, thirty calves were randomly assigned to a controlled feeding trial where: 15 calves were fed raw milk with no drug residues (NR), and 15 calves were fed raw milk with drug residues (DR) by adding ceftiofur, penicillin, ampicillin, and oxytetracycline at final concentrations in the milk of 0.1, 0.005, 0.01, and 0.3 µg/ml, respectively. Fecal samples were rectally collected from each calf once a week starting at birth prior to the first feeding in the trial (pre-treatment) until 6 weeks of age. A significantly greater proportion of E. coli resistant to ampicillin, cefoxitin, ceftiofur, streptomycin and tetracycline was observed in DR calves when compared to NR calves. Additionally, isolates from DR calves had a significant decrease in susceptibility to ceftriaxone and ceftiofur when compared to isolates from NR calves. A greater proportion of E. coli isolates from calves in the DR group were resistant to 3 or more antimicrobial drugs when compared to calves in the ND group. These findings highlight the role that low concentrations of antimicrobial drugs have on the evolution and selection of resistance to multiple antimicrobial drugs in vivo. PMID:25506918
Schneider, Lon S
The February 2013 Food and Drug Administration (FDA) draft guidance for developing drugs for early-stage Alzheimer's disease (AD) creates certain challenges as they guide toward the use of one cognitive outcome to gain accelerated marketing approval for preclinical AD drugs, and a composite clinical scale - the Clinical Dementia Rating Scale in particular - for the primary outcome for prodromal AD clinical trials. In light of the developing knowledge regarding early stage diagnoses and clinical trials outcomes, we recommend that FDA describe its requirements for validating preclinical AD diagnoses for drug development purposes, maintain the principle for requiring coprimary outcomes, and encourage the advancement of outcomes for early stage AD trials. The principles for drug development for early stage AD should not differ from those for clinical AD, especially as the diagnoses of prodromal and early AD impinge on each other. The FDA should not recommend that a composite scale be used as a sole primary efficacy outcome to support a marketing claim unless it requires that the cognitive and functional components of such a scale are demonstrated to be individually meaningful. The current draft guidelines may inadvertently constrain efforts to better assess the clinical effects of new drugs and inhibit innovation in an area where evidence-based clinical research practices are still evolving.
Zeng, Huahui; Wu, Xiangxiang
Alzheimer's disease (AD) is a common neurodegenerative disorder characterized by the excessive deposition of amyloids in the brain. The pathological features mainly include the extracellular amyloid plaques and intracellular neurofibrillary tangles, which are the production of amyloid precursor protein (APP) processed by the α-, β- and γ-secretases. Based on the amyloid cascade hypotheses of AD, a large number of amyloid-β agents and secretase inhibitors against AD have been recently developed by using computational methods. This review article describes pathophysiology of AD and the structure of the Aβ plaques, β- and γ-secretases, and discusses the recent advances in the development of the amyloid agents for AD therapy and diagnosis by using Computer-Aided Drug Design approach.
Despite intensive ongoing research, drug-induced live injury (DILI) remains a serious issue for care providers and patients, and has been a major cause of drug withdrawal and non-approval by regulatory authorities in the past 50 years. Consequently, DILI remains a major concern for the pharmaceutical industry and a leading cause for attrition during drug development. In most instances, severe DILI is an uncommon idiosyncratic reaction, which typically does not present during preclinical phases or early clinical phases of drug development. In the majority of cases, drugs that caused severe DILI in humans have not shown clear and consistent hepatotoxic signals in preclinical assessment including animal studies, cell cultures, or other methods. Despite intensive efforts to develop better biomarkers that would help in predicting DILI risk in earlier phases of drug development, such biomarkers are currently not supported by sufficient evidence and are not yet available for routine use by drug makers. Due to the lack of effective and accurate methods for prediction of idiosyncratic DILI during preclinical phases of drug development, different drug makers have adopted different approaches, which are often not supported by strong systematic evidence. Based on growing experience, it is becoming increasingly evident that milder forms of liver injury occurring during clinical development, when assessed correctly, may significantly enhance our ability to predict the drug's potential to cause more severe liver injury postmarketing. Strategies based on this concept have been adopted by many drug makers, and are being increasingly implemented during drug development. Meticulous causality assessment of individual hepatic cases and adherence to strict hepatic discontinuation rules are critical components of this approach and have to rely on thorough clinical evaluation and occasionally on assessment by liver experts experienced with DILI and drug development.
Mogra, Renu; Choudhry, Maya
Rab is a traditional Rajasthani preparation prepared by boiling maize grits and or flour in buttermilk for 2-3 h. It is sour in taste with curd and cumin seed flavour and has thick soup like consistency. Two instant mixes of rab were developed using two types of curds prepared from two different culture combination (i) S. lactis + S. thermophilus + S. diacetylactis and (ii) L. bulgaricus + S. diacetylactis. Processed greengram dhal and spinach leaves powder were added to the mixes for their value addition. In all, six mixes were developed from two types of curd. The mixes were analysed for nutritional composition at zero month and sensory characteristics and shelf life was evaluated for 4 months. The rab mixes provided moisture 4.0-5.5 g; protein 15.1-17.6 g; carbohydrate 62.3-70.29 g; energy 357-394 kcal; fat 4.4-6.1 g; iron 3.15-3.89 mg and calcium 346-386 mg per 100 g of mixes. There was an increase in protein, ash, fiber and iron content of mixes through value addition. Sensory evaluation of rab reconstituted from mixes revealed that the scores ranged between 7 and 8 depicting that rab was liked very much. The mixes were free from coliforms and S.aureus bacteria and the counts for TVC, yeast and molds were within safe limits during storage of 4 months at 28-30°C and RH 55-65%.
Lesko, L J
The development of orphan drugs for rare diseases has made impressive strides in the past 10 years. There has been a surge in orphan drug designations, but new drug approvals have not kept up. This article presents a three-pronged hierarchical strategy for quantitative analysis of data at the descriptive, mechanistic, and systems levels of the biological system that could represent a standardized and rational approach to orphan drug development. Examples are provided to illustrate the concept.
Sharma, Aarti; Jacob, Abraham; Tandon, Manas; Kumar, Dushyant
The growth of pharma industries has slowed in recent years because of various reasons such as patent expiries, generic competition, drying pipelines, and increasingly stringent regulatory guidelines. Many blockbuster drugs will loose their exclusivity in next 5 years. Therefore, the current economic situation plus the huge generic competition shifted the focus of pharmaceutical companies from the essential medicines to the new business model — niche busters, also called orphan drugs. Orphan drugs may help pharma companies to reduce the impact of revenue loss caused by patent expiries of blockbuster drugs. The new business model of orphan drugs could offer an integrated healthcare solution that enables pharma companies to develop newer areas of therapeutics, diagnosis, treatment, monitoring, and patient support. Incentives for drug development provided by governments, as well as support from the FDA and EU Commission in special protocols, are a further boost for the companies developing orphan drugs. Although there may still be challenges ahead for the pharmaceutical industry, orphan drugs seem to offer the key to recovery and stability within the market. In our study, we have compared the policies and orphan drug incentives worldwide alongwith the challenges faced by the pharmaceutical companies. Recent developments are seen in orphan drug approval, the various drugs in orphan drug pipeline, and the future prospectives for orphan drugs and diseases. PMID:21180460
Sharma, Aarti; Jacob, Abraham; Tandon, Manas; Kumar, Dushyant
The growth of pharma industries has slowed in recent years because of various reasons such as patent expiries, generic competition, drying pipelines, and increasingly stringent regulatory guidelines. Many blockbuster drugs will loose their exclusivity in next 5 years. Therefore, the current economic situation plus the huge generic competition shifted the focus of pharmaceutical companies from the essential medicines to the new business model - niche busters, also called orphan drugs. Orphan drugs may help pharma companies to reduce the impact of revenue loss caused by patent expiries of blockbuster drugs. The new business model of orphan drugs could offer an integrated healthcare solution that enables pharma companies to develop newer areas of therapeutics, diagnosis, treatment, monitoring, and patient support. Incentives for drug development provided by governments, as well as support from the FDA and EU Commission in special protocols, are a further boost for the companies developing orphan drugs. Although there may still be challenges ahead for the pharmaceutical industry, orphan drugs seem to offer the key to recovery and stability within the market. In our study, we have compared the policies and orphan drug incentives worldwide alongwith the challenges faced by the pharmaceutical companies. Recent developments are seen in orphan drug approval, the various drugs in orphan drug pipeline, and the future prospectives for orphan drugs and diseases.
Moors, Ellen H M; Cohen, Adam F; Schellekens, Huub
Drug development has become the exclusive activity of large pharmaceutical companies. However, the output of new drugs has been decreasing for the past decade and the prices of new drugs have risen steadily, leading to access problems for many patients. By analyzing the history of drug development and the pharmaceutical industry, we identified the main factors causing this system failure. Although many solutions have been suggested to fix the drug development system, we believe that a combination of reforms of the regulatory and patent systems is necessary to make drug development sustainable. These reforms must be combined with a larger, open-access role for public research institutes in the discovery, clinical evaluation and safety evaluation of new drugs.
hemorrhagic fever ( CCHF ) virus in infant mice. Most compounds were tested using a single dose of drug administered 45 minutes before virus. Nine...protection from mortality and reproducible prolongation of survival time in primary testing against CCHF virus. These drugs include AVS#1 which is...SUMMARY OF RESULTS OF TESTING IN CCHF MODEL 11 TABLE 2 TEST VARIATION: VIRUS CONTROL (VC)1 4 TABLE 3 TEST VARIATION: POSVE CONTROL (VR+) 1 4 TABLE 4
Wang, Yi-Xiang; Deng, Min
Medical imaging can help answer key questions that arise during the drug development process. The role of medical imaging in new drug clinical trials includes identification of likely responders; detection and diagnosis of lesions and evaluation of their severity; and therapy monitoring and follow-up. Nuclear imaging techniques such as PET can be used to monitor drug pharmacokinetics and distribution and study specific molecular endpoints. In assessing drug efficacy, imaging biomarkers and imaging surrogate endpoints can be more objective and faster to measure than clinical outcomes, and allow small group sizes, quick results and good statistical power. Imaging also has important role in drug safety monitoring, particularly when there is no other suitable biomarkers available. Despite the long history of radiological sciences, its application to the drug development process is relatively recent. This review highlights the processes, opportunities, and challenges of medical imaging in new drug development.
Yin, Tian; Cao, Xiuxiu; Liu, Xiaolin; Wang, Jian; Shi, Caihong; Su, Jia; Zhang, Yu; Gou, Jingxin; He, Haibing; Guo, Haiyan; Tang, Xing; Zhao, Yuqing
In this study, molecular interactions between the anti-cancer agent 20(R)-25-methoxyl-dammarane-3β, 12β, 20-triol (AD-1) and phospholipid 1,2-Distearoyl-sn-glycero-3-phosphocholine (DSPC) were investigated using the Langmuir film balance technique. The characteristics of binary Langmuir monolayers consisting of DSPC and AD-1 were conducted on the basis of the surface pressure-area per molecule (π-A) isotherms. It was found that the drug was able to become efficiently inserted into preformed DSPC monolayers, indicating a preferential interaction between AD-1 and DSPC. For the examined lateral pressure at 20mN/m, the largest negative values of ΔGex were found for the AD-1/DSPC monolayer, which should be the most stable. Based on the calculated values of ΔGex, we found that the AD-1/DSPC systems exhibited the best mixed characteristics when the molar fraction of the AD-1 was 0.8; at that relative concentration, the AD-1 molecules can mix better and interact with the phospholipid molecules. In addition, the drug-DSPC binary supramolecular structure was also deposited on the mica plates as shown by atomic force microscopy (AFM). Finally, molecular docking calculations explained satisfactorily that, based on the conformations interactions (conformation recognition), even at an AD-1/DSPC molar ratio as high as 8:2, the interfacial stabilization of the AD-1/DSPC system was fairly strong due to hydrophobic interactions. A higher loading capacity of DSPC might be possible, as it is associated with a more flexible geometrical environment, which allows these supramolecular structures to accept larger increases in drug loading upon steric binding.
Cummings, Jeffrey; Aisen, Paul S; DuBois, Bruno; Frölich, Lutz; Jack, Clifford R; Jones, Roy W; Morris, John C; Raskin, Joel; Dowsett, Sherie A; Scheltens, Philip
The global impact of Alzheimer's disease (AD) continues to increase, and focused efforts are needed to address this immense public health challenge. National leaders have set a goal to prevent or effectively treat AD by 2025. In this paper, we discuss the path to 2025, and what is feasible in this time frame given the realities and challenges of AD drug development, with a focus on disease-modifying therapies (DMTs). Under the current conditions, only drugs currently in late Phase 1 or later will have a chance of being approved by 2025. If pipeline attrition rates remain high, only a few compounds at best will meet this time frame. There is an opportunity to reduce the time and risk of AD drug development through an improvement in trial design; better trial infrastructure; disease registries of well-characterized participant cohorts to help with more rapid enrollment of appropriate study populations; validated biomarkers to better detect disease, determine risk and monitor disease progression as well as predict disease response; more sensitive clinical assessment tools; and faster regulatory review. To implement change requires efforts to build awareness, educate and foster engagement; increase funding for both basic and clinical research; reduce fragmented environments and systems; increase learning from successes and failures; promote data standardization and increase wider data sharing; understand AD at the basic biology level; and rapidly translate new knowledge into clinical development. Improved mechanistic understanding of disease onset and progression is central to more efficient AD drug development and will lead to improved therapeutic approaches and targets. The opportunity for more than a few new therapies by 2025 is small. Accelerating research and clinical development efforts and bringing DMTs to market sooner would have a significant impact on the future societal burden of AD. As these steps are put in place and plans come to fruition, e.g., approval
Summary Phase-1 (also known as “First-in-Man”) clinical trials initiate the early clinical development of possible new medicines. Patient participation in this early phase of clinical trials is rather limited. After successful phase 1 trials, further phase 2 and phase 3 clinical trials in patients may lead to a marketing authorization. In the first 15 years of the European Union Orphan Drug Directive, 4.5% of the orphan drug applications were authorized. However, for many of these orphan drugs, no phase 1 studies were required, as these products were already well known pharmaceutical substances, with a clearly defined pharmacological profile. Furthermore, for 19 orphan drugs, already authorized by the European Medicines Agency (EMA), the original rare indication was extended to another rare disease and no phase 1 trials were needed. Phase 1 studies need to be performed in a sufficient number of volunteers even for medicinal products intended for a very limited number of patients. PMID:28357178
National IQs and measures of technological development given by Comin, Easterly and Gong (2010) are presented for 133 nations for the year 1000 BC, for 134 nations for 0 AD, for 120 nations for 1500 AD and for 133 nations for 2000 AD. It is shown that national IQs are significantly correlated with national differences in technological development…
Altstiel, L D
The major barrier to Alzheimer disease (AD) drug discovery and development in the biotechnology industry is scale. Most biotechnology companies do not have the personnel or expertise to carry a drug from the bench to the market. Much effort in the industry has been directed toward the elucidation of molecular mechanisms of AD and the identification of new targets. Advances in biotechnology have generated new insights into disease mechanisms, increased the number of lead compounds, and accelerated biologic screening. The majority of costs associated with drug development are in clinical testing and development activities, many of which are driven by regulatory issues. For most biotechnology companies, the costs of such trials and the infrastructure necessary to support them are prohibitive. Another significant barrier is the definition of therapeutic benefit for AD drugs; Food and Drug Administration (FDA) precedent has established that a drug must show superiority to placebo on a performance-based test of cognition and a measure of global clinical function. This restrictive definition is biased toward drugs that enhance performance on memory-based tests. Newer AD drugs are targeted toward slowing disease progression; however, there is currently no accepted definition of what constitutes efficacy in disease progression. Despite these obstacles, the biotechnology industry has much to offer AD drug discovery and development. Biotechnology firms have already developed essential technology for AD drug development and will continue to do so. Biotechnology companies can move more quickly; of course, the trick is to move quickly in the right direction. Speed may offset some of the problems associated with lack of scale. Additionally, biotechnology companies can afford to address markets that may be too restricted for larger pharmaceutical companies. This advantage will have increasing importance, as therapies are developed to address subtypes of AD.
Groft, S C
Drug research and development in the U.S. tends to focus on drugs to treat common diseases because of the anticipated return on investment. To stimulate pharmaceutical manufacturers to pursue the development of drugs for rare conditions, the Orphan Drug Act was enacted by Congress on January 4, 1983. Under the provisions of this Act, the FDA can make recommendations on the investigations necessary for marketing approval; exclusive marketing privileges can be obtained; tax credits for expenses incurred are allowed; availability of orphan drugs on an investigational basis is encouraged; and the Orphan Product Board is established for the coordination of research efforts and their reimbursement. The effects of this legislation are evident in the continuing increase in orphan drug designations.
Morgan, Steven G.; Li, Winny; Yau, Brandon; Persaud, Nav
BACKGROUND: Canada’s universal health care system does not include universal coverage of prescription drugs. We sought to estimate the effects of adding universal public coverage of an essential medicines list to existing public drug plans in Canada. METHODS: We used administrative and market research data to estimate the 2015 shares of the volume and cost of prescriptions filled in the community setting that were for 117 drugs on a model list of essential medicines for Canada. We compared prices of these essential medicines in Canada with prices in the United States, Sweden and New Zealand. We estimated the cost of adding universal public drug coverage of these essential medicines based on anticipated effects on medication use and pricing. RESULTS: The 117 essential medicines on the model list accounted for 44% of all prescriptions and 30% of total prescription drug expenditures in 2015. Average prices of generic essential medicines were 47% lower in the US, 60% lower in Sweden and 84% lower in New Zealand; brand-name drugs were priced 43% lower in the US. Estimated savings from universal public coverage of these essential medicines was $4.27 billion per year (range $2.72 billion to $5.83 billion; 28% reduction) for patients and private drug plan sponsors, at an incremental government cost of $1.23 billion per year (range $373 million to $1.98 billion; 11% reduction). INTERPRETATION: Our analysis showed that adding universal public coverage of essential medicines to the existing public drug plans in Canada could address most of Canadians’ pharmaceutical needs and save billions of dollars annually. Doing so may be a pragmatic step forward while more comprehensive pharmacare reforms are planned. PMID:28246223
Zhong, Wei-Zhu; Zhou, Shu-Feng
With the avalanche of biological sequences generated in the postgenomic age, molecular science is facing an unprecedented challenge, i.e., how to timely utilize the huge amount of data to benefit human beings. Stimulated by such a challenge, a rapid development has taken place in molecular science, particularly in the areas associated with drug development and biomedicine, both experimental and theoretical. The current thematic issue was launched with the focus on the topic of "Molecular Science for Drug Development and Biomedicine", in hopes to further stimulate more useful techniques and findings from various approaches of molecular science for drug development and biomedicine.[...].
Fu, Weiqi; Wichuk, Kristine; Brynjólfsson, Sigurður
As a major primary producer in marine environments, diatoms have been considered as promising feedstocks for their applications in functional foods, bioactive pharmaceuticals, and cosmetics. This review focuses on the biotechnology potential of diatoms for value-added products like carotenoids. The impact of abiotic environmental stresses, such as intensity and quality of incident light, nutrient deficiency and silicon depletion, on diatoms has been examined to determine key factors that affect the growth performance and the accumulation of valuable compounds. Previous studies suggested that adaptive evolution could be an efficient method to improve the diatom productivity of valuable compounds. Light emitting diode (LED)-based photobioreactors were introduced and proposed as a promising new technology for producing quality products from diatoms. Currently available molecular biology tools were also summarized and discussed in relation to their application in the production of carotenoids and other valuable products. Taken together, systems biology and synthetic biology approaches have the potential to address the challenges faced while working toward the industrial application of diatoms.
Wu, Hongjin; Wang, Charles; Wu, Shixiu
Next-generation sequencing (NGS), particularly single-cell sequencing, has revolutionized the scale and scope of genomic and biomedical research. Recent technological advances in NGS and single-cell studies have made the deep whole-genome (DNA-seq), whole epigenome and whole-transcriptome sequencing (RNA-seq) at single-cell level feasible. NGS at the single-cell level expands our view of genome, epigenome and transcriptome and allows the genome, epigenome and transcriptome of any organism to be explored without a priori assumptions and with unprecedented throughput. And it does so with single-nucleotide resolution. NGS is also a very powerful tool for drug discovery and drug development. In this review, we describe the current state of single-cell sequencing techniques, which can provide a new, more powerful and precise approach for analyzing effects of drugs on treated cells and tissues. Our review discusses single-cell whole genome/exome sequencing (scWGS/scWES), single-cell transcriptome sequencing (scRNA-seq), single-cell bisulfite sequencing (scBS), and multiple omics of single-cell sequencing. We also highlight the advantages and challenges of each of these approaches. Finally, we describe, elaborate and speculate the potential applications of single-cell sequencing for drug discovery and drug development.
Pidd, Ken; Carne, Amanda; Roche, Ann
This document was produced by the authors, based on their research for the report "The Role of VET in Alcohol and Other Drugs Workforce Development", and is an added resource for further information. "The Role of VET in Alcohol and Other Drugs Workforce Development" uncovers concerns managers have around the training content,…
The needs of newly developed antitubercular agents are required for the control of tuberculosis in the present time. In the discovery of new antitubercular drugs, the emergence of multidrug-resistant (MDR) and extensively drug resistant (XDR) strains of Mycobacterium tuberculosis (Mtb) has encouraged the researchers to intensify the efforts to discover novel antitubercular drugs. These novel drugs will predominantly target the persistent state of mycobacterium strains, which are resistant to conventional drugs including non resistant mycobacterium strains. In the last three to four decades no new effective drug has been developed for the treatment of resistant tuberculosis. However, in recent years, the research and development programs for the control of TB, there is a lot works is going on to enhancement of the anti-TB activity of new drugs particularly against resistant mycobacterium strains. Simultaneously, practical usefulness of some new targets is being identified and validated for the treatment of TB. Some compounds are presently in clinical trials, while others are being investigated in an attempt to explore new compounds for the target based treatment. The present review provides an overview of the new anti-TB agents with different molecular structures that are being clinically used and advanced stages of preclinical as well as clinical stages and also attempted to highlight the efforts that are being made in the development of new drug molecules as lead anti-TB agents.
o-A179 W1? MOLECULAR MODELING IN DRUG DESIGN FOR THE DEVELOPMENT 1/1 OF ORGANOPHOSPHORUS RNTIDOTES/PROPHYLACTICS(U) ARIZONA UNIV TUCSON DEPT OF...IESI CHART -- K . Kw" % - -,"--. AD__ Molecular Modeling in Drug Design for the 0Development of Organophosphorus Antidotes/Prophylactics Annual Report...in Drug Design for the Development of Organophosphorus Antidotes/ Prohvlactics 12. PERSONAL AUTHOR(S) Wah Chiu, Ph.D. 13a. TYPE OF REPORT 13b. TIME
FitzGerald, Garret A
The rate of new drug approvals in the US has remained essentially constant since 1950, while the costs of drug development have soared. Many commentators question the sustainability of the current model of drug development, in which large pharmaceutical companies incur markedly escalating costs to deliver the same number of products to market. This Issue Brief summarizes the problem, describes ongoing governmental efforts to influence the process, and suggests changes in regulatory science and translational medicine that may promote more successful development of safe and effective therapeutics
Pandey, Saurabh; Pandey, Preeti; Tiwari, Gaurav; Tiwari, Ruchi
Recent years have witnessed the introduction of several high-quality review articles into the literature covering various scientific and technical aspects of bioanalysis. Now it is widely accepted that bioanalysis is an integral part of the pharmacokinetic/pharmacodynamic characterization of a novel chemical entity from the time of its discovery and during various stages of drug development, leading to its market authorization. In this compilation, the important bioanalytical parameters and its application to drug discovery and development approaches are discussed, which will help in the development of safe and more efficacious drugs with reduced development time and cost. It is intended to give some general thoughts in this area which will form basis of a general framework as to how one would approach bioanalysis from inception (i.e., discovery of a lead molecule) and progressing through various stages of drug development. PMID:23781412
Collett, Marc S; Neyts, Johan; Modlin, John F
Polio eradication is within sight. In bringing the world close to this ultimate goal, the Global Polio Eradication Initiative (GPEI) has relied exclusively on the live, attenuated oral poliovirus vaccine (OPV). However, as eradication nears, continued OPV use becomes less tenable due to the incidence of vaccine associated paralytic poliomyelitis (VAPP) in vaccine recipients and disease caused by circulating vaccine-derived polioviruses (cVDPVs) in contacts. Once wild poliovirus transmission has been interrupted globally, OPV use will stop. This will leave the inactivated poliovirus vaccine (IPV) as the only weapon to defend a polio-free world. Outbreaks caused by cVDPVs are expected post-OPV cessation, and accidental or deliberate releases of virus could also occur. There are serious doubts regarding the ability of IPV alone to control outbreaks. Here, we argue that antiviral drugs against poliovirus be added to the arsenal. Anti-poliovirus drugs could be used to treat the infected and protect the exposed, acting rapidly on their own to contain an outbreak and used as a complement to IPV. While there are no polio antiviral drugs today, the technological feasibility of developing such drugs and their probability of clinical success have been established by over three decades of drug development targeting the related rhinoviruses and non-polio enteroviruses (NPEVs). Because of this history, there are known compounds with anti-poliovirus activity in vitro that represent excellent starting points for polio drug development. Stakeholders must come to understand the potential public health benefits of polio drugs, the feasibility of their development, and the relatively modest costs involved. Given the timelines for eradication and those for drug development, the time for action is now.
Power, M. J.; Green, A. M.
Background: This paper describes the development of an Attitudes to Disability Scale for use with adults with physical or intellectual disabilities (ID). The aim of the research was to design a scale that could be used to assess the personal attitudes of individuals with either physical or ID. Method: The measure was derived following standard…
Purohit, Vivek S
Pediatric drug development is a required consideration for all drug development programs. Age-appropriate formulations such as suspensions, chewable tablets, oral disintegrating tablets, etc., are typically developed and used in the pediatric clinical studies. However, it is not uncommon to use enabling formulations in the pivotal pediatric clinical study followed by bridging bioavailability and/or bioequivalence studies. Development of age-appropriate formulations is an essential part of pediatric drug development and adds additional biopharmaceutical considerations to an already complex problem. Careful planning of biopharmaceutic data collection during the adult and pediatric development program can contribute significantly to the biopharmaceutic risk assessment and planning of appropriate clinical studies leading to successful development of pediatric formulations.
Lagassé, H.A. Daniel; Alexaki, Aikaterini; Simhadri, Vijaya L.; Katagiri, Nobuko H.; Jankowski, Wojciech; Sauna, Zuben E.; Kimchi-Sarfaty, Chava
Therapeutic protein drugs are an important class of medicines serving patients most in need of novel therapies. Recently approved recombinant protein therapeutics have been developed to treat a wide variety of clinical indications, including cancers, autoimmunity/inflammation, exposure to infectious agents, and genetic disorders. The latest advances in protein-engineering technologies have allowed drug developers and manufacturers to fine-tune and exploit desirable functional characteristics of proteins of interest while maintaining (and in some cases enhancing) product safety or efficacy or both. In this review, we highlight the emerging trends and approaches in protein drug development by using examples of therapeutic proteins approved by the U.S. Food and Drug Administration over the previous five years (2011–2016, namely January 1, 2011, through August 31, 2016). PMID:28232867
5012 61102A 1102BS11 EB 025 11. TITLE (Include Security Classification) Molecular Modeling in Drug Design for the Development of Organophosphorous...t ....................................., ’ i.° AD MOLECULAR MODELING IN DRUG DESIGN FOR THE DEVELOPMENT OF ORGANOPHOSPHOROUS ANTIDOTES...Reed, W.J. Murray, E.B. Roche and L.N. Donelsmith, Gen. Pharmac., 12, 177-185 (1981). 5. L.B.Kier, "Molecular Orbital Theory in Drug Design ", Academic
Over the last 25 years, profound changes have been seen in both the development and regulation of pharmaceutical dosage forms, due primarily to the extensive use of the biopharmaceutical classification system (BCS) in both academia and industry. The BCS and the FDA scale-up and post-approval change guidelines were both developed during the 1990s and both are currently widely used to claim biowaivers. The development of the BCS and its wide acceptance were important steps in pharmaceutical science that contributed to the more rational development of oral dosage forms. The effective permeation (Peff) of drugs through the intestine often depends on the combined outcomes of passive diffusion and multiple parallel transport processes. Site-specific jejunal Peff cannot reflect the permeability of the whole intestinal tract, since this varies along the length of the intestine, but is a useful approximation of the fraction of the oral dose that is absorbed. It appears that drugs with a jejunal Peff>1.5×10(-4)cm/s will be completely absorbed no matter which transport mechanisms are utilized. In this paper, historical clinical data originating from earlier open, single-pass perfusion studies have been used to calculate the Peff of different substances from sites in the jejunum and ileum. More exploratory in vivo studies are required in order to obtain reliable data on regional intestinal drug absorption. The development of experimental and theoretical methods of assessing drug absorption from both small intestine and various sites in the colon is encouraged. Some of the existing human in vivo data are discussed in relation to commonly used cell culture models. It is crucial to accurately determine the input parameters, such as the regional intestinal Peff, as these will form the basis for the expected increase in modeling and simulation of all the processes involved in GI drug absorption, thus facilitating successful pharmaceutical development in the future. It is suggested
Broad, Lisa M.; Mogg, Adrian J.; Eberle, Elizabeth; Tolley, Marcia; Li, Dominic L.; Knopp, Kelly L.
Transient receptor potential vanilloid 3 (TRPV3) is a member of the TRP (Transient Receptor Potential) super-family. It is a relatively underexplored member of the thermo-TRP sub-family (Figure 1), however, genetic mutations and use of gene knock-outs and selective pharmacological tools are helping to provide insights into its role and therapeutic potential. TRPV3 is highly expressed in skin, where it is implicated in skin physiology and pathophysiology, thermo-sensing and nociception. Gain of function TRPV3 mutations in rodent and man have enabled the role of TRPV3 in skin health and disease to be particularly well defined. Pre-clinical studies provide some rationale to support development of TRPV3 antagonists for therapeutic application for the treatment of inflammatory skin conditions, itch and pain. However, to date, only one compound directed towards block of the TRPV3 receptor (GRC15300) has progressed into clinical trials. Currently, there are no known clinical trials in progress employing a TRPV3 antagonist. PMID:27618069
Broad, Lisa M; Mogg, Adrian J; Eberle, Elizabeth; Tolley, Marcia; Li, Dominic L; Knopp, Kelly L
Transient receptor potential vanilloid 3 (TRPV3) is a member of the TRP (Transient Receptor Potential) super-family. It is a relatively underexplored member of the thermo-TRP sub-family (Figure 1), however, genetic mutations and use of gene knock-outs and selective pharmacological tools are helping to provide insights into its role and therapeutic potential. TRPV3 is highly expressed in skin, where it is implicated in skin physiology and pathophysiology, thermo-sensing and nociception. Gain of function TRPV3 mutations in rodent and man have enabled the role of TRPV3 in skin health and disease to be particularly well defined. Pre-clinical studies provide some rationale to support development of TRPV3 antagonists for therapeutic application for the treatment of inflammatory skin conditions, itch and pain. However, to date, only one compound directed towards block of the TRPV3 receptor (GRC15300) has progressed into clinical trials. Currently, there are no known clinical trials in progress employing a TRPV3 antagonist.
Althoff, Michael E.
The objective of the study was to develop a test which could measure both the qualitative and quantitative aspects of drug-using behavior, including such factors as attitudes toward drugs, experience with drugs, and knowledge about drugs. The Drug Use Scale was developed containing 134 items and dealing with five classes of drugs: marijuana,…
Drugs are often seen as ancillary to the purpose of fighting diseases. Here an alternative view is proposed in which they occupy a spearheading role. In this view, drugs are technologies with an inherent therapeutic potential. Once created, they can spread from disease to disease independently of the drug creator's original intentions. Through the analysis of extensive literature and clinical trial records, it can be observed that successful drugs follow a life cycle in which they are studied at an increasing rate, and for the treatment of an increasing number of diseases, leading to clinical advancement. Such initial growth, following a power law on average, has a degree of momentum, but eventually decelerates, leading to stagnation and decay. A network model can describe the propagation of drugs from disease to disease in which diseases communicate with each other by receiving and sending drugs. Within this model, some diseases appear more prone to influence other diseases than be influenced, and vice versa. Diseases can also be organized into a drug-centric disease taxonomy based on the drugs that each adopts. This taxonomy reflects not only biological similarities across diseases, but also the level of differentiation of existing therapies. In sum, this study shows that drugs can become contagious technologies playing a driving role in the fight against disease. By better understanding such dynamics, pharmaceutical developers may be able to manage drug projects more effectively.
Drugs are often seen as ancillary to the purpose of fighting diseases. Here an alternative view is proposed in which they occupy a spearheading role. In this view, drugs are technologies with an inherent therapeutic potential. Once created, they can spread from disease to disease independently of the drug creator’s original intentions. Through the analysis of extensive literature and clinical trial records, it can be observed that successful drugs follow a life cycle in which they are studied at an increasing rate, and for the treatment of an increasing number of diseases, leading to clinical advancement. Such initial growth, following a power law on average, has a degree of momentum, but eventually decelerates, leading to stagnation and decay. A network model can describe the propagation of drugs from disease to disease in which diseases communicate with each other by receiving and sending drugs. Within this model, some diseases appear more prone to influence other diseases than be influenced, and vice versa. Diseases can also be organized into a drug-centric disease taxonomy based on the drugs that each adopts. This taxonomy reflects not only biological similarities across diseases, but also the level of differentiation of existing therapies. In sum, this study shows that drugs can become contagious technologies playing a driving role in the fight against disease. By better understanding such dynamics, pharmaceutical developers may be able to manage drug projects more effectively. PMID:27124390
Corbett, Anne; Williams, Gareth; Ballard, Clive
Alzheimer’s Disease (AD) is the most common cause of dementia, affecting approximately two thirds of the 35 million people worldwide with the condition. Despite this, effective treatments are lacking, and there are no drugs that elicit disease modifying effects to improve outcome. There is an urgent need to develop and evaluate more effective pharmacological treatments. Drug repositioning offers an exciting opportunity to repurpose existing licensed treatments for use in AD, with the benefit of providing a far more rapid route to the clinic than through novel drug discovery approaches. This review outlines the current most promising candidates for repositioning in AD, their supporting evidence and their progress through trials to date. Furthermore, it begins to explore the potential of new transcriptomic and microarray techniques to consider the future of drug repositioning as a viable approach to drug discovery. PMID:24275851
Modern drug research is mechanism-based and the development of disease modifying therapies involves the identification of molecular key players in the pathological cascade. Today, noninvasive imaging tools enable the visualization and quantitative assessment of the expression of molecular targets, of their interaction with potential ligands, as well as of the functional consequence of this interaction at a molecular (e.g. activation of signaling cascades), cellular, metabolic, physiological, and morphological level in a temporo-spatially resolved manner. The ability to gather such information from the intact organism with all regulatory processes in place renders imaging highly attractive for the biomedical researcher and for the drug developer in particular. Molecular imaging is potentially capable of providing this information. Today, proof-of-principle has been established that imaging is in fact adding value to the drug discovery and development processes. Numerous studies have used structural and functional imaging readouts to document therapy efficacy, mainly during lead optimization. Similarly, major efforts have been devoted to the development and evaluation of imaging biomarkers that might serve as early readouts for therapy response with the potential of being used in the clinical drug evaluation thereby facilitating translational research. In this contribution, we illustrate the role and potential of imaging in modern drug discovery and development with selected examples. Yet, despite its huge potential the impact of imaging on drug discovery has been modest in the past; potential reasons will be discussed. Nevertheless, noninvasive imaging methods are rapidly evolving and it is beyond doubt that their importance for biomedical research will increase.
The practice of regulatory science (RS) for drug development is described. In the course material for education in pharmaceutical sciences drafted by the RS Division of the Pharmaceutical Society of Japan, RS for pharmaceuticals is defined as the science of predicting, assessing, and judging the quality, efficacy, and safety of pharmaceutical products throughout their lifespan. RS is also described as an integrated science based on basic and applied biomedical sciences, including analytical chemistry, biochemistry, pharmacology, toxicology, genetics, biostatistics, epidemiology, and clinical trial methodology, and social sciences such as decision science, risk assessment, and communication science. The involvement of RS in drug development generally starts after the optimization of lead compounds. RS plays important roles governing pharmaceuticals during their entire life cycle management phase as well as the drug development phase.
Tamimi, Nihad A M; Ellis, Peter
Drug development is an expensive, long and high-risk business taking 10-15 years and is associated with a high attrition rate. It is driven by medical need, disease prevalence and the likelihood of success. Drug candidate selection is an iterative process between chemistry and biology, refining the molecular properties until a compound suitable for advancing to man is found. Typically, about one in a thousand synthesised compounds is ever selected for progression to the clinic. Prior to administration to humans, the pharmacology and biochemistry of the drug is established using an extensive range of in vitro and in vivo test procedures. It is also a regulatory requirement that the drug is administered to animals to assess its safety. Later-stage animal testing is also required to assess carcinogenicity and effects on the reproductive system. Clinical phases of drug development include phase I in healthy volunteers to assess primarily pharmacokinetics, safety and toleration, phase II in a cohort of patients with the target disease to establish efficacy and dose-response relationship and large-scale phase III studies to confirm safety and efficacy. Experience tells us that approximately only 1 in 10 drugs that start the clinical phase will make it to the market. Each drug must demonstrate safety and efficacy in the intended patient population and its benefits must outweigh its risks before it will be approved by the regulatory agencies. Strict regulatory standards govern the conduct of pre-clinical and clinical trials as well as the manufacturing of pharmaceutical products. The assessment of the new medicinal product's safety continues beyond the initial drug approval through post-marketing monitoring of adverse events.
Lee, Hyeong-Min; Kim, Yuna
Better the drugs you know than the drugs you do not know. Drug repurposing is a promising, fast, and cost effective method that can overcome traditional de novo drug discovery and development challenges of targeting neuropsychiatric and other disorders. Drug discovery and development targeting neuropsychiatric disorders are complicated because of the limitations in understanding pathophysiological phenomena. In addition, traditional de novo drug discovery and development are risky, expensive, and time-consuming processes. One alternative approach, drug repurposing, has emerged taking advantage of off-target effects of the existing drugs. In order to identify new opportunities for the existing drugs, it is essential for us to understand the mechanisms of action of drugs, both biologically and pharmacologically. By doing this, drug repurposing would be a more effective method to develop drugs against neuropsychiatric and other disorders. Here, we review the difficulties in drug discovery and development in neuropsychiatric disorders and the extent and perspectives of drug repurposing. PMID:27073698
Jubb, Adrian M; Koeppen, Hartmut; Reis-Filho, Jorge S
The rapid pace of drug discovery and drug development in oncology, immunology and ophthalmology brings new challenges; the efficient and effective development of new targeted drugs will require more detailed molecular classifications of histologically homogeneous diseases that show heterogeneous clinical outcomes. To this end, single companion diagnostics for specific drugs will be replaced by multiplex diagnostics for entire therapeutic areas, preserving tissue and enabling rapid molecular taxonomy. The field will move away from the development of new molecular entities as single agents, to which resistance is common. Instead, a detailed understanding of the pathological mechanisms of resistance, in patients and in preclinical models, will be key to the validation of scientifically rational and clinically effective drug combinations. To remain at the heart of disease diagnosis and appropriate management, pathologists must evolve into translational biologists and biomarker scientists. Herein, we provide examples of where this metamorphosis has already taken place, in lung cancer and melanoma, where the transformation has yet to begin, in the use of immunotherapies for ophthalmology and oncology, and where there is fertile soil for a revolution in treatment, in efforts to classify glioblastoma and personalize treatment. The challenges of disease heterogeneity, the regulatory environment and adequate tissue are ever present, but these too are being overcome in dedicated academic centres. In summary, the tools necessary to overcome the 'whens' and 'ifs' of the molecular revolution are in the hands of pathologists today; it is a matter of standardization, training and leadership to bring these into routine practice and translate science into patient benefit. This Annual Review Issue of the Journal of Pathology highlights the central role for pathology in modern drug discovery and development.
Often called chemical antibodies, aptamers are poised to take on the monoclonal antibodies in therapeutics, diagnostics, and drug development. Stability, low toxicity and immunogenicity, and, perhaps, a higher safety profile – not to mention low-cost advantages – are drawing the attention of big pharma and biotech. PMID:23372509
Locating development efforts within the context of globalism and global drug capitalism, this article examines the significant health and social impact both legal and illegal drugs have on international development efforts. The paper takes on an issue that is generally overlooked in the development debate and is not much addressed in the current international development standard, the Millennium Development Goals, and yet is one that places serious constraints on the ability of underdeveloped nations to achieve improvement. The relationship between psychotropic or "mind/mood altering" drugs and sustainable development is rooted in the contribution that the legal and illegal drug trade makes to a set of barriers to development, including: (1) interpersonal crime and community violence; (2) the corruption of public servants and the disintegration of social institutions; (3) the emergence of new or enhanced health problems; (4) the lowering of worker productivity; (5) the ensnarement of youth in drug distribution and away from productive education or employment; (6) the skewing of economies to drug production and money laundering. The paper emphasizes the need for new approaches for diminishing the burden placed by drugs on development.
The 2003 UK higher education White Paper suggested that the sector needed to re-examine the potential of the value added concept. This paper describes a possible methodology for developing a performance indicator based on the economic value added to graduates. The paper examines how an entry-quality-adjusted measure of a graduate's…
Sage, Daniel P.; Kulczar, Christopher; Roth, Wyatt; Liu, Wanqing; Knipp, Gregory T.
The development of new therapeutic agents for the mitigation of pediatric disorders is largely hindered by the inability for investigators to assess pediatric pharmacokinetics (PK) in healthy patients due to substantial safety concerns. Pediatric patients are a clinical moving target for drug delivery due to changes in absorption, distribution, metabolism and excretion (ADME) and the potential for PK related toxicological (T) events to occur throughout development. These changes in ADMET can have profound effects on drug delivery, and may lead to toxic or sub-therapeutic outcomes. Ethical, economical, logistical, and technical barriers have resulted in insufficient investigation of these changes by industrial, regulatory, and academic bodies, leading to the classification of pediatric patients as therapeutic orphans. In response to these concerns, regulatory agencies have incentivized investigation into these ontogenic changes and their effects on drug delivery in pediatric populations. The intent of this review is to briefly present a synopsis of the development changes that occur in pediatric patients, discuss the effects of these changes on ADME and drug delivery strategies, highlight the hurdles that are still being faced, and present some opportunities to overcome these challenges. PMID:25221567
The spread of multiresistant strains of Plasmodium falciparum in south-east Asia and South America and the appearance of chloroquine resistance in Africa indicates the urgent need for alternative drugs against these parasites. Mefloquine, a 4-quinoline methanol, is the only new drug that is currently at an advanced stage of development. Studies in animal models and in the clinic have shown that it is highly active as a blood schizontocide against strains that are resistant to many established antimalarials, e.g., chloroquine and pyrimethamine. It is not, however, effective as a causal prophylactic agent. Preclinical toxicological, teratological, and carcinogenicity studies do not indicate any major contraindications to its use. Intensive clinical studies have been carried out in Africa, North and South America, south-east Asia, and Europe. These studies have indicated that the compound is generally well tolerated, safe, and effective in the treatment of malaria, particularly infections with chloroquine-resistant parasites. In order to protect this new and promising drug against the development of resistance to it in endemic areas, it is important that its introduction should be accomplished in a rational and deliberate manner. Appropriate precautionary measures include the development of mefloquine combinations (a combination of mefloquine with pyrimethamine—sulfadoxine is presently under investigation), its use with primaquine as a gametocytocidal drug to prevent transmission, and its deployment primarily for treatment, being used for prophylaxis only in special risk groups. PMID:6407767
Croft, Simon L; Seifert, Karin; Yardley, Vanessa
Although three new drugs or drug formulations, liposomal amphotericin B (AmBisome), miltefosine and paromomycin should be available for the treatment of visceral leishmaniasis (VL) within the next year, they all suffer from limitations of either cost, specific toxicities or parenteral administration. As part of research to identify better treatments for VL and cutaneous leishmaniasis (CL), alternative and potentially cheaper formulations of amphotericin B, alklyphosphocholines other than miltefosine and improved formulations of paromomycin for CL have been identified. Other drugs or compounds that have demonstrated activity in experimental rodent models of infection include licochalcone derivatives, quinoline derivatives, bisphosphonates and a maesabalide; further chemistry based upon these leads is warranted. The process for discovery and development of new antileishmanials would also benefit from improved models, for example, transfected parasites, and non invasive methods of measuring parasite load in rodent models of infection.
Zhang, L; Wu, F; Lee, S C; Zhao, H; Zhang, L
Absorption of an orally administered drug with pH-dependent solubility may be altered when it is coadministered with a gastric acid-reducing agent (ARA). Assessing a drug's potential for pH-dependent drug-drug interactions (DDIs), considering study design elements for such DDI studies, and interpreting and communicating study results in the drug labeling to guide drug dosing are important for drug development. We collected pertinent information related to new molecular entities approved from January 2003 to May 2013 by the US Food and Drug Administration for which clinical DDI studies with ARAs were performed. On the basis of assessments of data on pH solubility and in vivo DDIs with ARAs, we proposed a conceptual framework for assessing the need for clinical pH-dependent DDI studies for weak base drugs (WBDs). Important study design considerations include selection of ARAs and timing of dosing of an ARA relative to the WBD in a DDI study. Labeling implications for drugs having DDIs with ARAs are also illustrated.
Ali, Imran; Lone, Mohammad Nadeem; Al-Othman, Zeid A; Al-Warthan, Abdulrahman; Sanagi, Mohd Marsin
Cancer has been cursed for human beings for long time. Millions people lost their lives due to cancer. Despite of the several anticancer drugs available, cancer cannot be cured; especially at the late stages without showing any side effect. Heterocyclic compounds exhibit exciting medicinal properties including anticancer. Some market selling heterocyclic anticancer drugs include 5-flourouracil, methortrexate, doxorubicin, daunorubicin, etc. Besides, some natural products such as vinblastine and vincristine are also used as anticancer drugs. Overall, heterocyclic moeities have always been core parts in the expansion of anticancer drugs. This article describes the importance of heterocyclic nuclei in the development of anticancer drugs. Besides, the attempts have been made to discuss both naturally occurring and synthetic heterocyclic compounds as anticancer agents. In addition, some market selling anticancer heterocyclic compounds have been described. Moreover, the efforts have been made to discuss the mechanisms of actions and recent advances in heterocyclic compounds as anticancer agents. The current challenges and future prospectives of heterocyclic compounds have also been discussed. Finally, the suggestions for syntheses of effective, selective, fast and human friendly anticancer agents are discussed into the different sections.
Ramaekers, J G
Medicinal drugs that cause drowsiness and inattentiveness may impair driving. The FDA recently emphasized that standardized procedures for measuring drug effects on driving are needed as part of drug registration. Here, I provide an overview of a standardized on-the-road driving test that offers maximal drug sensitivity and uses a real-life outcome measure of driver impairment that is strongly associated with crash risk.
Siddiqui, Ruqaiyyah; Aqeel, Yousuf; Khan, Naveed Ahmed
For the past several decades, there has been little improvement in the morbidity and mortality associated with Acanthamoeba keratitis and Acanthamoeba encephalitis, respectively. The discovery of a plethora of antiacanthamoebic compounds has not yielded effective marketed chemotherapeutics. The rate of development of novel antiacanthamoebic chemotherapies of translational value and the lack of interest of the pharmaceutical industry in developing such chemotherapies have been disappointing. On the other hand, the market for contact lenses/contact lens disinfectants is a multi-billion-dollar industry and has been successful and profitable. A better understanding of drugs, their targets, and mechanisms of action will facilitate the development of more-effective chemotherapies. Here, we review the progress toward phenotypic drug discovery, emphasizing the shortcomings of useable therapies.
Ali, Rehiana; Nicholas, Richard St John; Muraro, Paolo Antonio
Drug development for multiple sclerosis (MS), as with any other neurological disease, faces numerous challenges, with many drugs failing at various stages of development. The disease-modifying therapies (DMTs) first introduced for MS are only moderately effective, but given the lack of competition, they have been widely accepted in clinical practice. Although safety and efficacy continue to be the two main metrics by which drugs will be judged, the newer agents in the market also face challenges of a more comparative nature-are they more efficacious than the currently available drugs on the market? Are they safer or better tolerated? Do they offer any practical advantages over current treatments? Fingolimod represented a milestone following its approval as an oral drug for MS in 2010, offering patients a far more convenient administration route. However, association with cardiovascular complications has led to a more cautious approach in its initial prescribing, now requiring cardiac monitoring for the first 6 h as well as subsequent monitoring of blood pressure and for macular oedema. Natalizumab, amongst licensed drugs, represents the current benchmark for efficacy. The risk of progressive multifocal leukoencephalopathy during natalizumab treatment is now more quantifiable. Other monoclonal antibodies are in various phases of development. Marketing authorisation for alemtuzumab has been filed, and whilst trial data suggest that its efficacy outperforms both licensed drugs and others in development, there is a significant risk of secondary autoimmunity. Its once-yearly administration, however, seems particularly advantageous. Rituximab is unlikely to be developed further as its license will expire, but ocrelizumab, another monoclonal antibody directly targeting B cells, is currently in phase 2 development and looks promising. Daclizumab is also moderately efficacious but may struggle to establish itself given its monthly subcutaneous dosing. There are new oral
Azam, Amir; Peerzada, Mudasir N.; Ahmad, Kamal
Diarrhea is the manifestation of gastrointestinal infection and is one of the major causes of mortality and morbidity specifically among the children of less than 5 years age worldwide. Moreover, in recent years there has been a rise in the number of reports of intestinal infections continuously in the industrialized world. These are largely related to waterborne and food borne outbreaks. These occur by the pathogenesis of both prokaryotic and eukaryotic organisms like bacteria and parasites. The parasitic intestinal infection has remained mostly unexplored and under assessed in terms of therapeutic development. The lack of new drugs and the risk of resistance have led us to carry out this review on drug development for parasitic diarrheal diseases. The major focus has been depicted on commercially available drugs, currently synthesized active heterocyclic compounds and unique drug targets, that are vital for the existence and growth of the parasites and can be further exploited for the search of therapeutically active anti-parasitic agents. PMID:26617574
Loughran, Hilda; McCann, Mary Ellen
The EU Action Plan on Drugs (2005-2008) calls for member states of the European Union to provide information on five key epidemiological indicators. These are: general population surveys, prevalence and patterns of problem drug use, drug related infectious diseases, drug related deaths and mortality of drug users, and demand for drug treatment.…
... HUMAN SERVICES Food and Drug Administration Investigational New Drug Applications; Co-development of Investigational Drugs AGENCY: Food and Drug Administration, HHS. ACTION: Notice; establishment of docket; request for comments. SUMMARY: The Food and Drug Administration (FDA) is establishing a public docket...
Suay-García, B; Pérez-Gracia, M T
Gonorrhea is the second most frequently reported notifiable disease in the United States and is becoming increasingly common in Europe. The purpose of this review was to assess the current state of drug-resistant Neisseria gonorrhoeae in order to evaluate future prospects for its treatment. An exhaustive literature search was conducted to include the latest research regarding drug resistance and treatment guidelines for gonorrhea. Gonococci have acquired all known resistance mechanisms to all antimicrobials used for treatment. Currently, the European Union, the United States, and the United Kingdom have established surveillance programs to assess, on a yearly basis, the development of gonococcal resistance. Current treatment guidelines are being threatened by the increasing number of ceftriaxone-, cefixime-, and azithromycin-resistant N. gonorrhoeae strains being detected worldwide. This has led the scientific community to develop new treatment options with new molecules in order to persevere in the battle against this "superbug".
Trees have made an enormous phytochemical contribution in anticancer drugs' development more than any other life form. The contributions include alkaloids that are biosynthesized in various ways and yield. Lead alkaloids isolated from the trees are taxol and camptothecins that currently have annual sales in billion dollars. Other important alkaloids isolated from these life forms include rohitukine, harringtonine, acronycine, thalicarpine, usambarensine, ellipticine, and matrines. Studies on their mechanism of action and target on the DNA and protein of cancerous cells aided the development of potent hemisynthesized congeners. The molecules and their congeners passed/are passing a long period of historical development before approved as antineoplastic drugs for cancer chemotherapy. Some of them did not find the application as anticancer drugs due to ineffectiveness in clinical trials; others are generating research interest in the antineoplastic activity at the present and have reached clinical trial stages. Potentials in antineoplastic molecules from trees are high and are hoped to be commensurate with cancer types afflicting human society in the future. PMID:28082790
Mould, Diane R; Meibohm, Bernd
Monoclonal antibodies (MAbs) have become a substantial part of many pharmaceutical company portfolios. However, the development process of MAbs for clinical use is quite different than for small-molecule drugs. MAb development programs require careful interdisciplinary evaluations to ensure the pharmacology of both the MAb and the target antigen are well-understood. Selection of appropriate preclinical species must be carefully considered and the potential development of anti-drug antibodies (ADA) during these early studies can limit the value and complicate the performance and possible duration of preclinical studies. In human studies, many of the typical pharmacology studies such as renal or hepatic impairment evaluations may not be needed but the pharmacokinetics and pharmacodynamics of these agents is complex, often necessitating more comprehensive evaluation of clinical data and more complex bioanalytical assays than might be used for small molecules. This paper outlines concerns and strategies for development of MAbs from the early in vitro assessments needed through preclinical and clinical development. This review focuses on how to develop, submit, and comply with regulatory requirements for MAb therapeutics.
potential drug target enzymes. The yeast expression system should allow rapid screening of new drugs , greatly increasing the rate at which new...medication yet the world faces a crisis--drug resistance is emerging and spreading faster than drugs are being developed and the flow in the pipeline of new ... drugs has all but stopped. This represents a particular threat to the U.S. Military. A new strategy for drug development is urgently needed. Current
Biologically active peptides aree typified by their unbiquity of distribution, their high receptor affinity and an almost infinite diversity of structure. For these reasons, considerable effort is now being expended to elucidate the possible role of peptides in brain function. This effort has been stimulated by the discovery of a number of new endogenous peptides, such as the enkephalins, endorphins, vasoactive intestinal peptide and neurotensin. At present, there is no clearly defined role for these peptides, although they may form an important basis for the chemical coding of various brain functions, including pain, mood and memory. At present, the potential for drug development of peptide agonists remains in fairly circumscribed areas such as analgesia, pituitary hormone control, and gastrointestinal motor and secretory control. Peptide antagonists may provide a vast field for future development, although only one area, that of antifertility drugs based on LHRH antagonists, shows any promise of immediate success. Industrial research approaches to new peptide agonists and antagonists mainly rely at present on rational drug design through structural analogies. Other fruitful approaches to be considered are the screening of natural microbial and plant products and the possible application of genetic engineering techniques.
Armstrong, Andrew J; George, Daniel J
In 2007, drug development in castration-resistant metastatic prostate cancer (CRPC) remains challenging, due to the number of potentially viable molecular targets and clinical trials available, the lack of established surrogates for overall survival, and competing causes of mortality. This review will highlight the highest impact phase II and phase III trials of novel agents in the current CRPC landscape, and focus on both molecular targets and clinical trial designs that are more likely to demonstrate clinical benefit. The need for tissue correlative studies for target evaluation and drug mechanism is stressed to continue to advance the field and to define biomarkers that may identify patient populations that may derive a greater benefit from these molecular agents.
Technology has caught up with retinal diseases of neovasculature. Work with anti-cancer, anti-angiogenic agents has fueled the way for ocular therapeutics. The market size for age-related macular degeneration and diabetic retinopathy is huge. Fifteen million people in the United States alone have age-related macular degeneration with 2 million new cases each year (1). About 20.8 million people in the United States have diabetes. Of those, 14.6 million are diagnosed and 6.2 million are undiagnosed (2). Of patients who have had type 1 diabetics for more than 20 years, 50% will have proliferative diabetic retinopathy (3). Between 60% and 80% of type 2 diabetics will manifest retinopathy after 15 years, and 20% will progress to proliferative retinopathy after 25 years of duration (4). Big pharma and biotech were complacent in developing drugs capable of having effect on ocular neovascular diseases even though technologies were available, at least on the research level, long before there was serious activity to bring such technologies to the clinic. Finally, over the last three years, triple digit million dollar business development deals have been consummated, mostly for VEGF-A targeted modalities. Such biodollar partnerships were the eye openers which have now led to a concerted action to develop ocular drugs to combat ocular neovascularization. Anti-VEGF-A technologies do not constitute the whole story. Agents with broader activity, activity that occurs later down the angiogenic pathway and those drugs which are capable to synergize with anti-VEGF-A technologies will dominate the next wave in ocular diseases of neovascularization and will lead the next round of significant business development deals.
Wise, Roy A; Koob, George F
What is the defining property of addiction? We dust off a several-decades-long debate about the relative importance of two forms of reinforcement—positive reinforcement, subjectively linked to drug-induced euphoria, and negative reinforcement, subjectively linked to the alleviation of pain—both of which figure importantly in addiction theory; each of these forms has dominated addiction theory in its time. We agree that addiction begins with the formation of habits through positive reinforcement and that drug-opposite physiological responses often establish the conditions for negative reinforcement to come into play at a time when tolerance, in the form of increasing reward thresholds, appears to develop into positive reinforcement. Wise’s work has tended to focus on positive-reinforcement mechanisms that are important for establishing drug-seeking habits and reinstating them quickly after periods of abstinence, whereas Koob’s work has tended to focus on the negative-reinforcement mechanisms that become most obvious in the late stages of sustained addiction. While we tend to agree with each other about the early and late stages of addiction, we hold different views as to (i) the point between early and late at which the diagnosis of ‘addiction’ should be invoked, (ii) the relative importance of positive and negative reinforcement leading up to this transition, and (iii) the degree to which the specifics of negative reinforcement can be generalized across the range of addictive agents.
Readhead, Ben; Dudley, Joel
Significance A majority of therapeutic interventions occur late in the pathological process, when treatment outcome can be less predictable and effective, highlighting the need for new precise and preventive therapeutic development strategies that consider genomic and environmental context. Translational bioinformatics is well positioned to contribute to the many challenges inherent in bridging this gap between our current reactive methods of healthcare delivery and the intent of precision medicine, particularly in the areas of drug development, which forms the focus of this review. Recent Advances A variety of powerful informatics methods for organizing and leveraging the vast wealth of available molecular measurements available for a broad range of disease contexts have recently emerged. These include methods for data driven disease classification, drug repositioning, identification of disease biomarkers, and the creation of disease network models, each with significant impacts on drug development approaches. Critical Issues An important bottleneck in the application of bioinformatics methods in translational research is the lack of investigators who are versed in both biomedical domains and informatics. Efforts to nurture both sets of competencies within individuals and to increase interfield visibility will help to accelerate the adoption and increased application of bioinformatics in translational research. Future Directions It is possible to construct predictive, multiscale network models of disease by integrating genotype, gene expression, clinical traits, and other multiscale measures using causal network inference methods. This can enable the identification of the “key drivers” of pathology, which may represent novel therapeutic targets or biomarker candidates that play a more direct role in the etiology of disease. PMID:24527359
Ignatiev, Sviatoslav; Leonchuk, Mikhail; Orlov, Yury; Pankratov, Dmitry; Suvorov, Gennady; Zabudko, Alexey
Available in abstract form only. Full text of publication follows: Main problems on development of pilot molten lead-bismuth target circuit of 1 MW proton beam power (TC-1) as an important part of target-blanket accelerator driven system (ADS) for nuclear waste incineration are analyzed. (authors)
The Northern Ireland Guardian Ad Litem Agency was established consequent upon the implementation of The Children (NI) Order 1995. The role of the guardian has developed and become embedded in a changing socio-legal context. This paper will review the key influences that have impacted on predominant social work thinking. Anticipated legislative…
Berk, Camryn; Sabbagh, Marwan
To date, symptomatic medications prevail as the mainstay of treatment options for Alzheimer's disease (AD). There have been tremendous investments made to increase the numbers of drugs approved and the targets engaged, in an effort to alter the disease course or pathophysiology of AD. Unfortunately, almost all studies have not met expectations and no new drug (beyond medical foods) has been approved for the treatment of AD in the last decade. This review is a comparison of novel AD therapies in the late phases of clinical testing with recent high-profile clinical failures and agents in development with relatively unexplored mechanisms of action, with a focus on their potential as therapeutic agents and their proposed advantages over the treatments currently in use. PMID:23943247
Hagman, Brett T; Kuerbis, Alexis N; Morgenstern, Jon; Bux, Donald A; Parsons, Jeffrey T; Heidinger, Bram E
The Short Inventory of Problems-Alcohol and Drugs (SIP-AD) is a 15-item measure that assesses concurrently negative consequences associated with alcohol and illicit drug use. Current psychometric evaluation has been limited to classical test theory (CTT) statistics, and it has not been validated among non-treatment seeking men-who-have-sex-with-men (MSM). Methods from Item Response Theory (IRT) can improve upon CTT by providing an in-depth analysis of how each item performs across the underlying latent trait that it is purported to measure. The present study examined the psychometric properties of the SIP-AD using methods from both IRT and CTT among a non-treatment seeking MSM sample (N=469). Participants were recruited from the New York City area and were asked to participate in a series of studies examining club drug use. Results indicated that five items on the SIP-AD demonstrated poor item misfit or significant differential item functioning (DIF) across race/ethnicity and HIV status. These five items were dropped and two-parameter IRT analyses were conducted on the remaining 10 items, which indicated a restricted range of item location parameters (-.15 to -.99) plotted at the lower end of the latent negative consequences severity continuum, and reasonably high discrimination parameters (1.30 to 2.22). Additional CTT statistics were compared between the original 15-item SIP-AD and the refined 10-item SIP-AD and suggest that the differences were negligible with the refined 10-item SIP-AD indicating a high degree of reliability and validity. Findings suggest the SIP-AD can be shortened to 10 items and appears to be a non-biased reliable and valid measure among non-treatment seeking MSM.
Hagman, Brett T.; Kuerbis, Alexis N.; Morgenstern, Jon; Bux, Donald A.; Parsons, Jeffrey T.; Heidinger, Bram E.
The Short Inventory of Problems-Alcohol and Drugs (SIP-AD) is a 15-item measure that assesses concurrently negative consequences associated with alcohol and illicit drug use. Current psychometric evaluation has been limited to classical test theory (CTT) statistics, and it has not been validated among non-treatment seeking men-who-have-sex-with-men (MSM). Methods from Item Response Theory (IRT) can improve upon CTT by providing an in-depth analysis of how each item performs across the underlying latent trait that it is purported to measure. The present study examined the psychometric properties of the SIP-AD using methods from both IRT and CTT among a non-treatment seeking MSM sample (N = 469). Participants were recruited from the New York City area and were asked to participate in a series of studies examining club drug use. Results indicated that five items on the SIP-AD demonstrated poor item misfit or significant differential item functioning (DIF) across race/ethnicity and HIV status. These five items were dropped and two-parameter IRT analyses were conducted on the remaining 10 items, which indicated a restricted range of item location parameters (−.15 to −.99) plotted at the lower end of the latent negative consequences severity continuum, and reasonably high discrimination parameters (1.30 to 2.22). Additional CTT statistics were compared between the original 15-item SIP-AD and the refined 10-item SIP-AD and suggest that the differences were negligible with the refined 10-item SIP-AD indicating a high degree of reliability and validity. Findings suggest the SIP-AD can be shortened to 10 items and appears to be a non-biased reliable and valid measure among non-treatment seeking MSM. PMID:19564078
Bhargava, Prachi; Singh, Rajni
Leishmaniasis ranks the third in disease burden in disability-adjusted life years caused by neglected tropical diseases and is the second cause of parasite-related deaths after malaria; but for a variety of reasons, it is not receiving the attention that would be justified seeing its importance. Leishmaniasis is a diverse group of clinical syndromes caused by protozoan parasites of the genus Leishmania. It is estimated that 350 million people are at risk in 88 countries, with a global incidence of 1–1.5 million cases of cutaneous and 500,000 cases of visceral leishmaniasis. Improvements in diagnostic methods for early case detection and latest combitorial chemotherapeutic methods have given a new hope for combating this deadly disease. The cell biology of Leishmania and mammalian cells differs considerably and this distinctness extends to the biochemical level. This provides the promise that many of the parasite's proteins should be sufficiently different from hosts and can be successfully exploited as drug targets. This paper gives a brief overview of recent developments in the diagnosis and approaches in antileishmanial drug discovery and development. PMID:23118748
Sun, Wei; Tanaka, Takeshi Q.; Magle, Crystal T.; Huang, Wenwei; Southall, Noel; Huang, Ruili; Dehdashti, Seameen J.; McKew, John C.; Williamson, Kim C.; Zheng, Wei
Control of parasite transmission is critical for the eradication of malaria. However, most antimalarial drugs are not active against P. falciparum gametocytes, responsible for the spread of malaria. Consequently, patients can remain infectious for weeks after the clearance of asexual parasites and clinical symptoms. Here we report the identification of 27 potent gametocytocidal compounds (IC50 < 1 μM) from screening 5,215 known drugs and compounds. All these compounds were active against three strains of gametocytes with different drug sensitivities and geographical origins, 3D7, HB3 and Dd2. Cheminformatic analysis revealed chemical signatures for P. falciparum sexual and asexual stages indicative of druggability and suggesting potential targets. Torin 2, a top lead compound (IC50 = 8 nM against gametocytes in vitro), completely blocked oocyst formation in a mouse model of transmission. These results provide critical new leads and potential targets to expand the repertoire of malaria transmission-blocking reagents.
Huang, Xiaodong; Dixit, Vishva M
Dynamic modulation of protein levels is tightly controlled in response to physiological cues. In mammalian cells, much of the protein degradation is carried out by the ubiquitin-proteasome system (UPS). Similar to kinases, components of the ubiquitin system are often dysregulated, leading to a variety of diseases, including cancer and neurodegeneration, making them attractive drug targets. However, so far there are only a handful of drugs targeting the ubiquitin system that have been approved by the FDA. Here, we review possible therapeutic intervention nodes in the ubiquitin system, analyze the challenges, and highlight the most promising strategies to target the UPS. PMID:27002218
Wang, Nuozhou; Bartlow, Patrick; Ouyang, Qin; Xie, Xiang-Qun
Multiple myeloma (MM) is the second most common hematological malignancy and is characterized by the aberrant proliferation of terminally differentiated plasma B cells with impairment in apoptosis capacity. Particularly, osteolytic bone diseases and renal failure resulting from hyperparaproteinemia and hypercalcemia have been the major serious sequelae that are inextricably linked with MM tumor progression. Despite the introduction of new treatment regimens, problematic neuropathy, thrombocytopenia, drug resistance and high MM relapse rates continue to plague the current therapies. New chemical agents are in development on the basis of understanding several signaling pathways and molecular mechanisms like tumor necrosis factor-α, proteasome, PI3K and MARKs. This review focuses on the most recent patents and clinical trials in the development of new medicine for the treatment of multiple myeloma. Furthermore, the important signaling pathways involved in the proliferation, survival and apoptosis of myeloma cells will be discussed. PMID:24998287
Hoffman, Freddie Ann
Botanicals are ingredients that can be marketed as foods, drugs, cosmetics, and medical devices in the United States. When a botanical is intended to diagnose, treat, prevent, mitigate, or cure a disease, it is considered to be a "drug". This article reviews the US regulatory requirements for botanicals as "new" drugs. An overview of the regulatory principles used to determine product category and the basic elements of an Investigational New Drug application and New Drug Application with the US Food and Drug Administration are presented. This article is part of a Special Issue entitled "Botanicals for Epilepsy".
Issa, Naiem T; Wathieu, Henri; Ojo, Abiola; Byers, Stephen W; Dakshanamurthy, Sivanesan
Increased R & D spending and high failure rates exist in drug development, due in part to inadequate prediction of drug metabolism and its consequences in the human body. Hence, there is a need for computational methods to supplement and complement current biological assessment strategies. In this review, we provide an overview of drug metabolism in pharmacology, and discuss the current in vitro and in vivo strategies for assessing drug metabolism in preclinical drug development. We highlight computational tools available to the scientific community for the in silico prediction of drug metabolism, and examine how these tools have been implemented to produce drug-target signatures relevant to metabolic routes. Computational workflows that assess drug metabolism and its toxicological and pharmacokinetic effects, such as by applying the adverse outcome pathway framework for risk assessment, may improve the efficiency and speed of preclinical drug development.
Singh, Sukhdev; Sharma, Bhupender; Kanwar, Shamsher S.; Kumar, Ashok
Cancer is a serious concern at present. A large number of patients die each year due to cancer illnesses in spite of several interventions available. Development of an effective and side effects lacking anticancer therapy is the trending research direction in healthcare pharmacy. Chemical entities present in plants proved to be very potential in this regard. Bioactive phytochemicals are preferential as they pretend differentially on cancer cells only, without altering normal cells. Carcinogenesis is a complex process and includes multiple signaling events. Phytochemicals are pleiotropic in their function and target these events in multiple manners; hence they are most suitable candidate for anticancer drug development. Efforts are in progress to develop lead candidates from phytochemicals those can block or retard the growth of cancer without any side effect. Several phytochemicals manifest anticancer function in vitro and in vivo. This article deals with these lead phytomolecules with their action mechanisms on nuclear and cellular factors involved in carcinogenesis. Additionally, druggability parameters and clinical development of anticancer phytomolecules have also been discussed. PMID:27877185
Singh, Sukhdev; Sharma, Bhupender; Kanwar, Shamsher S; Kumar, Ashok
Cancer is a serious concern at present. A large number of patients die each year due to cancer illnesses in spite of several interventions available. Development of an effective and side effects lacking anticancer therapy is the trending research direction in healthcare pharmacy. Chemical entities present in plants proved to be very potential in this regard. Bioactive phytochemicals are preferential as they pretend differentially on cancer cells only, without altering normal cells. Carcinogenesis is a complex process and includes multiple signaling events. Phytochemicals are pleiotropic in their function and target these events in multiple manners; hence they are most suitable candidate for anticancer drug development. Efforts are in progress to develop lead candidates from phytochemicals those can block or retard the growth of cancer without any side effect. Several phytochemicals manifest anticancer function in vitro and in vivo. This article deals with these lead phytomolecules with their action mechanisms on nuclear and cellular factors involved in carcinogenesis. Additionally, druggability parameters and clinical development of anticancer phytomolecules have also been discussed.
Tan, Christine L.; Hassali, Mohamed A.; Saleem, Fahad; Shafie, Asrul A.; Aljadhey, Hisham; Gan, Vincent B.
Objective: (i) To develop the Pharmacy Value-Added Services Questionnaire (PVASQ) using emerging themes generated from interviews. (ii) To establish reliability and validity of questionnaire instrument. Methods: Using an extended Theory of Planned Behavior as the theoretical model, face-to-face interviews generated salient beliefs of pharmacy value-added services. The PVASQ was constructed initially in English incorporating important themes and later translated into the Malay language with forward and backward translation. Intention (INT) to adopt pharmacy value-added services is predicted by attitudes (ATT), subjective norms (SN), perceived behavioral control (PBC), knowledge and expectations. Using a 7-point Likert-type scale and a dichotomous scale, test-retest reliability (N=25) was assessed by administrating the questionnaire instrument twice at an interval of one week apart. Internal consistency was measured by Cronbach’s alpha and construct validity between two administrations was assessed using the kappa statistic and the intraclass correlation coefficient (ICC). Confirmatory Factor Analysis, CFA (N=410) was conducted to assess construct validity of the PVASQ. Results: The kappa coefficients indicate a moderate to almost perfect strength of agreement between test and retest. The ICC for all scales tested for intra-rater (test-retest) reliability was good. The overall Cronbach’ s alpha (N=25) is 0.912 and 0.908 for the two time points. The result of CFA (N=410) showed most items loaded strongly and correctly into corresponding factors. Only one item was eliminated. Conclusions: This study is the first to develop and establish the reliability and validity of the Pharmacy Value-Added Services Questionnaire instrument using the Theory of Planned Behavior as the theoretical model. The translated Malay language version of PVASQ is reliable and valid to predict Malaysian patients’ intention to adopt pharmacy value-added services to collect partial medicine
Miller, M R; Megson, I L
During the 1980s, the free radical, nitric oxide (NO), was discovered to be a crucial signalling molecule, with wide-ranging functions in the cardiovascular, nervous and immune systems. Aside from providing a credible explanation for the actions of organic nitrates and sodium nitroprusside that have long been used in the treatment of angina and hypertensive crises respectively, the discovery generated great hopes for new NO-based treatments for a wide variety of ailments. Decades later, however, we are still awaiting novel licensed agents in this arena, despite an enormous research effort to this end. This review explores some of the most promising recent advances in NO donor drug development and addresses the challenges associated with NO as a therapeutic agent. PMID:17401442
Nowacek, Ari; Kosloski, Lisa M; Gendelman, Howard E
Degenerative and inflammatory diseases of the CNS include, but are not limited to, Alzheimer’s and Parkinson’s disease, amyotrophic lateral sclerosis, stroke, multiple sclerosis and HIV-1-associated neurocognitive disorders. These are common, debilitating and, unfortunately, hold few therapeutic options. In recent years, the application of nanotechnologies as commonly used or developing medicines has served to improve pharmacokinetics and drug delivery specifically to CNS-diseased areas. In addition, nanomedical advances are leading to therapies that target CNS pathobiology and as such, can interrupt disordered protein aggregation, deliver functional neuroprotective proteins and alter the oxidant state of affected neural tissues. This article focuses on the pathobiology of common neurodegenerative disorders with a view towards how nanomedicine may be used to improve the clinical course of neurodegenerative disorders. PMID:19572820
Barnes, Peter J
Chronic obstructive pulmonary disease (COPD) is an increasing global health problem and cause of death. COPD is a chronic inflammatory disease predominantly affecting small airways and lung parenchyma that leads to progressive airway obstruction. However, current therapies fail to prevent either disease progression or mortality. The mainstay of current drug therapy is long-acting bronchodilators. Several once daily inhaled β(2)-agonists and muscarinic antagonists (and combinations) are now in development. No treatments effectively suppress chronic inflammation in COPD lungs. With better understanding of the inflammatory and destructive process in the pathophysiology of COPD, several new therapeutic targets have been identified. Several mediator antagonists or inhibitors tested in COPD have so far been disappointing, but CXCR2 antagonists that block pulmonary neutrophil and monocyte recruitment are more promising. Broad spectrum anti-inflammatory drugs may be more effective, and include inhibitors of the proinflammatory enzymes phosphodiesterase-4, p38 mitogen-activated protein kinase, Janus kinases, NF-κB kinase and PI3 kinase-γ and -δ, but side effects after oral administration are a major limitation so that in future inhaled delivery may be necessary. A new promising approach is reversal of corticosteroid resistance through increasing histone deacetylase-2 (HDAC2) activity. This might be achieved by existing treatments such as theophylline, nortriptyline and macrolides, or more selectively by PI3 kinase-δ inhibitors. Thus although there have been major advances in the development of long-acting bronchodilators for COPD, it has proved difficult to find anti-inflammatory treatments that are safe and effective.
Fernandez, R.; Abderrahim, H. Aït; Baeten, P.; de Bruyn, D.; Maes, D.; Mazouzi, A. Al; Ariën, B.; Malambu, E.; Schuurmans, P.; Schyns, M.; Sobolev, V.; van den Eynde, G.; Vandeplassche, D.
The coupling between an accelerator, a spallation target and a subcritical core has been studied for the first time at SCK•CEN in collaboration with Ion Beam Applications (IBA, Louvain-la-Neuve) in the frame of the ADONIS project (1995-1997). ADONIS was a small irradiation facility, based on the ADS concept, having a dedicated objective to produce radioisotopes for medical purposes and more particularly 99Mo as a fission product from highly enriched 235U (HEU) fissile targets. The ad-hoc scientific advisory committee recommended extending the purpose of the ADONIS machine to become a Material Testing Reactor (MTR) for material and fuel research, to study the feasibility of transmutation of the minor actinides and to demonstrate at a reasonable power scale the principle of the ADS. The project, since 1998 named MYRRHA, has then evolved to a larger installation. MYRRHA is now conceived as a flexible irradiation facility, able to work as an Accelerator Driven (subcritical mode) and in critical mode. In this way, MYRRHA will allow fuel developments for innovative reactor systems, material developments for GEN IV systems, material developments for fusion reactors, radioisotope production for medical and industrial applications and industrial applications, such as Si-doping. MYRRHA will also demonstrate the ADS full concept by coupling the three components (accelerator, spallation target and subcritical reactor) at reasonable power level to allow operation feedback, scalable to an industrial demonstrator and allow the study of efficient transmutation of high-level nuclear waste. Since MYRRHA is based on the heavy liquid metal technology, the eutectic lead-bismuth, it will be able to significantly contribute to the development of Lead Fast Reactor Technology. Since MYRRHA will also be operated in critical mode, MYRRHA can even better play the role of European Technology Pilot Plant in the roadmap for LFR.
Mirsadeghi, Somayeh; Larijani, Bagher
Personalized medicine aims is to supply the proper drug to the proper patient within the right dose. Pharmacogenomics (PGx) is to recognize genetic variants that may influence drug efficacy and toxicity. All things considered, the fields cover a wide area, including basic drug discovery researches, the genetic origin of pharmacokinetics and pharmacodynamics, novel drug improvement, patient genetic assessment and clinical patient administration. At last, the objective of Pharmacogenomics is to anticipate a patient's genetic response to a particular drug as a way of presenting the best possible medical treatment. By predicting the drug response of an individual, it will be possible to increase the success of therapies and decrease the incidence of adverse side effect.
Tobler, Amy L; Komro, Kelli A; Dabroski, Alexis; Aveyard, Paul; Markham, Wolfgang A
We examined whether schools achieving better than expected educational outcomes for their students influence the risk of drug use and delinquency among urban, racial/ethnic minority youth. Adolescents (n = 2,621), who were primarily African American and Hispanic and enrolled in Chicago public schools (n = 61), completed surveys in 6th (aged 12) and 8th (aged 14) grades. Value-added education was derived from standardized residuals of regression equations predicting school-level academic achievement and attendance from students' sociodemographic profiles and defined as having higher academic achievement and attendance than that expected given the sociodemographic profile of the schools' student composition. Multilevel logistic regression estimated the effects of value-added education on students' drug use and delinquency. After considering initial risk behavior, value-added education was associated with lower incidence of alcohol, cigarette and marijuana use; stealing; and participating in a group-against-group fight. Significant beneficial effects of value-added education remained for cigarette and marijuana use, stealing and participating in a group-against-group fight after adjustment for individual- and school-level covariates. Alcohol use (past month and heavy episodic) showed marginally significant trends in the hypothesized direction after these adjustments. Inner-city schools may break the links between social disadvantage, drug use and delinquency. Identifying the processes related to value-added education in order to improve school environments is warranted given the high costs associated with individual-level interventions.
Wu, Wan-Ying; Hou, Jin-Jun; Long, Hua-Li; Yang, Wen-Zhi; Liang, Jian; Guo, De-An
Over the past 30 years, China has significantly improved the drug development environment by establishing a series of policies for the regulation of new drug approval. The regulatory system for new drug evaluation and registration in China was gradually developed in accordance with international standards. The approval and registration of TCM in China became as strict as those of chemical drugs and biological products. In this review, TCM-based new drug discovery and development are introduced according to the TCM classification of nine categories.
Safren, Steven A.; O'Cleirigh, Conall M.; Bullis, Jacqueline R.; Otto, Michael W.; Stein, Michael D.; Pollack, Mark H.
Objective: Depression and substance use, the most common comorbidities with HIV, are both associated with poor treatment adherence. Injection drug users comprise a substantial portion of individuals with HIV in the United States and globally. The present study tested cognitive behavioral therapy for adherence and depression (CBT-AD) in patients…
Collier, Thomas Lee; Waterhouse, Rikki N; Kassiou, Michael
Sigma receptors have been implicated in a myriad of cellular functions, biological processes and diseases. While the precise biological functions of sigma receptors have not been elucidated, recent work has shed some light on to these enigmatic systems. Sigma receptors have recently been a target of drug development related to psychiatric and neurological disorders. Sigma ligands have also been shown to modulate endothelial cell proliferation and can control angiogenesis which makes them a promising target for oncology applications. Other areas currently being investigated include treatment of gastrointestinal, cardiovascular, endocrine and immune system disorders. Of interest is that the human sigma-1 receptor gene contains a steroid binding component, and several gonadal steroids, including progesterone, testosterone and dehydroepiandrosterone (DHEA), interact with sigma-1 receptors. Of the steroids examined thus far, progesterone binds with the highest affinity to human sigma-1 receptors, with a reported affinity (Ki) as high as 30 nM while the other steroids exhibit lower affinity. For this and other reasons, sigma-1 receptors have been proposed as a link between the central nervous system and the endocrine and reproductive systems. Taken together, the above information highlights an important yet largely unexplored but promising area of research to examine the biological function and therapeutic potential of sigma receptors. This review provides an overview of the current knowledge of these sites with a focus on specific areas where in vivo sigma receptor imaging is currently being investigated.
Wada, Fumito; Harada-Shiba, Mariko
Abnormal elevation of low-density lipoprotein (LDL) and triglyceride-rich lipoproteins in plasma as well as dysfunction of anti-atherogenic high-density lipoprotein (HDL) have both been recognized as essential components of the pathogenesis of atherosclerosis and are classified as dyslipidemia. This review describes the arc of development of antisense oligonucleotides for the treatment of dyslipidemia. Chemically-armed antisense candidates can act on various kinds of transcripts, including mRNA and miRNA, via several different endogenous antisense mechanisms, and have exhibited potent systemic anti-dyslipidemic effects. Here, we present specific cutting-edge technologies have recently been brought into antisense strategies, and describe how they have improved the potency of antisense drugs in regard to pharmacokinetics and pharmacodynamics. In addition, we discuss perspectives for the use of armed antisense oligonucleotides as new clinical options for dyslipidemia, in the light of outcomes of recent clinical trials and safety concerns indicated by several clinical and preclinical studies. PMID:27466159
Dykens, James A; Will, Yvonne
Mitochondrial dysfunction is increasingly implicated in the etiology of drug-induced toxicities. Members of diverse drug classes undermine mitochondrial function, and among the most potent are drugs that have been withdrawn from the market, or have received Black Box warnings from the FDA. To avoid mitochondrial liabilities, routine screens need to be positioned within the drug-development process. Assays for mitochondrial function, cell models that better report mitochondrial impairment, and new animal models that more faithfully reflect clinical manifestations of mitochondrial dysfunction are discussed in the context of how such data can reduce late stage attrition of drug candidates and can yield safer drugs in the future.
AD_________________ Award Number: W81XWH-12-1-0207 TITLE: Developing Xenopus Laevis as a Model to...COVERED 30 September 2012 – 31 March 2014 4. TITLE AND SUBTITLE Developing Xenopus Laevis as a Model to Screen Drugs for Fragile X 5a. CONTRACT...that Xenopus is a valuable system in which to model Fragile X Syndrome. 15. SUBJECT TERMS Fragile X Syndrome, Fragile X Mental Retardation Protein
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. Some of the data we gathered in order to evaluate the indigenous claims are also discussed, focusing on the transcription factor NF-kappaB as a molecular target. This led to the identification of sesquiterpene lactones such as parthenolide as potent and relatively specific inhibitors of this transcription factor.
Li, Chun; Wallace, Sidney
Targeted drug delivery aims to increase the therapeutic index by making more drug molecules available at the diseased sites while reducing systemic drug exposure. In this update, we provide an overview of polymer-drug conjugates that have advanced into the clinical trials. These systems use synthetic water-soluble polymers as the drug carriers. The preclinical pharmacology and recent data in clinical trials with poly(L-glutamic acid)-paclitaxel (PG-TXL) are discussed first. This is followed by a summary of conjugates of a variety of polymeric conjugates with chemotherapeutic agents. Results from early clinical trials of these polymer-drug conjugates have demonstrated several advantages over the corresponding parent drugs, including fewer side effects, enhanced therapeutic efficacy, ease of drug administration, and improved patient compliance. Collectively, these data warrant further clinical development of polymer-drug conjugates as a new class of anticancer agents. PMID:18374448
... COMMISSION ADS Media Group, Inc., American Enterprise Development Corp., and Arcland Energy Corp.; Order of... lack of current and accurate information concerning the securities of ADS Media Group, Inc. because it... securities of American Enterprise Development Corp. because it has not filed any periodic reports since...
Stenvang, Jan; Kümler, Iben; Nygård, Sune Boris; Smith, David Hersi; Nielsen, Dorte; Brünner, Nils; Moreira, José M. A.
Cancer is a leading cause of mortality worldwide and matters are only set to worsen as its incidence continues to rise. Traditional approaches to combat cancer include improved prevention, early diagnosis, optimized surgery, development of novel drugs, and honing regimens of existing anti-cancer drugs. Although discovery and development of novel and effective anti-cancer drugs is a major research area, it is well known that oncology drug development is a lengthy process, extremely costly and with high attrition rates. Furthermore, those drugs that do make it through the drug development mill are often quite expensive, laden with severe side-effects and unfortunately, to date, have only demonstrated minimal increases in overall survival. Therefore, a strong interest has emerged to identify approved non-cancer drugs that possess anti-cancer activity, thus shortcutting the development process. This research strategy is commonly known as drug repurposing or drug repositioning and provides a faster path to the clinics. We have developed and implemented a modification of the standard drug repurposing strategy that we review here; rather than investigating target-promiscuous non-cancer drugs for possible anti-cancer activity, we focus on the discovery of novel cancer indications for already approved chemotherapeutic anti-cancer drugs. Clinical implementation of this strategy is normally commenced at clinical phase II trials and includes pre-treated patients. As the response rates to any non-standard chemotherapeutic drug will be relatively low in such a patient cohort it is a pre-requisite that such testing is based on predictive biomarkers. This review describes our strategy of biomarker-guided repurposing of chemotherapeutic drugs for cancer therapy, taking the repurposing of topoisomerase I (Top1) inhibitors and Top1 as a potential predictive biomarker as case in point. PMID:24400218
Agafonov, Roman V.; Wilson, Christopher; Kern, Dorothee
Sophisticated protein kinase networks, empowering complexity in higher organisms, are also drivers of devastating diseases such as cancer. Accordingly, these enzymes have become major drug targets of the twenty-first century. However, the holy grail of designing specific kinase inhibitors aimed at specific cancers has not been found. Can new approaches in cancer drug design help win the battle with this multi-faced and quickly evolving enemy? In this perspective we discuss new strategies and ideas that were born out of a recent breakthrough in understanding the molecular basis underlying the clinical success of the cancer drug Gleevec. An “old” method, stopped-flow kinetics, combined with old enzymes, the ancestors dating back up to about billion years, provides an unexpected outlook for future intelligent design of drugs. PMID:26052517
Lodén, Henrik; Shariatgorji, Mohammadreza; Nilsson, Anna; Andrén, Per E
A vital process in drug discovery and development is to assess the absorption, distribution, metabolism, excretion and toxicology of potentially therapeutic compounds in the body. The potential utility of MS imaging has been demonstrated in many studies focusing on molecules including peptides, proteins and lipids. However, MS imaging also permits the direct analysis of drugs and drug metabolites in tissue samples without requiring the use of target-specific labels or reagents. Here, a brief technical description of the technique is presented along with examples of its usefulness at different stages of the drug discovery and development process including absorption, distribution, metabolism, excretion and toxicology, and blood-brain barrier drug penetration investigations.
Park, Kevin . E-mail: firstname.lastname@example.org; Williams, Dominic P.; Naisbitt, Dean J.; Kitteringham, Neil R.; Pirmohamed, Munir
Adverse drug reactions (ADRs) are a significant human health problem. Any organ system can be affected, including the liver, skin and kidney. Drug-induced liver injury is the most frequent reason for the withdrawal of an approved drug from the market, and it also accounts for up to 50% of cases of acute liver failure. The clinical picture is often diverse, even for the same drug. Mild, asymptomatic effects occur at a relatively high frequency with a number of drugs. Idiosyncratic toxicity is rare but potentially life-threatening. Many serious ADRs that occur in man are unpredictable from routine pathology and clinical chemistry in laboratory animals and are therefore poorly understood. The drug metabolist can determine the propensity of a novel chemical entity to either accumulate in the hepatocyte or undergo bioactivation in numerous model systems, from expressed enzymes, genetically engineered cells to whole animals. Bioactivation can be measured using trapping experiments with model nucleophiles or by measurement of non-specific covalent binding. The chemistry of the process is defined and the medicinal chemist can address the issue by seeking a metabolically stable pharmacophore to replace the potential toxicophore. However, we require a more fundamental understanding of the role of drug chemistry and biochemistry in ADRs. This requires knowledge of the ultimate toxin, signalling in cell defense and the sequence of molecular events, which ultimately lead to cell and tissue damage. It is imperative that such studies have a clinical level, but then translated into laboratory-based molecular studies. This will provide a deeper understanding of potential toxicophores for drug design and define candidate genes for pharmacogenomic approaches to individualized medicines.
Mdluli, Khisimuzi; Kaneko, Takushi; Upton, Anna
The recent accelerated approval for use in extensively drug-resistant and multidrug-resistant-tuberculosis (MDR-TB) of two first-in-class TB drugs, bedaquiline and delamanid, has reinvigorated the TB drug discovery and development field. However, although several promising clinical development programs are ongoing to evaluate new TB drugs and regimens, the number of novel series represented is few. The global early-development pipeline is also woefully thin. To have a chance of achieving the goal of better, shorter, safer TB drug regimens with utility against drug-sensitive and drug-resistant disease, a robust and diverse global TB drug discovery pipeline is key, including innovative approaches that make use of recently acquired knowledge on the biology of TB. Fortunately, drug discovery for TB has resurged in recent years, generating compounds with varying potential for progression into developable leads. In parallel, advances have been made in understanding TB pathogenesis. It is now possible to apply the lessons learned from recent TB hit generation efforts and newly validated TB drug targets to generate the next wave of TB drug leads. Use of currently underexploited sources of chemical matter and lead-optimization strategies may also improve the efficiency of future TB drug discovery. Novel TB drug regimens with shorter treatment durations must target all subpopulations of Mycobacterium tuberculosis existing in an infection, including those responsible for the protracted TB treatment duration. This review summarizes the current TB drug development pipeline and proposes strategies for generating improved hits and leads in the discovery phase that could help achieve this goal.
Mitchell, J.S.; Brown, I.; Chir, B.; Carpenter, R.N.
Since 1953, attempts have been made to develop radioactive drugs. Preparations of tritiated menadiol sodium diphosphate (T-MNDP) of high specific activity showed a definite, though limited, but sometimes useful effect in the treatment of certain patients with advanced tumors, especially adenocarcinoma of the colon and of the pancreas and malignant melanoma of the skin. The next step was to use a much more effective isotope. 6-/sup 125/I-iodo-2-methyl-1,4-naphthoquinol bis (diammonium phosphate) - abbreviated 6-/sup 125/I-iodo-MNDP - has been synthesized, and in laboratory studies appears more promising. /sup 125/I provides radiations which behave predominately like high LET radiation, despite the accompanying X and gamma radiations. The astatine analogue, 6-/sup 211/At-astato-2-methyl-1,4-naphthoquinol bis (disodium phosphate) has also been synthesized. Confirming and greatly extending the earlier findings with T-MNDP, in vitro experiments showed that 6-/sup 125/I-iodo-MNDP is concentrated selectively in the cells of some human malignant tumors by a factor of about 15 to 20 or more in relation to the cells of normal origin that were studied. Macrodosimetric considerations and comparison with clinical treatments with T-MNDP suggest practical dosage. A typical treatment for a patient of body weight 70 kg with localized inoperable carcinoma of the colon could be 8 intravenous injections each of approximately 120mCi of 6-/sup 125/I-iodo-MNDP to a toal of 0.97 Ci in 25 days. Risks of late carcinogenesis and leukemogenesis are calculated to be less than 1%. Clinical indications are discussed briefly. Animal experiments are in progress and further preclinical studies are required.
Seif, Salem; Franzen, Lutz; Windbergs, Maike
For the development of novel therapeutics, uncontrolled crystallization of drugs within delivery systems represents a major challenge. Especially for thin and flexible polymeric systems such as oral films or dermal wound dressings, the formation and growth of drug crystals can significantly affect drug distribution and release kinetics as well as physical storage stability. In this context, electrospinning was introduced as a fabrication technique with the potential to encapsulate drugs within ultrafine fibers by rapid solvent evaporation overcoming drug crystallization during fabrication and storage. However, these effects could so far only be shown for specific drug-polymer combinations and an in-depth understanding of the underlying processes of drug-loaded fiber formation and influencing key parameters is still missing. In this study, we systematically investigated crystal formation of caffeine as a model drug in electrospun fibers comparing different polymers. The solvent polarity was found to have a major impact on the drug crystal formation, whereas only a minor effect was attributed to the electrospinning process parameters. Based on an in-depth understanding of the underlying processes determining drug crystallization processes in electrospun fibers, key parameters could be identified which allow for the rational development of drug-loaded electrospun fibers overcoming drug crystallization.
Natural product drugs, or botanical drugs, are drugs composed of natural substances which have constituents with healthenhancing or medicinal activities. In Korea, government-led projects brought attention to botanical drugs invigorating domestic botanical drug industry. Foreign markets, as well, are growing bigger as the significance of botanical drugs stood out. To follow along with the tendency, Korea puts a lot of effort on developing botanical drugs suitable for global market. However, standards for approving drug sales vary by countries. And also, thorough standardization, certification, clinical studies and data of these will be required as well as data confirming safety and effectiveness. Meanwhile, as an international exchange in botanical drug market continues, the importance of plant resources was emphasized. Thus countries' ownership of domestic natural resources became vital. Not only establishing a systematic method to secure domestic plant resources, but also cooperation with other countries on sharing natural resources is essential to procure natural resources effectively. Korea started to show visible results with botanical drugs, and asthma/COPD treatment made out of speedwell is one example. Sufficient investment and government's active support for basic infrastructure for global botanical drugs will bring Korea to much higher level of botanical drug development. [BMB Reports 2017; 50(3): 111-116].
Swaminathan, Soumya; Sundaramurthi, Jagadish Chandrabose; Palaniappan, Alangudi Natarajan; Narayanan, Sujatha
Emergence of drug-resistant tuberculosis (DR-TB) is a big challenge in TB control. The delay in diagnosis of DR-TB leads to its increased transmission, and therefore prevalence. Recent developments in genomics have enabled whole genome sequencing (WGS) of Mycobacterium tuberculosis (M. tuberculosis) from 3-day-old liquid culture and directly from uncultured sputa, while new bioinformatics tools facilitate to determine DR mutations rapidly from the resulting sequences. The present drug discovery and development pipeline is filled with candidate drugs which have shown efficacy against DR-TB. Furthermore, some of the FDA-approved drugs are being evaluated for repurposing, and this approach appears promising as several drugs are reported to enhance efficacy of the standard TB drugs, reduce drug tolerance, or modulate the host immune response to control the growth of intracellular M. tuberculosis. Recent developments in genomics and bioinformatics along with new drug discovery collectively have the potential to result in synergistic impact leading to the development of a rapid protocol to determine the drug resistance profile of the infecting strain so as to provide personalized medicine. Hence, in this review, we discuss recent developments in WGS, bioinformatics and drug discovery to perceive how they would transform the management of tuberculosis in a timely manner.
Fujiwara, Yasuhiro; Kobayashi, Ken
In 1996 the Japanese Diet amended the Pharmaceutical Affairs Law (PAL) and its related laws based on 1996 report of the ad-hoc Committee for Drug Safety Ensuring Measures. Between 1996 and 2000, the drug approval system in Japan underwent a series of radical reforms. We describe in this paper the current system for drug approval, discuss the post-approval reexamination and reevaluation system, conditions under which development and review may be expedited, and mechanisms for approval of off-label usage. Finally, we discuss the impact of the International Conference on Harmonization (ICH) agreement on drug development and review in Japan.
Guzior, Natalia; ckowska,, Anna Wię; Panek, Dawid; Malawska, Barbara
Alzheimer’s disease (AD) is a complex and progressive neurodegenerative disorder. The available therapy is limited to the symptomatic treatment and its efficacy remains unsatisfactory. In view of the prevalence and expected increase in the incidence of AD, the development of an effective therapy is crucial for public health. Due to the multifactorial aetiology of this disease, the multi-target-directed ligand (MTDL) approach is a promising method in search for new drugs for AD. This review updates information on the development of multifunctional potential anti-AD agents published within the last three years. The majority of the recently reported structures are acetylcholinesterase inhibitors, often endowed with some additional properties. These properties enrich the pharmacological profile of the compounds giving hope for not only symptomatic but also causal treatment of the disease. Among these advantageous properties, the most often reported are an amyloid-β anti-aggregation activity, inhibition of β-secretase and monoamine oxidase, an antioxidant and metal chelating activity, NO-releasing ability and interaction with cannabinoid, NMDA or histamine H3 receptors. The majority of novel molecules possess heterodimeric structures, able to interact with multiple targets by combining different pharmacophores, original or derived from natural products or existing therapeutics (tacrine, donepezil, galantamine, memantine). Among the described compounds, several seem to be promising drug candidates, while others may serve as a valuable inspiration in the search for new effective therapies for AD. PMID:25386820
Guzior, Natalia; Wieckowska, Anna; Panek, Dawid; Malawska, Barbara
Alzheimer's disease (AD) is a complex and progressive neurodegenerative disorder. The available therapy is limited to the symptomatic treatment and its efficacy remains unsatisfactory. In view of the prevalence and expected increase in the incidence of AD, the development of an effective therapy is crucial for public health. Due to the multifactorial aetiology of this disease, the multi-target-directed ligand (MTDL) approach is a promising method in search for new drugs for AD. This review updates information on the development of multifunctional potential anti-AD agents published within the last three years. The majority of the recently reported structures are acetylcholinesterase inhibitors, often endowed with some additional properties. These properties enrich the pharmacological profile of the compounds giving hope for not only symptomatic but also causal treatment of the disease. Among these advantageous properties, the most often reported are an amyloid-β antiaggregation activity, inhibition of β-secretase and monoamine oxidase, an antioxidant and metal chelating activity, NOreleasing ability and interaction with cannabinoid, NMDA or histamine H3 receptors. The majority of novel molecules possess heterodimeric structures, able to interact with multiple targets by combining different pharmacophores, original or derived from natural products or existing therapeutics (tacrine, donepezil, galantamine, memantine). Among the described compounds, several seem to be promising drug candidates, while others may serve as a valuable inspiration in the search for new effective therapies for AD.
Type 2 diabetes has been identified as a risk factor for Alzheimer's disease (AD) and Parkinson's disease (PD). In the brains of patients with AD and PD, insulin signaling is impaired. This finding has motivated new research that showed good effects using drugs that initially had been developed to treat diabetes. Preclinical studies showed good neuroprotective effects applying insulin or long lasting analogues of incretin peptides. In transgenic animal models of AD or PD, analogues of the incretin GLP-1 prevented neurodegenerative processes and improved neuronal and synaptic functionality and reduced the symptoms of the diseases. Amyloid plaque load and synaptic loss as well as cognitive impairment had been prevented in transgenic AD mouse models, and dopaminergic loss of transmission and motor function has been reversed in animal models of PD. On the basis of these promising findings, several clinical trials are being conducted with the first encouraging clinical results already published. In several pilot studies in AD patients, the nasal application of insulin showed encouraging effects on cognition and biomarkers. A pilot study in PD patients testing a GLP-1 receptor agonist that is currently on the market as a treatment for type 2 diabetes (exendin-4, Byetta) also showed encouraging effects. Several other clinical trials are currently ongoing in AD patients, testing another GLP-1 analogue that is on the market (liraglutide, Victoza). Recently, a third GLP-1 receptor agonist has been brought to the market in Europe (Lixisenatide, Lyxumia), which also shows very promising neuroprotective effects. This review will summarise the range of these protective effects that those drugs have demonstrated. GLP-1 analogues show promise in providing novel treatments that may be protective or even regenerative in AD and PD, something that no current drug does.
Carpenter, William T; Koenig, James I
Schizophrenia is a disease syndrome with major public health implications. The primary advance in pharmacotherapeutics was in 1952 with the introduction of antipsychotic medications (ie, chlorpromazine, dopamine D2 antagonism). Barriers to progress have been substantial, but many will be subject to rapid change based on current knowledge. There are attractive psychopathology indications for drug discovery (eg, impaired cognition and negative symptoms), and drugs with efficacy in these domains may have application across a number of disease classes. These pathologies are observed prior to psychosis raising the possibility of very early intervention and secondary prevention. Success in drug discovery for cognition and negative symptom pathologies may bring forth issues in ethics as the potential for enhancing normal function is explored. PMID:18046305
Levin, Victor A.; Tonge, Peter J.; Gallo, James M.; Birtwistle, Marc R.; Dar, Arvin C.; Iavarone, Antonio; Paddison, Patrick J.; Heffron, Timothy P.; Elmquist, William F.; Lachowicz, Jean E.; Johnson, Ted W.; White, Forest M.; Sul, Joohee; Smith, Quentin R.; Shen, Wang; Sarkaria, Jann N.; Samala, Ramakrishna; Wen, Patrick Y.; Berry, Donald A.; Petter, Russell C.
Following the first CNS Anticancer Drug Discovery and Development Conference, the speakers from the first 4 sessions and organizers of the conference created this White Paper hoping to stimulate more and better CNS anticancer drug discovery and development. The first part of the White Paper reviews, comments, and, in some cases, expands on the 4 session areas critical to new drug development: pharmacological challenges, recent drug approaches, drug targets and discovery, and clinical paths. Following this concise review of the science and clinical aspects of new CNS anticancer drug discovery and development, we discuss, under the rubric “Accelerating Drug Discovery and Development for Brain Tumors,” further reasons why the pharmaceutical industry and academia have failed to develop new anticancer drugs for CNS malignancies and what it will take to change the current status quo and develop the drugs so desperately needed by our patients with malignant CNS tumors. While this White Paper is not a formal roadmap to that end, it should be an educational guide to clinicians and scientists to help move a stagnant field forward. PMID:26403167
Levin, Victor A; Tonge, Peter J; Gallo, James M; Birtwistle, Marc R; Dar, Arvin C; Iavarone, Antonio; Paddison, Patrick J; Heffron, Timothy P; Elmquist, William F; Lachowicz, Jean E; Johnson, Ted W; White, Forest M; Sul, Joohee; Smith, Quentin R; Shen, Wang; Sarkaria, Jann N; Samala, Ramakrishna; Wen, Patrick Y; Berry, Donald A; Petter, Russell C
Following the first CNS Anticancer Drug Discovery and Development Conference, the speakers from the first 4 sessions and organizers of the conference created this White Paper hoping to stimulate more and better CNS anticancer drug discovery and development. The first part of the White Paper reviews, comments, and, in some cases, expands on the 4 session areas critical to new drug development: pharmacological challenges, recent drug approaches, drug targets and discovery, and clinical paths. Following this concise review of the science and clinical aspects of new CNS anticancer drug discovery and development, we discuss, under the rubric "Accelerating Drug Discovery and Development for Brain Tumors," further reasons why the pharmaceutical industry and academia have failed to develop new anticancer drugs for CNS malignancies and what it will take to change the current status quo and develop the drugs so desperately needed by our patients with malignant CNS tumors. While this White Paper is not a formal roadmap to that end, it should be an educational guide to clinicians and scientists to help move a stagnant field forward.
Javitt, Daniel C.; Spencer, Kevin M.; Thaker, Gunvant K.; Winterer, Georg; Hajós, Mihály
Schizophrenia represents a pervasive deficit in brain function, leading to hallucinations and delusions, social withdrawal and a decline in cognitive performance. As the underlying genetic and neuronal abnormalities in schizophrenia are largely unknown, it is challenging to measure the severity of its symptoms objectively, or to design and evaluate psychotherapeutic interventions. Recent advances in neurophysiological techniques provide new opportunities to measure abnormal brain functions in patients with schizophrenia and to compare these with drug-induced alterations. Moreover, many of these neurophysiological processes are phylogenetically conserved and can be modelled in preclinical studies, offering unique opportunities for use as translational biomarkers in schizophrenia drug discovery. PMID:18064038
Rational development and deployment of antituberculosis drugs depend on a comprehensive understanding of the pharmacokinetics and pharmacodynamics that underlie their clinical behavior. Successful implementation of a pharmacokinetic-pharmacodynamic approach faces difficulties that, although not unique to tuberculosis as a therapeutic area, in combination pose a significant scientific challenge. In recent years, a multidisciplinary response combining new technological and analytical approaches has begun to directly address many of these issues, shedding light on some previously poorly understood aspects of drug distribution and response. These advances have important implications for optimization of existing and development of novel drug regimens, putting quantitative pharmacology at the heart of preclinical and early drug development.
Bhardwaj, Anshu; Scaria, Vinod; Raghava, Gajendra Pal Singh; Lynn, Andrew Michael; Chandra, Nagasuma; Banerjee, Sulagna; Raghunandanan, Muthukurussi V; Pandey, Vikas; Taneja, Bhupesh; Yadav, Jyoti; Dash, Debasis; Bhattacharya, Jaijit; Misra, Amit; Kumar, Anil; Ramachandran, Srinivasan; Thomas, Zakir; Brahmachari, Samir K
It is being realized that the traditional closed-door and market driven approaches for drug discovery may not be the best suited model for the diseases of the developing world such as tuberculosis and malaria, because most patients suffering from these diseases have poor paying capacity. To ensure that new drugs are created for patients suffering from these diseases, it is necessary to formulate an alternate paradigm of drug discovery process. The current model constrained by limitations for collaboration and for sharing of resources with confidentiality hampers the opportunities for bringing expertise from diverse fields. These limitations hinder the possibilities of lowering the cost of drug discovery. The Open Source Drug Discovery project initiated by Council of Scientific and Industrial Research, India has adopted an open source model to power wide participation across geographical borders. Open Source Drug Discovery emphasizes integrative science through collaboration, open-sharing, taking up multi-faceted approaches and accruing benefits from advances on different fronts of new drug discovery. Because the open source model is based on community participation, it has the potential to self-sustain continuous development by generating a storehouse of alternatives towards continued pursuit for new drug discovery. Since the inventions are community generated, the new chemical entities developed by Open Source Drug Discovery will be taken up for clinical trial in a non-exclusive manner by participation of multiple companies with majority funding from Open Source Drug Discovery. This will ensure availability of drugs through a lower cost community driven drug discovery process for diseases afflicting people with poor paying capacity. Hopefully what LINUX the World Wide Web have done for the information technology, Open Source Drug Discovery will do for drug discovery.
Lai, Yurong; Hsiao, Peng
Over the recent years there has been a greater appreciation in the important roles drug transporters play in drug-drug interactions (DDI), safety and effectiveness of drugs. Notable consequence of this recognition includes the white paper published by the International Transporter Consortium (ITC) and the guidance documents drafted by regulatory agencies for investigating transporter-mediated DDIs during drug development. While DDIs as a result of transporter-mediated alterations in drug absorption, disposition, or excretion are typically undesirable, there are exceptions. When specific transporters selectively regulate the exposure of a drug at the site of action and/or toxicity, the use of these transporters as molecular targets has been proposed as a promising strategy for tissue-selective drug delivery to enhance efficacy or mitigate toxicity. Furthermore, membrane transporters play a pivotal role in the transport of nutrients and endogenous compounds into or out of cells to sustain cell survival. Genetic polymorphism of drug transporters as well as transporter-inhibiting drugs can alter the transporter functional activity and/or protein expression, causing transporter-specific diseases. Therefore, investigating drug-transporter interactions is a critical aspect in candidate drug selection, in order to enhance the pharmacological effects and/or prevent the unintended off-target toxicity. The goal of this review is to provide the drug discovery scientists with a cadre of concepts beyond the ITC White Paper that facilitate rational drug design for optimal safety and efficacy. To that end, this review focuses on the following aspects: 1) regulatory landscape on drug transporter-mediated DDIs, 2) transporter related organ toxicity, 3) utility of drug transporters for target organ delivery, and 4) to highlight the diseases known thus far that are associated with variants of transporter genes.
Elizabeth Royer described the Ad Hoc On-Demand Distance Vector (AODV) routing protocol as “providing quick and efficient route establishment between...Network.” Thesis, Naval Postgraduate School, December 2000. 8. Das, Samir R., Perkins, Charles E., and Royer, Elizabeth M. “ The Ad-hoc On-Demand...Lidong. “Securing Ad Hoc Networks.” Paper Cornell University, Itaca, New York, NY. 16. Corson , Scott S., and Macker, J. “Mobile Ad Hoc
Aliyar, Hyder; Schalau, Gerald
Silicones have been used in medicines, cosmetics and medical devices for over 60 years. Polydimethylsiloxanes are polymers that are typically used either as an active in oral drug products or as excipients in topical and transdermal drug products. Inherent characteristics like hydrophobicity, adhesion and aesthetics allow silicones to offer function and performance to drug products. Recent technologies like swollen crosslinked silicone elastomer blend networks, sugar siloxanes, amphiphilic resin linear polymers and silicone hybrid pressure sensitive adhesives promise potential performance advantages and improved drug delivery efficacy. This article presents a review of recent silicone material developments focusing on their function as excipients influencing drug delivery in topical and transdermal systems.
Drug developers are grappling with the impact of personalized medicine on their portfolios. The combination of molecular diagnostics with targeted biologic therapies has been hailed as a recent innovation with few historical analogs to guide behavior. However, if the definition of companion diagnostics is broadened to include any drug whose FDA approved label requires diagnostic testing before prescription then over 50 drugs across multiple therapeutic areas arise. Most importantly for current drug developers, these drugs represent a wide variety of market situations and with sufficient historical data to evaluate different commercialization strategies for the combination. Included in these examples are drugs which were not initially launched with companion diagnostics but were required to implement companion diagnostics after they were on the market for a period of time. The historical case studies demonstrate that companion diagnostics are neither a universal panacea nor an unmitigated disaster for drug developers but require an understanding of specific situations to determine the utility of companion diagnostics. Numerous case studies highlight how companion diagnostics have been a boon to drug developers including Iressa, statins, Soriatane, Arthrotec, Promacta, Nplate, Letairis, and Tracleer. Other examples provide lessons on how to avoid pitfalls such as Accutane, Ticlid, Tegretol, Ziagen, Actigall and Clozaril. By carefully evaluating these case studies, drug developers can gain insight on the appropriate companion diagnostic strategy to implement for their specific situation and develop the elements of a successful companion diagnostic strategy.
Clancy, Colleen E.; An, Gary; Cannon, William R.; Liu, Yaling; May, Elebeoba E.; Ortoleva, Peter; Popel, Aleksander S.; Sluka, James P.; Su, Jing; Vicini, Paolo; Zhou, Xiaobo; Eckmann, David M.
A wide range of length and time scales are relevant to pharmacology, especially in drug development, drug design and drug delivery. Therefore, multi-scale computational modeling and simulation methods and paradigms that advance the linkage of phenomena occurring at these multiple scales have become increasingly important. Multi-scale approaches present in silico opportunities to advance laboratory research to bedside clinical applications in pharmaceuticals research. This is achievable through the capability of modeling to reveal phenomena occurring across multiple spatial and temporal scales, which are not otherwise readily accessible to experimentation. The resultant models, when validated, are capable of making testable predictions to guide drug design and delivery. In this review we describe the goals, methods, and opportunities of multi-scale modeling in drug design and development. We demonstrate the impact of multiple scales of modeling in this field. We indicate the common mathematical techniques employed for multi-scale modeling approaches used in pharmacology and present several examples illustrating the current state-of-the-art regarding drug development for: Excitable Systems (Heart); Cancer (Metastasis and Differentiation); Cancer (Angiogenesis and Drug Targeting); Metabolic Disorders; and Inflammation and Sepsis. We conclude with a focus on barriers to successful clinical translation of drug development, drug design and drug delivery multi-scale models.
van Hasselt, Johan GC; van Eijkelenburg, Natasha KA; Beijnen, Jos H; Schellens, Jan HM; Huitema, Alwin DR
Modelling and simulation (M&S)-based approaches have been proposed to support paediatric drug development in order to design and analyze clinical studies efficiently. Development of anti-cancer drugs in the paediatric population is particularly challenging due to ethical and practical constraints. We aimed to review the application of M&S in the development of anti-cancer drugs in the paediatric population, and to identify where M&S-based approaches could provide additional support in paediatric drug development of anti-cancer drugs. A structured literature search on PubMed was performed. The majority of identified M&S-based studies aimed to use population PK modelling approaches to identify determinants of inter-individual variability, in order to optimize dosing regimens and to develop therapeutic drug monitoring strategies. Prospective applications of M&S approaches for PK-bridging studies have scarcely been reported for paediatric oncology. Based on recent developments of M&S in drug development there are several opportunities where M&S could support more informative bridging between children and adults, and increase efficiency of the design and analysis of paediatric clinical trials, which should ultimately lead to further optimization of drug treatment strategies in this population. PMID:23216601
Feizi, H.; Ranjbar, A. H.
An ADS based on electron accelerators has been developed specifically for energy generation and medical applications. Monte Carlo simulations have been performed using FLUKA code to design a hybrid electron target and the core components. The composition, geometry of conversion targets and the coolant system have been optimized for electron beam energies of 20 to 100 MeV . Furthermore, the photon and photoneutron energy spectra, distribution and energy deposition for various incoming electron beam powers have been studied. Light-heavy water of various mixtures have been used as heat removal for the targets, as γ-n converters and as neutron moderators. We have shown that an electron LINAC, as a neutron production driver for ADSs, is capable of producing a neutron output of > 3.5 × 1014 (n/s/mA). Accordingly, the feasibility of an electron-based ADS employing the designed features is promising for energy generation and high intense neutron production which have various applications such as medical therapies.
Pharmacometricians require three skills to be influential: technical, business (e.g., drug development), and soft skills (e.g., communication). Effective communication is required to translate technical and often complicated quantitative findings to interdisciplinary team members in order to influence drug development or regulatory decisions. In this tutorial, we highlight important aspects related to communicating pharmacometric analysis to influence decisions. PMID:27299706
Pritchard, John N
Nebulized treatment is an important delivery option for the young, elderly, and those with severe chronic respiratory disease, but there is a lack of new nebulized drug products being produced for these patients, leading to the potential for under-treatment. This communication describes a new drug development paradigm as a timely solution to this issue. Often, drug development is initiated with nebulizers in the early stages, to provide cheaper and faster drug development, and then switched to inhaler devices in later clinical trials to address the majority of patients. However, the waste of resource on parallel development of the inhaler can be large due to the high early attrition rate of new drug development. The new paradigm uses the nebulizer to continue drug development through to market, and initiates inhaler development after completion of the riskier early phase studies. New drug safety and efficacy can be assessed faster and more efficiently by using a nebulized formulation rather than developing an inhaler. The results of calculations of expected net present value showed that the new paradigm produced higher expected net present values than the conventional model over a range of economic scenarios. This new paradigm could therefore provide improved returns on investments, as well as more modern drugs in nebulized form for those patients unable to use inhalers.
Curtis, C Gerald; Bilyard, Kevin; Stephenson, Hugo
Among the challenges facing translational medicine today is the need for greater productivity and safety during the drug development process. To meet this need, practitioners of translational medicine are developing new technologies that can facilitate decision making during the early stages of drug discovery and clinical development. Ex Vivo Metrics is an emerging technology that addresses this need by using intact human organs ethically donated for research. After hypothermic storage, the organs are reanimated by blood perfusion, providing physiologically and biochemically stable preparations. In terms of emulating human exposure to drugs, Ex Vivo Metrics is the closest biological system available for clinical trials. Early application of this tool for evaluating drug targeting, efficacy, and toxicity could result in better selection among promising drug candidates, greater drug productivity, and increased safety.
Leurent, C; Ehlers, M D
For many neurological and psychiatric diseases, novel therapeutics have been elusive for decades. By focusing on attention interference in Alzheimer's disease (AD), we provide a future vision on how emerging mobile, computer, and device-based cognitive tools are converting classically noisy, subjective, data-poor clinical endpoints associated with neuropsychiatric disease assessment into a richer, scalable, and objective set of measurements. Incorporation of such endpoints into clinical drug trials holds promise for more quickly and efficiently developing new medicines.
Buchwald, P; Bodor, N
This paper summarizes recent developments in the field of soft drug development as collected and reviewed for the 9th Retrometabolism-Based Drug Design and Targeting Conference. Soft drugs are still often confused with prodrugs because they both require metabolic transformations; however, they are conceptual opposites: whereas, prodrugs are pharmacologically inactive and are converted by a predictable mechanism to the active drug, soft drugs are active therapeutic agents as such and are designed to undergo a predictable and controllable metabolic deactivation after exerting their desired therapeutic effect. Several rationally designed soft drug examples including clinically approved ones (e.g., clevidipine, esmolol, landiolol, loteprednol etabonate, and remifentanil) as well as others that have reached clinical investigations within different therapeutic areas (e.g., budiodarone, naronapride, remimazolam, tecarfarine) are briefly summarized. Anesthesiology, which requires a high degree of pharmacologic control during the surgical procedure to maintain the anesthetic state together with a quick return to responsiveness at the end of this procedure, is a particularly well-suited area for soft drug development. Several new initiatives (e.g., MOC-etomidate, AZD3043) are focused in this area; they are also briefly reviewed. Finally, just as there are many 'accidental' prodrugs, there are 'accidental' soft drugs too: i.e., therapeutics that were not intentionally designed to be soft drugs, but turned out to be essentially soft drugs. Some examples, such as articaine or methylphenidate, are briefly reviewed.
Becker, Robert E.; Greig, Nigel H.; Giacobini, Ezio
Alzheimer's disease (AD) drug developments and clinical trials (CT) remain vulnerable to problems that undermine research validity. Investigations of CT methods reveal how numerous factors decrease active drug-placebo group differences and increase variance, thereby reducing power to reach statistical significance for outcome measure differences in AD CTs. Such factors include, amongst many, inaccuracy, imprecision, bias, failures to follow or lack of operational protocols for applying CT methods, inter-site variance, lack of homogeneous sampling using disorder criteria. After a review of the literature and survey of a sample of AD and Mild Cognitive Impairment (MCI) CTs, the authors question whether problems of human error preclude AD researchers from continuing their dependence on rated outcome measures for CTs. The authors propose that the realities of AD, especially a probable irreversible progression of neuropathology prior to onset of clinical symptoms or signs capable of differentiating persons at risk for AD from normal aged, require AD investigators and clinicians to privilege biomarkers and encourage their development as surrogate targets for preventive AD treatment developments, testing, and use in clinical practice. PMID:18953116
Quan, Hui; Ma, Yingqiu; Zheng, Yan; Cho, Meehyung; Lorenzato, Christelle; Hecquet, Carole
During a new drug development process, it is desirable to timely detect potential safety signals. For this purpose, repeated meta-analyses may be performed sequentially on accumulating safety data. Moreover, if the amount of safety data from the originally planned program is not enough to ensure adequate power to test a specific hypothesis (e.g., the noninferiority hypothesis of an event of interest), the total sample size may be increased by adding new studies to the program. Without appropriate adjustment, it is well known that the type I error rate will be inflated because of repeated analyses and sample size adjustment. In this paper, we discuss potential issues associated with adaptive and repeated cumulative meta-analyses of safety data conducted during a drug development process. We consider both frequentist and Bayesian approaches. A new drug development example is used to demonstrate the application of the methods.
Jeevanandam, Jaison; Chan, Yen San; Danquah, Michael K
Nano-formulations of medicinal drugs have attracted the interest of many researchers for drug delivery applications. These nano-formulations enhance the properties of conventional drugs and are specific to the targeted delivery site. Dendrimers, polymeric nanoparticles, liposomes, nano-emulsions and micelles are some of the nano-formulations that are gaining prominence in pharmaceutical industry for enhanced drug formulation. Wide varieties of synthesis methods are available for the preparation of nano-formulations to deliver drugs in biological system. The choice of synthesis methods depend on the size and shape of particulate formulation, biochemical properties of drug, and the targeted site. This article discusses recent developments in nano-formulation and the progressive impact on pharmaceutical research and industries. Additionally, process challenges relating to consistent generation of nano-formulations for drug delivery are discussed.
Thoene, J G
The Orphan Drug Act has successfully stimulated the production of many orphan products for a number of orphan diseases. The success of its exclusive marketing provision in bringing otherwise unprofitable products to market has attracted the attention of manufacturers who use this provision to gain a monopoly for products with much larger annual sales than were contemplated by the original legislation. Corrective legislation to close this loophole is being prepared for introduction to Congress.
any. sip of infection or disese (11. Also, laboratory work with CCHF has beeni limited because accidental infections which have had serious or even fata...were unldrgoir. i,,¢rois. No leb’ons were found in submaxillary or sublingual salivary gland, kidney , heart, eye, lacrimal gland, thyroid, trachea, or...examined including kidney , lung, liver and brain. e. Active chemotherapeutic agents in the vaccinia tail lesion model. Most drugs tested in thit model gave
caspase-8. TWO TYPES OF APOPTOSIS INVOLVE CASPASE-8 Cell death can be initiated by receptor-dependent and -independent signaling, and different cell...8.44 This strategy of combining chemother- apy with biologic or immunotherapy to stimulate apoptosis may prove effective for drug-resistant tumors...exciting new data point to caspase-8- dependent tumor response to chemotherapy in vitro. They suggest that biological manipulation of caspase-8
Lach, D.; Hixson, P.; Silbernagel, M.; Branch, K.; Heerwagen, J.; Bradbury, J.
As more managers realize that public input in public sector decision making is a given in the current political and social climate, many are turning to public involvement (PI) as a way to manage the input so that it is beneficial to their decisions and projects. Public involvement is starting to become a familiar way of doing business for the Department of Energy (DOE) and its contractors. DOE and contractors are still unclear about the value and costs that PI can provide to their projects. Proponents claim that PI increases the acceptability of project goals by increasing stakeholders knowledge about and involvement in decisions of importance to them. In spite of these assertions avowing the benefits of PI, proponents have not generated methods that demonstrate or provide evidence of the value added through incorporating PI into projects. As DOE and contract managers are increasingly directed to incorporate public input in their project planning and decision making, questions are beginning to surface about the value and costs of PI as a way to manage that input. There is a pressing need to document the value and costs of PI for the participants in these processes--the stakeholders--and to present this information to decision makers in a way that helps them assess the value and costs of managing public input through a PI program. This research project focuses on developing a series of indicators to assess the value and costs of using public involvement programs to manage public input in decision making processes. The dimensions of public involvement that participants perceive as adding value or costs to projects; and developing ways to measure those dimensions through social indicators and metrics of behavior are outlined.
Potterat, Olivier; Hamburger, Matthias
An overview is given on current efforts in drug development based on plant-derived natural products. Emphasis is on projects which have advanced to clinical development. Therapeutic areas covered include cancer, viral infections including HIV, malaria, inflammatory diseases, nociception and vaccine adjuvants, metabolic disorders, and neurodegenerative diseases. Aspects which are specific to plant-based drug discovery and development are also addressed, such as supply issues in the commercial development, and the Convention on Biological Diversity.
Burckart, Gilbert J; Amur, Shashi; Goodsaid, Federico M; Lesko, Lawrence J; Frueh, Felix W; Huang, Shiew-Mei; Cavaille-Coll, Marc W
The drug development process is dependent upon having established end points for measuring drug efficacy and adverse effects. New drug development in organ transplantation suffers from having end points which are either outdated or which do not serve the purpose of addressing the current critical drug therapy problems. Numerous biomarkers have been examined in organ transplantation, but almost all would be classified as exploratory for drug development purposes. Some of the possible pathways out of this dilemma include investigator- or consortium-initiated research that would qualify the biomarkers as either probable or known valid biomarkers, help in identification of new end points in transplantation and their associated biomarkers, co-development of a new biomarker and drug for transplantation and the use of new clinical trial design methods which facilitate enriched or stratified transplant patient populations. With new biomarkers and new study design methodologies for drug development, improvement in the drug development process for transplantation is a real possibility that the transplant clinical and research community can help to bring about.
Warner, Amelia W
Alopecia areata, alopecia totalis, and alopecia universalis likely represent a constellation of related diseases with similar, yet distinct heritability markers. There is currently no known curative therapy that works universally for all patients. Pharmacogenomic research enables the pharmaceutical industry to understand variability of patient responses to drugs during clinical drug development and during post-marketing surveillance. Understanding the genetic basis for patient response/non-response can enable the development of individualized therapies for those patients with an inherited basis for altered response to drug therapy. There are multiple examples of drugs that now contain a recommendation for genetic testing before dosing in their drug labels, directing clinicians to obtain genetic information for each individual patient in order to help direct drug therapy.
Kesselheim, A S; Wang, B; Avorn, J
Some observers of drug development argue that the pace of pharmaceutical innovation is declining, but others deny that contention. This controversy may be due to different methods of defining and assessing innovation. We conducted a systematic review of the literature to develop a taxonomy of methods for measuring innovation in drug development. The 42 studies fell into four main categories: counts of new drugs approved, assessments of therapeutic value, economic outcomes, and patents issued. The definition determined whether a study found a positive or negative trend in innovative drug development. Of 21 studies that relied on counts, 9 (43%) concluded that the trend for drug discovery was favorable, 11 (52%) concluded that the trend was not favorable, and 1 reached no conclusion. By contrast, of 21 studies that used other measures of innovation, 0 concluded that the trend was favorable, 8 (47%) concluded that the trend was not favorable, and 13 reached no conclusion (P = 0.03).
Sabbagh, Marwan N.
Objective To provide a brief survey of the clinical development of Alzheimer's disease (AD) pharmacotherapy. Methods The search process included PubMed, www.ClinicalTrials.gov, the International Conference on Alzheimer's Disease 2008 (ICAD), and pharmaceutical company and AD advocacy Web sites. Selected articles were primary manuscripts reporting clinical trial or preclinical study results in English in peer-reviewed journals. Results The AD pipeline comprises a large number of drugs with differing targets and mechanisms of action. No novel agent, since the approval of memantine in 2002, has successfully completed a phase 3 trial however, encouraging phase 2 results were reported for several compounds at ICAD 2008, and the overall number and variety of novel agents in clinical development continues to expand. Conclusions Despite clearly disappointing results of recently completed phase 3 trials for several leading novel compounds, the breadth and depth of the clinical development pipeline at all phases of development provides ample justification to expect that new pharmacotherapeutic options will become available for the treatment of AD within the next 3 to 5 years. Nonetheless, it is not yet clear which agent or therapeutic strategy will be the next to be approved for clinical use. In the meantime, it is important to not underestimate the value of currently available treatments, and to ensure that every patient with AD is prescribed optimal pharmacotherapy as early in the course of the disease as possible. PMID:19616185
Heath, James R.; Ribas, Antoni; Mischel, Paul S.
The genetic, functional, or compositional heterogeneity of healthy and diseased tissues presents major challenges in drug discovery and development.1-3 In cancers, heterogeneity may be essential for tumor stability,4 but its precise role in tumor biology is poorly resolved. This challenges the design of accurate disease models for use in drug development, and can confound the interpretation of biomarker levels, and of patient responses to specific therapies. The complex nature of heterogeneous tissues has motivated the development of tools for single cell genomic, transcriptomic, and multiplex proteomic analysis. We review these tools, assess their advantages and limitations, and explore their potential applications in drug discovery and development. PMID:26669673
Disease ailments are changing the patterns, and the new diseases are emerging due to changing environments. The enormous growth of world population has overburdened the existing resources for the drugs. And hence, the drug manufacturers are always on the lookout for new resources to develop effective and safe drugs for the increasing demands of the world population. Seventy-five percentage of earth's surface is covered by water but research into the pharmacology of marine organisms is limited, and most of it still remains unexplored. Marine environment represents countless and diverse resource for new drugs to combat major diseases such as cancer or malaria. It also offers an ecological resource comprising a variety of aquatic plants and animals. These aquatic organisms are screened for antibacterial, immunomodulator, anti-fungal, anti-inflammatory, anticancer, antimicrobial, neuroprotective, analgesic, and antimalarial properties. They are used for new drug developments extensively across the world. Marine pharmacology offers the scope for research on these drugs of marine origin. Few institutes in India offer such opportunities which can help us in the quest for new drugs. This is an extensive review of the drugs developed and the potential new drug candidates from marine origin along with the opportunities for research on marine derived products. It also gives the information about the institutes in India which offer marine pharmacology related courses.
Disease ailments are changing the patterns, and the new diseases are emerging due to changing environments. The enormous growth of world population has overburdened the existing resources for the drugs. And hence, the drug manufacturers are always on the lookout for new resources to develop effective and safe drugs for the increasing demands of the world population. Seventy-five percentage of earth's surface is covered by water but research into the pharmacology of marine organisms is limited, and most of it still remains unexplored. Marine environment represents countless and diverse resource for new drugs to combat major diseases such as cancer or malaria. It also offers an ecological resource comprising a variety of aquatic plants and animals. These aquatic organisms are screened for antibacterial, immunomodulator, anti-fungal, anti-inflammatory, anticancer, antimicrobial, neuroprotective, analgesic, and antimalarial properties. They are used for new drug developments extensively across the world. Marine pharmacology offers the scope for research on these drugs of marine origin. Few institutes in India offer such opportunities which can help us in the quest for new drugs. This is an extensive review of the drugs developed and the potential new drug candidates from marine origin along with the opportunities for research on marine derived products. It also gives the information about the institutes in India which offer marine pharmacology related courses. PMID:27134458
Alemayehu, Demissie; Berger, Marc L
The explosion of data sources, accompanied by the evolution of technology and analytical techniques, has created considerable challenges and opportunities for drug development and healthcare resource utilization. We present a systematic overview these phenomena, and suggest measures to be taken for effective integration of the new developments in the traditional medical research paradigm and health policy decision making. Special attention is paid to pertinent issues in emerging areas, including rare disease drug development, personalized medicine, Comparative Effectiveness Research, and privacy and confidentiality concerns.
Shih, Ming-Hsiang; Sung, Wen-Pei; Go, Cheer-Germ
Energy dissipators, isolated-resistant and specific structural forms for earthquake resistance are popular topics in the research to improve shock-resistance. In this work, experimental methods were used to investigate the property of low yield strength steel. Carbon content in LYS material is lower than that in other steels; the ultimate stress is three times the yield stress. The ultimate elongation rate is about 62% and the ductility is 2-3 times that of A36 steel. In order to overcome some defects of ordinary use metallic dampers, the mechanical characteristic of low yield strength steel is used to develop added damping and stiffness for rhombic steel plate absorber. Test of the energy dissipation behavior for this newly developed device indicated that LYS could stably dissipate or absorb the input energy of earthquake. Then, the analytical model for the hysteretic behavior of this new device is proposed. Comparison of experimental data and numerical simulation results showed that this analytical model is suitable for simulating the hysteretic energy behavior of this new device.
... HUMAN SERVICES Food and Drug Administration Medical Device Development Tools; Draft Guidance for Industry, Tool Developers, and Food and Drug Administration Staff; Availability AGENCY: Food and Drug Administration, HHS. ACTION: Notice. SUMMARY: The Food and Drug Administration (FDA) is announcing...
Kelloff, Gary J; Sigman, Caroline C
Although several new oncology drugs have reached the market, more than 80% of drugs for all indications entering clinical development do not get marketing approval, with many failing late in development often in Phase III trials, because of unexpected safety issues or difficulty determining efficacy, including confounded outcomes. These factors contribute to the high costs of oncology drug development and clearly show the need for faster, more cost-effective strategies for evaluating oncology drugs and better definition of patients who will benefit from treatment. Remarkable advances in the understanding of neoplastic progression at the cellular and molecular levels have spurred the discovery of molecularly targeted drugs. This progress along with advances in imaging and bioassay technologies are the basis for describing and evaluating new biomarker endpoints as well as for defining other biomarkers for identifying patient populations, potential toxicity, and providing evidence of drug effect and efficacy. Definitions and classifications of these biomarkers for use in oncology drug development are presented in this paper. Science-based and practical criteria for validating biomarkers have been developed including considerations of mechanistic plausibility, available methods and technology, and clinical feasibility. New promising tools for measuring biomarkers have also been developed and are based on genomics and proteomics, direct visualisation by microscopy (e.g., confocal microscopy and computer-assisted image analysis of cellular features), nanotechnologies, and direct and remote imaging (e.g., fluorescence endoscopy and anatomical, functional and molecular imaging techniques). The identification and evaluation of potential surrogate endpoints and other biomarkers require access to and analysis of large amounts of data, new technologies and extensive research resources. Further, there is a requirement for a convergence of research, regulatory and drug developer
Bialer, Meir; Walker, Matthew C; Sander, Josemir W
There continues to be an escalation in the number of new antiepileptic drugs, with many recently marketed drugs and many more entering clinical trials. This growth begs the question as to whether we need additional antiepileptic drugs. We consider the answer to this question from the medical perspective and also from the viewpoint of the pharmaceutical industry, health providers and from a more global, international perspective. There is undoubtedly a medical need for new antiepileptic drugs, and despite growing competition, the antiepileptic drug market remains profitable. However, in health services with limited resources, it is important that this expense is not offset by failure to research more appropriate use of existing antiepileptic drugs that may have a greater impact on healthcare. This is especially true for developing countries where resources would be much better spent on prevention and closing the treatment gap (the difference between those who can be treated and those who are treated).
Durán, I; Salazar, R; Casanovas, O; Arrazubi, V; Vilar, E; Siu, L L; Yao, J; Tabernero, J
The traditional cytotoxic agents are of limited efficacy in the treatment of neuroendocrine tumors of the gastrointestinal tract (NETs). Recent investigations have brought up a number of biological features in this family of neoplasms that could represent targets for anticancer treatment. NETs seem to have an extraordinary tumor vascularization with high expression of proangiogenic molecules such as the vascular endothelial growth factor along with overexpression of certain tyrosine kinase receptors such as the epidermal growth factor receptor (EGFR), the insulin growth factor receptor (IGFR) and their downstream signaling pathway components (PI3K-AKT-mTOR). The rationale of an antiangiogenic approach in the treatment of NETs and the use of other pharmacological strategies such as EGFR, IGFR and mammalian target of rapamycin inhibitors are discussed. Additionally, the emerging results of recent clinical trials with these targeted drugs are presented.
Dieterich, Lothar C; Detmar, Michael
Traditionally, tumor-associated lymphatic vessels have been regarded as passive by-standers, serving simply as a drainage system for interstitial fluid generated within the tumor. However, with growing evidence that tumors actively induce lymphangiogenesis, and that the number of lymphatic vessels closely correlates with metastasis and clinical outcome in various types of cancer, this picture has changed dramatically in recent years. Tumor-associated lymphatic vessels have now emerged as a valid therapeutic target to control metastatic disease, and the first specific anti-lymphangiogenic drugs have recently entered clinical testing. Furthermore, we are just beginning to understand the whole functional spectrum of tumor-associated lymphatic vessels, which not only concerns transport of fluid and metastatic cells, but also includes the regulation of cancer stemness and specific inhibition of immune responses, opening new venues for therapeutic applications. Therefore, we predict that specific targeting of lymphatic vessels and their function will become an important tool for future cancer treatment.
In this study, I explored how children develop and construct their ideas and alternative frameworks in science. Prior work in this area suggested that changes from alternative conceptions to understandings that more closely resemble scientists' models do not occur in a sequential, linear fashion, nor are they easily accomplished. By employing a constructivist framework grounded in dynamic systems to look at learning, alternative conceptions were viewed not as ideas that need to be "confronted and replaced" but rather as pieces of an intricate puzzle of understanding that when combined create a more complete, functional, continuous understanding of science. Specifically, the study examined students' understandings and conceptualizations of light as they studied it formally for eight weeks. Understandings were measured through interviews, student-generated concept maps, classroom interactions and by examining student work samples. The central questions guiding the investigation were: What were children's (ages 9 and 10) conceptions of light? Did children's ideas about light develop during their eight week study of it? If so, what was the nature of these changes? Results from the study indicated that children had numerous ideas about light before their formal study of it based on their experiences with the world. As children studied light, they learned about it in the dynamic, synergistic and interactive processes of adding new ideas, connecting ideas to one another and elaborating understandings to arrive at progressively more complex and scientific understandings of light. Alternative conceptions, served as both productive and non-productive resources for learning. Further, alternative conceptions and prior understandings did not disappear as children developed their ideas about light. Rather "old" ideas were used and reused to provide support the gradual process of cognitive development of children's ideas about light. Findings from this study can be used to
Safren, Steven A.; O’Cleirigh, Conall M.; Bullis, Jacqueline R.; Otto, Michael W.; Stein, Michael D.; Pollack, Mark H.
Objective Depression and substance use, the most common comorbidities with HIV, are both associated with poor treatment adherence. Injection drug users comprise a substantial portion of individuals with HIV in the U.S. and globally. The present study tested cognitive-behavioral therapy for adherence and depression (CBT-AD) in patients with HIV and depression in active substance abuse treatment for injection drug use. Method This is a two-arm, randomized controlled trial (N = 89) comparing CBT-AD to enhanced treatment as usual (ETAU). Analyses were conducted for two time-frames: 1) baseline to post-treatment 2) post-treatment to follow-up at 3- and 6-months after intervention discontinuation. Results At post-treatment, the CBT-AD condition showed significantly greater improvement than ETAU in MEMS (electronic pill cap) based adherence (γslope = 0.8873, t (86) = 2.38, p = .02; dGMA-raw = .64), and depression, assessed by blinded assessor [Mongomery-Asberg Depression Rating Scale (F(1,79) = 6.52, p<.01); d = .55)] and clinical global impression [(F(1,79) = 14.77, p<.001; d = .85)]. After treatment discontinuation, depression gains were maintained, though adherence gains were not. Viral load did not differ across condition, however, the CBT-AD condition had significant improvements in CD4 cell counts over time compared to ETAU (γslope= 2.09, t (76) = 2.20, p = .03; dGMA-raw = .60). Conclusions In patients managing multiple challenges including HIV, depression, substance dependence, and adherence, CBT-AD is a useful way to integrate treatment of depression with an adherence intervention. Continued adherence counseling is likely needed, however, to maintain or augment adherence gains in this population. PMID:22545737
Gupta, Umesh Chandra; Bhatia, Sandeep; Garg, Amit; Sharma, Amit; Choudhary, Vaibhav
Research focus of pharmaceutical industry has expanded to a larger extent in last few decades putting many more new molecules, particularly targeted agents, for the clinical development. On the other hand, researchers are facing serious challenges due to high failure rates of new molecules in clinical studies. The United States Food and Drug Administration (FDA) in combination with academia and industry experts identified many factors responsible for failures of new molecules, and with a vision of taking traditional drug development model toward an innovative paradigm shift, issued regulatory guidance on conduct of exploratory investigational new drug (exploratory IND) studies, often called as phase 0 clinical trials, requiring reduced preclinical testing, which has special relevance to life-threatening diseases such as cancer. Phase 0 trials, utilizing much lower drug doses, provide an opportunity to explore the clinical behavior of new molecules very early in the drug development pathway, helping to identify the promising candidates and eliminating non-promising molecules, thus improving the efficiency of overall drug development with significant savings of resources. Being non-therapeutic in nature, these studies, however, pose certain ethical challenges requiring careful study designing and informed consent process. This article reviews the insights and perspectives for the feasibility, utility, planning, designing and conduct of phase 0 clinical trials, in addition to ethical issues and industrial perspective focused at oncology new drug development. PMID:21584177
Gupta, Umesh Chandra; Bhatia, Sandeep; Garg, Amit; Sharma, Amit; Choudhary, Vaibhav
Research focus of pharmaceutical industry has expanded to a larger extent in last few decades putting many more new molecules, particularly targeted agents, for the clinical development. On the other hand, researchers are facing serious challenges due to high failure rates of new molecules in clinical studies. The United States Food and Drug Administration (FDA) in combination with academia and industry experts identified many factors responsible for failures of new molecules, and with a vision of taking traditional drug development model toward an innovative paradigm shift, issued regulatory guidance on conduct of exploratory investigational new drug (exploratory IND) studies, often called as phase 0 clinical trials, requiring reduced preclinical testing, which has special relevance to life-threatening diseases such as cancer. Phase 0 trials, utilizing much lower drug doses, provide an opportunity to explore the clinical behavior of new molecules very early in the drug development pathway, helping to identify the promising candidates and eliminating non-promising molecules, thus improving the efficiency of overall drug development with significant savings of resources. Being non-therapeutic in nature, these studies, however, pose certain ethical challenges requiring careful study designing and informed consent process. This article reviews the insights and perspectives for the feasibility, utility, planning, designing and conduct of phase 0 clinical trials, in addition to ethical issues and industrial perspective focused at oncology new drug development.
Jin, Xiaowei; Chen, Li
Summary Of over 7,000 known rare diseases, only 5% currently have an available treatment option worldwide. Moreover, the vast majority of rare disease patients in China have no access to treatment due to limited availability and the lack of appropriate infrastructure in China's healthcare system. Despite increased interest in orphan drug development, drug companies in China with active programs on drugs to treat rare diseases are still limited. Hence, there is a huge unmet need in China, with over 10 million patients suffering from rare diseases. Nonetheless, this has created unprecedented opportunities for the Chinese drug development market. Life science innovation in China has recently received a healthy boost from the 13th National Five-Year Plan and from on-going reform of the China Food and Drug Administration (CFDA). Rare diseases are now recognized as a national priority with increasing governmental support, creating tremendous opportunities for both domestic and multinational drug companies. China is anticipated to play an increasingly important role in the global fight against rare diseases. To ensure future success, Chinese drug companies should leverage the valuable knowledge assembled over the past three decades by Western countries in the area of orphan drug development. PMID:27904831
Jin, Xiaowei; Chen, Li
Of over 7,000 known rare diseases, only 5% currently have an available treatment option worldwide. Moreover, the vast majority of rare disease patients in China have no access to treatment due to limited availability and the lack of appropriate infrastructure in China's healthcare system. Despite increased interest in orphan drug development, drug companies in China with active programs on drugs to treat rare diseases are still limited. Hence, there is a huge unmet need in China, with over 10 million patients suffering from rare diseases. Nonetheless, this has created unprecedented opportunities for the Chinese drug development market. Life science innovation in China has recently received a healthy boost from the 13th National Five-Year Plan and from on-going reform of the China Food and Drug Administration (CFDA). Rare diseases are now recognized as a national priority with increasing governmental support, creating tremendous opportunities for both domestic and multinational drug companies. China is anticipated to play an increasingly important role in the global fight against rare diseases. To ensure future success, Chinese drug companies should leverage the valuable knowledge assembled over the past three decades by Western countries in the area of orphan drug development.
Sisignano, Marco; Parnham, Michael J; Geisslinger, Gerd
Drug development consumes huge amounts of time and money and the search for novel analgesics, which are urgently required, is particularly difficult, having resulted in many setbacks in the past. Drug repurposing - the identification of new uses for existing drugs - is an alternative approach, which bypasses most of the time- and cost-consuming components of drug development. Recent, unexpected findings suggest a role for several existing drugs, such as minocycline, ceftriaxone, sivelestat, and pioglitazone, as novel analgesics in chronic and neuropathic pain states. Here, we discuss these findings as well as their proposed antihyperalgesic mechanisms and outline the merits of pathway-based repurposing screens, in combination with bioinformatics and novel cellular reprogramming techniques, for the identification of novel analgesics.
Fukunishi, Yoshifumi; Lintuluoto, Masami
Chemical compound libraries are the basic database for virtual (in silico) drug screening, and the number of entries has reached 20 million. Many drug-like compound libraries for virtual drug screening have been developed and released. In this review, the process of constructing a database for virtual screening is reviewed, and several popular databases are introduced. Several kinds of focused libraries have been developed. The author has developed databases for metalloproteases, and the details of the libraries are described. The library for metalloproteases was developed by improving the generation of the dominant-ion forms. For instance, the SH group is treated as S- in this library while all SH groups are protonated in the conventional libraries. In addition, metal complexes were examined as new candidates of drug-like compounds. Finally, a method for generating chemical space is introduced, and the diversity of compound libraries is discussed.
Banerji, Udai; Workman, Paul
The Pharmacological Audit Trail (PhAT) comprises a set of critical questions that need to be asked during discovery and development of an anticancer drug. Key aspects include: (1) defining a patient population; (2) establishing pharmacokinetic characteristics; (3) providing evidence of target engagement, pathway modulation, and biological effect with proof of concept pharmacodynamic biomarkers; (4) determining intermediate biomarkers of response; (5) assessing tumor response; and (6) determining how to overcome resistance by combination or sequential therapy and new target/drug discovery. The questions asked in the PhAT should be viewed as a continuum and not used in isolation. Different drug development programmes derive different types of benefit from these questions. The PhAT is critical in making go-no-go decisions in the development of currently studied drugs and will continue to be relevant to discovery and development of future generations of anticancer agents.
... HUMAN SERVICES Food and Drug Administration Antibacterial Resistance and Diagnostic Device and Drug... resistance, rapid diagnostic device development for bacterial diseases, and antibacterial drug development. The workshop will address antibacterial drug resistance, mechanisms of resistance, epidemiology...
The earliest recorded animal disease notification on the territory of contemporary Switzerland is found in the chronicles of the monastery of St. Gall and dates back to A.D. 941. Disease control in Switzerland began in medieval towns, with the regulation of livestock and the meat trade. Later, there were attempts to keep entire small areas such as valleys free of animal epidemics. Because livestock tended to be transported in one direction only - away from rural areas for sale in towns and for export - disease in animal-raising areas usually did not spread very far. Albrecht von Haller's epidemiological research from 1773 established the fundamentals of effective disease control. The cantons introduced extensive measures for protecting their territories on the basis of animal transport controls. With the development of the railways and the international livestock trade around 1850, the risk of animal epidemics increased considerably, leading to the need for measures on national and international levels. The first federal law on animal disease control was introduced in Switzerland in 1872, thus creating a nation-wide "veterinary area". In 1886 the law was amended to include mandatory controls of imported livestock and meat by a newly-created border veterinary service.
Miller, Raymond; Ewy, Wayne; Corrigan, Brian W; Ouellet, Daniele; Hermann, David; Kowalski, Kenneth G; Lockwood, Peter; Koup, Jeffrey R; Donevan, Sean; El-Kattan, Ayman; Li, Cheryl S W; Werth, John L; Feltner, Douglas E; Lalonde, Richard L
The idea of model-based drug development championed by Lewis Sheiner, in which pharmacostatistical models of drug efficacy and safety are developed from preclinical and available clinical data, offers a quantitative approach to improving drug development and development decision-making. Examples are presented that support this paradigm. The first example describes a preclinical model of behavioral activity to predict potency and time-course of response in humans and assess the potential for differentiation between compounds. This example illustrates how modeling procedures expounded by Lewis Sheiner provided the means to differentiate potency and the lag time between drug exposure and response and allow for rapid decision making and dose selection. The second example involves planning a Phase 2a dose-ranging and proof of concept trial in Alzheimer's disease (AD). The issue was how to proceed with the study and what criteria to use for a go/no go decision. The combined knowledge of AD disease progression, and preclinical and clinical information about the drug were used to simulate various clinical trial scenarios to identify an efficient and effective Phase 2 study. A design was selected and carried out resulting in a number of important learning experiences as well as extensive financial savings. The motivation for this case in point was the "Learn-Confirm" paradigm described by Lewis Sheiner. The final example describes the use of Pharmacokinetic and Pharmacodynamic (PK/PD) modeling and simulation to confirm efficacy across doses. In the New Drug Application for gabapentin, data from two adequate and well-controlled clinical trials was submitted to the Food and Drug Administration (FDA) in support of the approval of the indication for the treatment of post-herpetic neuralgia. The clinical trial data was not replicated for each of the sought dose levels in the drug application presenting a regulatory dilemma. Exposure response analysis submitted in the New Drug
Stein, J; Mogk, S; Mudogo, C N; Sommer, B P; Scholze, M; Meiwes, A; Huber, M; Gray, A; Duszenko, M
Atoxyl, the first medicinal drug against human African trypanosomiasis (HAT), also known as sleeping sickness, was applied more than 100 years ago. Ever since, the search for more effective, more specific and less toxic drugs continued, leading to a set of compounds currently in use against this devastating disease. Unfortunately, none of these medicines fulfill modern pharmaceutical requirements and may be considered as therapeutic ultima ratio due to the many, often severe side effects. Starting with a historic overview on drug development against HAT, we present a selection of trypanosome specific pathways and enzymes considered as highly potent druggable targets. In addition, we describe cellular mechanisms the parasite uses for differentiation and cell density regulation and present our considerations how interference with these steps, elementary for life cycle progression and infection, may lead to new aspects of drug development. Finally we refer to our recent work about CNS infection that offers novel insights in how trypanosomes hide in an immune privileged area to establish a chronic state of the disease, thereby considering new ways for drug application. Depressingly, HAT specific drug development has failed over the last 30 years to produce better suited medicine. However, unraveling of parasite-specific pathways and cellular behavior together with the ability to produce high resolution structures of essential parasite proteins by X-ray crystallography, leads us to the optimistic view that development of an ultimate drug to eradicate sleeping sickness from the globe might just be around the corner.
van der Zanden, Tjitske M; de Wildt, Saskia N; Liem, Yves; Offringa, Martin; de Hoog, Matthijs
As many drugs in paediatrics are used off-label, prescribers face a lack of evidence-based dosing guidelines. A Dutch framework was developed to provide dosing guidelines based on best available evidence from registration data, investigator-initiated research, professional guidelines, clinical experience and consensus. This has clarified the scientific grounds of drug use for children and encouraged uniformity in prescribing habits in the Netherlands. The developed framework and the current content of the Dutch Paediatric Formulary could be used as basis for similar initiatives worldwide, preferably in a concerted effort to ultimately provide children with effective and safe drug therapy.
Shen, Bao-de; Shen, Cheng-ying; Yuan, Xu-dong; Bai, Jin-xia; Lv, Qing-yuan; Xu, He; Dai, Ling; Yu, Chao; Han, Jin; Yuan, Hai-long
In this study, a novel orodispersible film (ODF) containing drug nanoparticles was developed with the goal of transforming drug nanosuspensions into a solid dosage form and enhancing oral bioavailability of drugs with poor water solubility. Nanosuspensions were prepared by high pressure homogenization and then transformed into ODF containing drug nanoparticles by mixing with hydroxypropyl methylcellulose solution containing microcrystalline cellulose, low substituted hydroxypropylcellulose and PEG-400 followed by film casting and drying. Herpetrione, a novel and potent antiviral agent with poor water solubility that extracted from Herpetospermum caudigerum, was chosen as a model drug and studied systematically. The uniformity of dosage units of the preparation was acceptable according to the criteria of Japanese Pharmacopoeia 15. The ODF was disintegrated in water within 30s with reconstituted nanosuspensions particle size of 280 ± 11 nm, which was similar to that of drug nanosuspensions, indicating a good redispersibility of the fast dissolving film. Result of X-ray diffraction showed that HPE in the ODF was in the amorphous state. In the in vitro dissolution test, the ODF containing HPE nanoparticles showed an increased dissolution velocity markedly. In the pharmacokinetics study in rats, compared to HPE coarse suspensions, the ODF containing HPE nanoparticles exhibited significant increase in AUC0-24h, Cmax and decrease in Tmax, MRT. The result revealed that the ODF containing drug nanoparticles may provide a potential opportunity in transforming drug nanosuspensions into a solid dosage form as well as enhancing the dissolution rate and oral bioavailability of poorly water-soluble drugs.
Meldrum, Brian S.; Rogawski, Michael A.
Summary This review considers how recent advances in the physiology of ion channels and other potential molecular targets, in conjunction with new information on the genetics of idiopathic epilepsies, can be applied to the search for improved antiepileptic drugs (AEDs). Marketed AEDs predominantly target voltage-gated cation channels (the α subunits of voltage-gated Na+ channels and also T-type voltage-gated Ca2+ channels) or influence GABA-mediated inhibition. Recently, α2–δ voltage-gated Ca2+ channel subunits and the SV2A synaptic vesicle protein have been recognized as likely targets. Genetic studies of familial idiopathic epilepsies have identified numerous genes associated with diverse epilepsy syndromes, including genes encoding Na+ channels and GABAA receptors, which are known AED targets. A strategy based on genes associated with epilepsy in animal models and humans suggests other potential AED targets, including various voltage-gated Ca2+ channel subunits and auxiliary proteins, A- or M-type voltage-gated K+ channels, and ionotropic glutamate receptors. Recent progress in ion channel research brought about by molecular cloning of the channel subunit proteins and studies in epilepsy models suggest additional targets, including G-protein-coupled receptors, such as GABAB and metabotropic glutamate receptors; hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channel subunits, responsible for hyperpolarization-activated current Ih; connexins, which make up gap junctions; and neurotransmitter transporters, particularly plasma membrane and vesicular transporters for GABA and glutamate. New information from the structural characterization of ion channels, along with better understanding of ion channel function, may allow for more selective targeting. For example, Na+ channels underlying persistent Na+ currents or GABAA receptor isoforms responsible for tonic (extrasynaptic) currents represent attractive targets. The growing understanding of the
Ueno, T; Kobayashi, T; Inoue, K; Yanagi, Y; Yamada, Y
During the past 7 years since the enforcement of Japan's first GCP in October 1990, various standards and guidelines have been introduced in Japan. On the other hand, the harmonization of GCP has been the subject of major discussion at ICH in order to allow the mutual acceptance of clinical data from different countries. In order to further improve the reliability and consistency of clinical data and the ethics of clinical trials in Japan, the new GCP was enforced in April 1997. A clinical study is conducted by the sponsor, but will only be successful with the collaboration of trial subjects, medical institutions, heads of medical institutions, investigators, subinvestigators, pharmacists, nurses, laboratory technicians, and other assisting staff. Before the full enforcement of the new GCP, we, as sponsors of clinical trials, carried out a survey of the current status of clinical trials centering on the reactions of medical institutions to the new GCP, future of clinical trials on anti-cancer drugs in Japan, and differences in time from clinical trials to registration in Japan, the United State and Europe. We sent a questionnaire by facsimile to 21 pharmaceutical companies which have developed or are developing anti-cancer drugs and obtained replies from 20 companies (95%) from August 25 to 30, 1997. This paper reports issues concerning clinical trials on anti-cancer drugs based on the results of our survey.
O'Donoghue, Amie C; Boudewyns, Vanessa; Aikin, Kathryn J; Geisen, Emily; Betts, Kevin R; Southwell, Brian G
The U.S. Food and Drug Administration's Bad Ad program educates health care professionals about false or misleading advertising and marketing and provides a pathway to report suspect materials. To assess familiarity with this program and the extent of training about pharmaceutical marketing, a sample of 2,008 health care professionals, weighted to be nationally representative, responded to an online survey. Approximately equal numbers of primary care physicians, specialists, physician assistants, and nurse practitioners answered questions concerning Bad Ad program awareness and its usefulness, as well as their likelihood of reporting false or misleading advertising, confidence in identifying such advertising, and training about pharmaceutical marketing. Results showed that fewer than a quarter reported any awareness of the Bad Ad program. Nonetheless, a substantial percentage (43%) thought it seemed useful and 50% reported being at least somewhat likely to report false or misleading advertising in the future. Nurse practitioners and physician assistants expressed more openness to the program and reported receiving more training about pharmaceutical marketing. Bad Ad program awareness is low, but opportunity exists to solicit assistance from health care professionals and to help health care professionals recognize false and misleading advertising. Nurse practitioners and physician assistants are perhaps the most likely contributors to the program.
Garattini, Silvio; Perico, Norberto
Unfortunately, abundant examples could be given of pitfalls in the current drug development paradigm-including in the design, conduct and evaluation of phase III clinical trials. This article discusses issues of particular relevance to clinical trials in nephrology, including the inappropriate use of placebo, publication of reports that emphasize potential treatment benefits over adverse reactions, the sometimes dubious impartiality of independent guidelines, and inadequate recruitment of elderly patients. This Perspectives article aims to highlight and summarize the flaws in the current drug development process, while suggesting a way forward that equally satisfies the requirements of academia, patients and the pharmaceutical industry. We suggest improvements to the drug development process and related legislation that intend to balance public needs with commercial aims and ensure effective drug evaluation by regulatory authorities.
Hollingsworth, Simon J
A rapid expansion in precision medicine founded on the potential for durable clinical benefit through matching a drug to a predictive marker used to select patients has driven the development of targeted drugs with accompanied companion diagnostics for patient selection. Oncology has been at the forefront, with the improvements in patient survival notable. Increasing numbers of molecular subgroups require an equally increasing number (and new generation) of highly selective agents targeting inevitably lower incidence molecular segments, posing significant challenges for drug development. Innovative trial designs (umbrella or basket studies) are emerging as patient-centric approaches and public-private partnerships, cross-industry, government and non-profit sector collaborations are enabling implementation. Success will require continued innovation, new paradigms in oncology drug development and market approval and continued collaboration.
Berlin, Jesse A; Glasser, Susan C; Ellenberg, Susan S
Premarketing studies of drugs, although large enough to demonstrate efficacy and detect common adverse events, cannot reliably detect an increased incidence of rare adverse events or events with significant latency. For most drugs, only about 500 to 3000 participants are studied, for relatively short durations, before a drug is marketed. Systems for assessment of postmarketing adverse events include spontaneous reports, computerized claims or medical record databases, and formal postmarketing studies. We briefly review the strengths and limitations of each. Postmarketing surveillance is essential for developing a full understanding of the balance between benefits and adverse effects. More work is needed in analysis of data from spontaneous reports of adverse effects and automated databases, design of ad hoc studies, and design of economically feasible large randomized studies.
Jonsson, Bertil; Bergh, Jonas
Between January 2001 and January 2012, 48 new medicinal products for cancer treatment were licensed within the EU, and 77 new indications were granted for products already licensed. In some cases, a major improvement to existing therapies was achieved, for example, trastuzumab in breast cancer. In other cases, new fields for effective drug therapy opened up, such as in chronic myeloid leukemia, and renal-cell carcinoma. In most cases, however, the benefit-risk balance was considered to be only borderline favorable. Based on our assessment of advice procedures for marketing authorization, 'need for speed' seems to be the guiding principle in anticancer drug development. Although, for drugs that make a difference, early licensure is of obvious importance to patients, this is less evident in the case of borderline drugs. Without proper incentives and with hurdles inside and outside companies, a change in drug development cannot be expected; drugs improving benefit-risk modestly over available therapies will be brought forward towards licensure. In this Perspectives article, we discuss some hurdles to biomarker-driven drug development and provide some suggestions to overcome them.
Fridlyand, Jane; Yeh, Ru-Fang; Mackey, Howard; Bengtsson, Thomas; Delmar, Paul; Spaniolo, Greg; Lieberman, Grazyna
In the past decade, the cost of drug development has increased significantly. The estimates vary widely but frequently quoted numbers are staggering-it takes 10-15 years and billions of dollars to bring a drug to patients. To a large extent this is due to many long, expensive and ultimately unsuccessful drug trials. While one approach to combat the low yield on investment could be to continue searching for new blockbusters, an alternative method would lead us to focus on testing new targeted treatments that have a strong underlying scientific rationale and are more likely to provide enhanced clinical benefit in population subsets defined by molecular diagnostics. Development of these new treatments, however, cannot follow the usual established path; new strategies and approaches are required for the co-development of novel therapeutics and the diagnostic. In this paper we will review, from the point of view of industry, the approaches to, and challenges of drug development strategies incorporating predictive biomarkers into clinical programs. We will outline the basic concepts behind co-development with predictive biomarkers and summarize the current regulatory paradigm. We will present guiding principles of personalized health care (PHC) development and review the statistical, strategic, regulatory and operational challenges that statisticians regularly encounter on development programs with a PHC component. Some practical recommendations for team statisticians involved in PHC drug development are included. The majority of the examples and recommendations are drawn from oncology but broader concepts apply across all therapeutic areas.
Chatelain, Eric; Ioset, Jean-Robert
New models of drug discovery have been developed to overcome the lack of modern and effective drugs for neglected diseases such as human African trypanosomiasis (HAT; sleeping sickness), leishmaniasis, and Chagas disease, which have no financial viability for the pharmaceutical industry. With the purpose of combining the skills and research capacity in academia, pharmaceutical industry, and contract researchers, public-private partnerships or product development partnerships aim to create focused research consortia that address all aspects of drug discovery and development. These consortia not only emulate the projects within pharmaceutical and biotechnology industries, eg, identification and screening of libraries, medicinal chemistry, pharmacology and pharmacodynamics, formulation development, and manufacturing, but also use and strengthen existing capacity in disease-endemic countries, particularly for the conduct of clinical trials. The Drugs for Neglected Diseases initiative (DNDi) has adopted a model closely related to that of a virtual biotechnology company for the identification and optimization of drug leads. The application of this model to the development of drug candidates for the kinetoplastid infections of HAT, Chagas disease, and leishmaniasis has already led to the identification of new candidates issued from DNDi's own discovery pipeline. This demonstrates that the model DNDi has been implementing is working but its DNDi, neglected diseases sustainability remains to be proven.
Fenichel, Robert R.; Malik, Marek; Antzelevitch, Charles; Sanguinetti, Michael; Roden, Dan M.; Priori, Silvia G.; Ruskin, Jeremy N.; Lipicky, Raymond J.; Cantilena, Lou
Torsade de pointes is a potentially lethal arrhythmia that occasionally appears as an adverse effect of pharmacotherapy. Recently-developed understanding of the underlying electrophysiology allows better estimation of the drug-induced risks, and explains the failures of older approaches through the surface electrocardiogram. The article expresses a consensus reached by an independent academic task force on the physiologic understanding of drug-induced repolarisation changes, on their preclinical and clinical evaluation, and on the risk-benefit interpretation of drug-induced torsade de pointes. The consensus of the task force includes suggestions on how to evaluate the risk of torsade within drug development program. Individual sections of the text discuss the techniques and limitations of methods directed at drug-related ion-channel phenomena, investigations aimed at action potentials changes, preclinical studies of phenomena seen only in the whole (or nearly whole) heart, and at interpretation of human electrocardiograms obtained in clinical studies. Final section of the text discusses drug-induced torsade within the larger evaluation of drug-related risks and benefits. PMID:15090000
Maunder, Eleni M. W.; Nel, Johanna H.; Steyn, Nelia P.; Kruger, H. Salome; Labadarios, Demetre
Objective The objective of this study was to determine the relationship between added sugar and dietary diversity, micronutrient intakes and anthropometric status in a nationally representative study of children, 1–8.9 years of age in South Africa. Methods Secondary analysis of a national survey of children (weighted n = 2,200; non weighted n = 2818) was undertaken. Validated 24-hour recalls of children were collected from mothers/caregivers and stratified into quartiles of percentage energy from added sugar (% EAS). A dietary diversity score (DDS) using 9 food groups, a food variety score (FVS) of individual food items, and a mean adequacy ratio (MAR) based on 11 micronutrients were calculated. The prevalence of stunting and overweight/obesity was also determined. Results Added sugar intake varied from 7.5–10.3% of energy intake for rural and urban areas, respectively. Mean added sugar intake ranged from 1.0% of energy intake in Quartile 1 (1–3 years) (Q1) to 19.3% in Q4 (4–8 years). Main sources of added sugar were white sugar (60.1%), cool drinks (squash type) (10.4%) and carbonated cool drinks (6.0%). Added sugar intake, correlated positively with most micronutrient intakes, DDS, FVS, and MAR. Significant negative partial correlations, adjusted for energy intake, were found between added sugar intake and intakes of protein, fibre, thiamin, pantothenic acid, biotin, vitamin E, calcium (1–3 years), phosphorus, iron (4–8 years), magnesium and zinc. The prevalence of overweight/obesity was higher in children aged 4–8 years in Q4 of %EAS than in other quartiles [mean (95%CI) % prevalence overweight 23.0 (16.2–29.8)% in Q4 compared to 13.0 (8.7–17.3)% in Q1, p = 0.0063]. Conclusion Although DDS, FVS, MAR and micronutrient intakes were positively correlated with added sugar intakes, overall negative associations between micronutrients and added sugar intakes, adjusted for dietary energy, indicate micronutrient dilution. Overweight/obesity was
Macdonald, Judith C; Hartman, Helen; Jacobs, Ira A
Biosimilar monoclonal antibodies are being developed globally for patients with different types of solid tumors and hematologic malignancies. Applications for proposed biosimilar monoclonal antibodies are being submitted to the regulatory authorities around the world and may increase patient access to key treatment options upon approval. An understanding among stakeholders (e.g., physicians, patients and their caregivers, pharmacists, payers) of the approval criteria, as well as the similarities and differences in regulatory pathways involved in biosimilar approval in different countries, as presented in this review, will facilitate identification of high-quality, safe, monoclonal antibodies that have been developed according to strict, biosimilar regulatory standards. Further guidance and resolution of the ongoing discussions on biosimilar labeling, naming, automatic substitution, and indication extrapolation may ensure, in the future, an effective and appropriate use of biosimilar monoclonal antibodies by oncologists and other stakeholders in daily clinical practice.
Van Riet-Nales, Diana A; Kozarewicz, Piotr; Aylward, Brian; de Vries, Rutger; Egberts, Toine C G; Rademaker, Carin M A; Schobben, Alfred F A M
The availability of licensed paediatric drugs is lagging behind those for adults, and there is a lack of safe formulations in suitable doses that children are able and willing to take. As a consequence, children are commonly treated with off-label or unlicensed drugs. As off-label and unlicensed drug use are associated with a greater risk for harm than on-label drug use, a range of global initiatives have been developed to realize "better" medicines for children. This review describes the challenges and achievements of the European Union to realize this goal, with a focus on paediatric drug development and formulation design. In 2007, a European Paediatric Regulation was installed enforcing companies to consider children in the early development of drugs with a new drug substance, for a new indication or with a new route of administration. The Regulation, e.g. requires companies to develop a paediatric investigation plan discussing the proposed clinical trials in children of different ages and the formulations for future marketing. Since 2013, the pharmaceutical design of any newly marketed paediatric drug should comply with the "Guideline on the Pharmaceutical Development of Medicines for Paediatric Use." Companies should, e.g. justify the route of administration, dosage form, formulation characteristics, safety of excipients, dosing frequency, container closure system, administration device, patient acceptability and user information. In this review, the guideline's key aspects are discussed with a focus on novel formulations such as mini-tablets and orodispersible films, excipients with a potential risk for harm such as azo dyes and adequate user instructions.
Bakkar, Nadine; Boehringer, Ashley; Bowser, Robert
The past decade has seen a dramatic increase in the discovery of candidate biomarkers for ALS. These biomarkers typically can either differentiate ALS from control subjects or predict disease course (slow versus fast progression). At the same time, late-stage clinical trials for ALS have failed to generate improved drug treatments for ALS patients. Incorporation of biomarkers into the ALS drug development pipeline and the use of biologic and/or imaging biomarkers in early- and late-stage ALS clinical trials have been absent and only recently pursued in early-phase clinical trials. Further clinical research studies are needed to validate biomarkers for disease progression and develop biomarkers that can help determine that a drug has reached its target within the central nervous system. In this review we summarize recent progress in biomarkers across ALS model systems and patient population, and highlight continued research directions for biomarkers that stratify the patient population to enrich for patients that may best respond to a drug candidate, monitor disease progression and track drug responses in clinical trials. It is crucial that we further develop and validate ALS biomarkers and incorporate these biomarkers into the ALS drug development process. This article is part of a Special Issue entitled ALS complex pathogenesis.
Buckner, Frederick S.; Navabi, Nazlee
Purpose of Review The need for better drugs to treat patients with Chagas disease remains urgent. This review summarizes the advancements in drug development over the past two years. Recent Findings Drug development efforts are almost exclusively occurring as preclinical research. The exceptions being Phase I safety studies for the cruzain inhibitor, K-777, and potential Phase II studies for the antifungal drug, posaconazole, and a prodrug of ravuconazole. Several recent laboratory investigations demonstrate anti-T. cruzi activity of novel small molecules in animal models. These include nonpeptidic cruzain inhibitors, novel inhibitors of the sterol 14α-demethylase enzyme, new compounds (arylimidamides) related to pentamidine, derivatives of nifurtimox, compounds using ruthenium complexes, and several natural products. The recent implementation of a high-throughput screen of >300,000 compounds against intracellular T. cruzi amastigotes done at the Broad Institute is an important development, yielding ~300 selective inhibitors, many of which may serve as leads for medicinal chemistry efforts. Summary Progress is slow, but recent advancements in both drug development and advocacy for research on neglected diseases are encouraging. Efforts to define a target product profile and to harmonize methodologies for testing drugs for Chagas disease are described herein. PMID:20885320
Mozley, P David
The specific aim of this review is to assess the potential contribution of single photon emitting radiopharmaceutical technologies to new drug development. For each phase of therapeutic drug development, published literature was sought that shows single photon emitters can add value by quantifying pharmacokinetics, visualizing mechanisms of drug action, estimating therapeutic safety indices, or measuring dose-dependent pharmacodynamic effects. Not any published reports were found that describe using nuclear medicine techniques to help manage the progress of a new drug development program. As a consequence, most of the case in favor of weaving single photon imaging into the process had to be built on extrapolations from studies that showed feasibility post hoc. The strongest evidence of potential value was found for drug candidates that hope to influence diseases characterized by cell proliferation or cell death, particularly in the fields of oncology, cardiology, nephrology, and inflammation. Receptor occupancy studies were observed to occasionally offer unique advantages over analogous studies with positron emission tomography (PET). Enough hard data sets were found to justify the costs of using single photon imaging in a variety of new drug development paradigms.
The interaction of pathogens and its hosts causes a drastic change in the transcriptional landscape in both cells. Among the several mechanisms of gene regulation, transcriptional initiation is probably the main point. In such scenario, the access of transcriptional machinery to promoter is highly regulated by post-translational modification of histones, such as acetylation, phosphorylation and others. Inhibition of histone deacetylases is able to reduce fungal pathogens fitness during infection and, therefore, is currently being considered for the development of new antifungal therapy strategies. PMID:26151486
Adams, David J
The past decade has seen an explosion in our understanding of cancer biology and with it many new potential disease targets. Nonetheless, our ability to translate these advances into therapies is poor, with a failure rate approaching 90%. Much discussion has been devoted to this so-called 'Valley of Death' in anticancer drug development, but the problem persists. Could we have overlooked some straightforward explanations to this highly complex problem? Important aspects of tumor physiology, drug pharmacokinetics, preclinical models, drug delivery, and clinical translation are not often emphasized, but could be crucial. This perspective summarizes current views on the problem and suggests feasible alternatives.
Li, Jing; Yu, Fei; Chen, Yi; Oupický, David
Synthetic polymers play a critical role in pharmaceutical discovery and development. Current research and applications of pharmaceutical polymers are mainly focused on their functions as excipients and inert carriers of other pharmacologically active agents. This review article surveys recent advances in alternative pharmaceutical use of polymers as pharmacologically active agents known as polymeric drugs. Emphasis is placed on the benefits of polymeric drugs that are associated with their macromolecular character and their ability to explore biologically relevant multivalency processes. We discuss the main therapeutic uses of polymeric drugs as sequestrants, antimicrobials, antivirals, and anticancer and anti-inflammatory agents. PMID:26410809
Johnston, Tom H; Brotchie, Jonathan M
Pharmacological treatment of Parkinson's disease (PD) is entering a new and exciting era. Real promise now exists for the clinical application of a large range of molecules in development that will combat different aspects and stages of the condition. These include methyl- and ethyl-esterified forms of L-dopa (etilevodopa and melevodopa), inhibitors of enzymes such as monoamine oxidase type-B (eg, rasagiline), catechol-O-methyl transferase (eg, BIA-3202) and the monoamine re-uptake mechanism (eg, brasofensine). In addition, a range of full and partial dopamine agonists (eg, sumanirole, piribedil and BP-897) and their new formulations, for example, patch delivery systems (eg, rotigotine) are being developed. We also highlight non-dopaminergic treatments that will have wide ranging applications in the treatment of PD and L-dopa-induced dyskinesia. These include alpha2 adrenergic receptor antagonists (eg, fipamezole), adenosine A2A receptor antagonists (eg, istradefylline), AMPA receptor antagonists (eg, talampanel), neuronal synchronization modulators (eg, levetiracetam) and agents that interact with serotonergic systems such as 5-hydroxytryptamine (5-HT)1A agonists (eg, sarizotan) and 5-HT2A antagonists (eg, quetiapine). Lastly, we examine a growing number of neuroprotective agents that seek to halt or even reverse disease progression. These include anti-apoptotic kinase inhibitors (eg, CEP-1347), modulators of mitochondrial function (eg, creatine), growth factors (eg, leteprinim), neuroimmunophilins (eg, V-10367), estrogens (eg, MITO-4509), c-synuclein oligomerization inhibitors (eg, PAN-408) and sonic hedgehog ligands.
Malle, E; Furtmüller, P G; Sattler, W; Obinger, C
Myeloperoxidase (MPO), a member of the haem peroxidase-cyclooxygenase superfamily, is abundantly expressed in neutrophils and to a lesser extent in monocytes and certain type of macrophages. MPO participates in innate immune defence mechanism through formation of microbicidal reactive oxidants and diffusible radical species. A unique activity of MPO is its ability to use chloride as a cosubstrate with hydrogen peroxide to generate chlorinating oxidants such as hypochlorous acid, a potent antimicrobial agent. However, evidence has emerged that MPO-derived oxidants contribute to tissue damage and the initiation and propagation of acute and chronic vascular inflammatory disease. The fact that circulating levels of MPO have been shown to predict risks for major adverse cardiac events and that levels of MPO-derived chlorinated compounds are specific biomarkers for disease progression, has attracted considerable interest in the development of therapeutically useful MPO inhibitors. Today, detailed information on the structure of ferric MPO and its complexes with low- and high-spin ligands is available. This, together with a thorough understanding of reaction mechanisms including redox properties of intermediates, enables a rationale attempt in developing specific MPO inhibitors that still maintain MPO activity during host defence and bacterial killing but interfere with pathophysiologically persistent activation of MPO. The various approaches to inhibit enzyme activity of MPO and to ameliorate adverse effects of MPO-derived oxidants will be discussed. Emphasis will be put on mechanism-based inhibitors and high-throughput screening of compounds as well as the discussion of physiologically useful HOCl scavengers.
Goswami, Dipanjan; Gurule, Sanjay; Lahiry, Abhiroop; Anand, Amit; Khuroo, Arshad; Monif, Tausif
Background: A novel and accurate high-throughput tandem mass spectroscopic method has been developed and validated for determination of imatinib, a protein-tyrosine kinase inhibitor against chronic myeloid leukemia. Materials & methods: Chromatographic separation was carried on XTerra® RP18 column (150 mm × 4.6 mm, 5 µm particle size) manufactured by Waters Corporation, MA, USA. The detection was performed on a triple quadruple tandem mass spectrometer by multiple reactions monitoring mode via electrospray ionization source. Results: The selective and sensitive method was linear in the concentration range of 9.57–4513.29 ng/ml and reported no matrix effect. Conclusion: The mean Cmax was found to be 10–15% lower in European subjects as compared with Indian subjects. PMID:28031942
Gong, Xing; Li, Rui; Sun, Maozhou; Ren, Qisen; Liu, Tong; Short, Michael P.
Accelerator-driven systems (ADS) are a promising approach for nuclear waste disposal. Nevertheless, the principal candidate materials proposed for ADS construction, such as the ferritic/martensitic steel, T91, and austenitic stainless steels, 316L and 15-15Ti, are not fully compatible with the liquid lead-bismuth eutectic (LBE) coolant. Under some operating conditions, liquid metal embrittlement (LME) or liquid metal corrosion (LMC) may occur in these steels when exposed to LBE. These environmentally-induced material degradation effects pose a threat to ADS reactor safety, as failure of the materials could initiate a severe accident, in which fission products are released into the coolant. Meanwhile, parallel efforts to develop accident-tolerant fuels (ATF) in light water reactors (LWRs) could provide both general materials design philosophies and specific material solutions to the ADS program. In this paper, the potential contributions of the ATF materials development program to the ADS materials qualification program are evaluated and discussed in terms of service conditions and materials performance requirements. Several specific areas where coordinated development may benefit both programs, including composite materials and selected coatings, are discussed.
Yerragunta, Bhanusree; Jogala, Satheesh; Chinnala, Krishna Mohan; Aukunuru, Jithan
Objective: The purpose of this study was to develop an ideal microsphere formulation of risperidone that would prolong the drug release for 3 months in vivo and avoid the need for co-administration of oral tablets. Materials and Methods: Polycaprolactones (PCL) were used as polymers to prepare microspheres. The research included screening and optimizing of suitable commercial polymers of variable molecular weights: PCL-14000, PCL-45000, PCL-80000 or the blends of these polymers to prepare microspheres with zero-order drug-releasing properties without the lag phase. In the present study, the sustained release risperidone microspheres were prepared by o/w emulsion solvent evaporation technique and the yield was determined. Microspheres were evaluated for their drug content and in vitro drug release. Microspheres prepared using a blend of PCL-45000 and PCL-80000 at a ratio of 1:1 resulted in the release of the drug in a time frame of 90 days, demonstrated zero-order drug release without lag time and burst release. This formulation was considered optimized formulation. Optimized formulation was characterized for solid state of the drug using differential scanning calorimetry, surface morphology using scanning electron microscopy and in vivo drug release in rats. Results: The surface of the optimized formulation was smooth, and the drug changed its physical form in the presence of blends of polymers and upon fabrication of microspheres. The optimized formulation also released the drug in vivo for a period of 90 days. Conclusions: From our study, it was concluded that these optimized microspheres showed great potential for a better depot preparation than the marketed Risperdal Consta™ and, therefore, could further improve patient compliance. PMID:25709335
Zhuang, Xiaomei; Lu, Chuang
Physiologically based pharmacokinetic (PBPK) modeling and simulation can be used to predict the pharmacokinetic behavior of drugs in humans using preclinical data. It can also explore the effects of various physiologic parameters such as age, ethnicity, or disease status on human pharmacokinetics, as well as guide dose and dose regiment selection and aid drug-drug interaction risk assessment. PBPK modeling has developed rapidly in the last decade within both the field of academia and the pharmaceutical industry, and has become an integral tool in drug discovery and development. In this mini-review, the concept and methodology of PBPK modeling are briefly introduced. Several case studies were discussed on how PBPK modeling and simulation can be utilized through various stages of drug discovery and development. These case studies are from our own work and the literature for better understanding of the absorption, distribution, metabolism and excretion (ADME) of a drug candidate, and the applications to increase efficiency, reduce the need for animal studies, and perhaps to replace clinical trials. The regulatory acceptance and industrial practices around PBPK modeling and simulation is also discussed.
Li, Edward; Subramanian, Janakiraman; Anderson, Scott; Thomas, Dolca; McKinley, Jason; Jacobs, Ira A
Acute and chronic shortages of various pharmaceuticals and particularly of sterile injectable products are being reported on a global scale, prompting evaluation of more effective strategies to manage current shortages and development of new, high-quality pharmaceutical products to mitigate the risk of potential future shortages. Oncology drugs such as liposomal doxorubicin and 5-fluorouracil represent examples of first-choice drugs critically affected by shortages. Survey results indicate that the majority of hospitals and practicing oncologists have experienced drug shortages, which may have compromised patient safety and clinical outcomes, and increased health care costs, due to delays or changes in treatment regimens. Clinical trials evaluating novel agents in combination with standard-of-care drugs are also being affected by drug shortages. Clinical and ethical considerations on treatment objectives, drug indication, and availability of alternative options may help in prioritizing cancer patients involved in active drug shortages. The United States Food and Drug Administration and the European Medicines Agency have identified manufacturing problems, delays in supply, and lack of available active ingredients as the most frequent causes of recent or ongoing drug shortages, and have released specific guidance to monitor, manage, and reduce the risk of shortages. The upcoming loss of exclusivity for a number of anticancer biologics, together with the introduction of an abbreviated approval pathway for biosimilars, raises the question of whether these products will be vulnerable to shortages. Future supply by reliable manufacturers of well characterized biosimilar monoclonal antibodies, developed in compliance with regulatory and manufacturing guidelines and with substantial investments, may contribute to prevent future biologics shortages and ensure access to effective and safe treatment options for patients with cancer. Preclinical and clinical characterization
Tripp, Gail; Wickens, Jeff
Attention deficit hyperactivity disorder (ADHD) presents special challenges for drug development. Current treatment with psychostimulants and nonstimulants is effective, but their mechanism of action beyond the cellular level is incompletely understood. We review evidence suggesting that altered reinforcement mechanisms are a fundamental characteristic of ADHD. We show that a deficit in the transfer of dopamine signals from established positive reinforcers to cues that predict such reinforcers may underlie these altered reinforcement mechanisms, and in turn explain key symptoms of ADHD. We argue that the neural substrates controlling the excitation and inhibition of dopamine neurons during the transfer process are a promising target for future drug development. There is a need to develop animal models and behavioral paradigms that can be used to experimentally investigate these mechanisms and their effects on sensitivity to reinforcement. More specific and selective targeting of drug development may be possible through this approach.
AD______________ AWARD NUMBER: W81XWH-13-1-0379 TITLE: The Stromal Contribution to the Development of Resistance to New-Generation Drugs by...Generation Drugs by Castration-Resistant Prostate Cancer 5b. GRANT NUMBER W81XWH-13-1-0379 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) Lubik, Amy Anne, PhD 5d...supports renewed activity of the androgen receptor (AR) in tumor cells thus enabling tumor re-growth(3). While new generation of drugs (abiraterone [abi] or
Heath, James R; Ribas, Antoni; Mischel, Paul S
The genetic, functional or compositional heterogeneity of healthy and diseased tissues presents major challenges in drug discovery and development. Such heterogeneity hinders the design of accurate disease models and can confound the interpretation of biomarker levels and of patient responses to specific therapies. The complex nature of virtually all tissues has motivated the development of tools for single-cell genomic, transcriptomic and multiplex proteomic analyses. Here, we review these tools and assess their advantages and limitations. Emerging applications of single cell analysis tools in drug discovery and development, particularly in the field of oncology, are discussed.
Marrer, Estelle; Dieterle, Frank
Drug safety has always been a key aspect of drug development. Recently, the Vioxx case and several cases of serious adverse events being linked to high-profile products have increased the importance of drug safety, especially in the eyes of drug development companies and global regulatory agencies. Safety biomarkers are increasingly being seen as helping to provide the clarity, predictability, and certainty needed to gain confidence in decision making: early-stage projects can be stopped quicker, late-stage projects become less risky. Public and private organizations are investing heavily in terms of time, money and manpower on safety biomarker development. An illustrative and 'door opening' safety biomarker success story is the recent recognition of kidney safety biomarkers for pre-clinical and limited translational contexts by FDA and EMEA. This milestone achieved for kidney biomarkers and the 'know how' acquired is being transferred to other organ toxicities, namely liver, heart, vascular system. New technologies and molecular-based approaches, i.e., molecular pathology as a complement to the classical toolbox, allow promising discoveries in the safety biomarker field. This review will focus on the utility and use of safety biomarkers all along drug development, highlighting the present gaps and opportunities identified in organ toxicity monitoring. A last part will be dedicated to safety biomarker development in general, from identification to diagnostic tests, using the kidney safety biomarkers success as an illustrative example.
Prausnitz, Mark R.; Bommarius, Andreas S.
We developed a new interdisciplinary course on pharmaceuticals to address needs of undergraduate and graduate students in chemical engineering and other departments. This course introduces drug design, development, and delivery in an integrated fashion that provides scientific depth in context with broader impacts in business, policy, and ethics.…
O'Connor, Patrick J.
This study reports the results on the needs of an emerging population of Career-Technical Education (CTE) teachers in Ohio. The purposes of the study were to determine the needs of the teachers and the effectiveness of the teacher education program they completed to add the CTE license. Twenty six academic teachers added a CTE license through a…
Isenberg, Eric; Walsh, Elias
We outline the options available to policymakers for addressing co-teaching in a value-added model. Building on earlier work, we propose an improvement to a method of accounting for co-teaching that treats co-teachers as teams, with each teacher receiving equal credit for co-taught students. Hock and Isenberg (2012) described a method known as the…
Roskos, Kathleen A.; Sullivan, Shannon; Simpson, Danielle; Zuzolo, Nicole
Using a theory of affordances, this study examines the introduction of e-books into the early literacy environment as resources that can increase children's opportunity for learning vocabulary. Added value was observed under conditions of (1) book browsing, (2) instruction, and (3) a print-only condition. A total of 33 4-year-olds (18 boys, 15…
Mooij, Miriam G; Nies, Anne T; Knibbe, Catherijne A J; Schaeffeler, Elke; Tibboel, Dick; Schwab, Matthias; de Wildt, Saskia N
Membrane transporters play an essential role in the transport of endogenous and exogenous compounds, and consequently they mediate the uptake, distribution, and excretion of many drugs. The clinical relevance of transporters in drug disposition and their effect in adults have been shown in drug-drug interaction and pharmacogenomic studies. Little is known, however, about the ontogeny of human membrane transporters and their roles in pediatric pharmacotherapy. As they are involved in the transport of endogenous substrates, growth and development may be important determinants of their expression and activity. This review presents an overview of our current knowledge on human membrane transporters in pediatric drug disposition and effect. Existing pharmacokinetic and pharmacogenetic data on membrane substrate drugs frequently used in children are presented and related, where possible, to existing ex vivo data, providing a basis for developmental patterns for individual human membrane transporters. As data for individual transporters are currently still scarce, there is a striking information gap regarding the role of human membrane transporters in drug therapy in children.
Small organic molecules, including small molecule based fluorescent probes, small molecule based drugs or prodrugs, and smart multifunctional fluorescent drug delivery systems play important roles in biological research, drug discovery, and clinical practices. Despite the significant progress made in these fields, the development of novel and diverse small molecules is needed to meet various demands for research and clinical applications. My Ph.D study focuses on the development of novel functional molecules for recognition, imaging and drug release. In the first part, a turn-on fluorescent probe is developed for the detection of intracellular adenosine-5'-triphosphate (ATP) levels based on multiplexing recognitions. Considering the unique and complicated structure of ATP molecules, a fluorescent probe has been implemented with improved sensitivity and selectivity due to two synergistic binding recognitions by incorporating of 2, 2'-dipicolylamine (Dpa)-Zn(II) for targeting of phospho anions and phenylboronic acid group for cis-diol moiety. The novel probe is able to detect intracellular ATP levels in SH-SY5Y cells. Meanwhile, the advantages of multiplexing recognition design concept have been demonstrated using two control molecules. In the second part, a prodrug system is developed to deliver multiple drugs within one small molecule entity. The prodrug is designed by using 1-(2-nitrophenyl)ethyl (NPE) as phototrigger, and biphenol biquaternary ammonium as the prodrug. With controlled photo activation, both DNA cross-linking agents mechlorethamine and o-quinone methide are delivered and released at the preferred site, leading to efficient DNA cross-links formation and cell death. The prodrug shows negligible cytotoxicity towards normal skin cells (Hekn cells) with and without UV activation, but displays potent activity towards cancer cells (HeLa cells) upon UV activation. The multiple drug release system may hold a great potential for practical application. In the
Steinmetz, Karen L; Spack, Edward G
Preclinical development encompasses the activities that link drug discovery in the laboratory to initiation of human clinical trials. Preclinical studies can be designed to identify a lead candidate from several hits; develop the best procedure for new drug scale-up; select the best formulation; determine the route, frequency, and duration of exposure; and ultimately support the intended clinical trial design. The details of each preclinical development package can vary, but all have some common features. Rodent and nonrodent mammalian models are used to delineate the pharmacokinetic profile and general safety, as well as to identify toxicity patterns. One or more species may be used to determine the drug's mean residence time in the body, which depends on inherent absorption, distribution, metabolism, and excretion properties. For drugs intended to treat Alzheimer's disease or other brain-targeted diseases, the ability of a drug to cross the blood brain barrier may be a key issue. Toxicology and safety studies identify potential target organs for adverse effects and define the Therapeutic Index to set the initial starting doses in clinical trials. Pivotal preclinical safety studies generally require regulatory oversight as defined by US Food and Drug Administration (FDA) Good Laboratory Practices and international guidelines, including the International Conference on Harmonization. Concurrent preclinical development activities include developing the Clinical Plan and preparing the new drug product, including the associated documentation to meet stringent FDA Good Manufacturing Practices regulatory guidelines. A wide range of commercial and government contract options are available for investigators seeking to advance their candidate(s). Government programs such as the Small Business Innovative Research and Small Business Technology Transfer grants and the National Institutes of Health Rapid Access to Interventional Development Pilot Program provide funding and
Kumar, Rakesh; Lal, Neena
Anti-cancer drug development is a major area of research. Monitoring of response to newer anti-cancer drugs has undergone an evolution from structural imaging modalities to targeting functional metabolic activity at cellular level to better define responsive and non-responsive cancerous tissue. This review article highlights the contribution of Positron Emission Tomography (PET) in this field. PET holds a promising role in the future by providing us information pertaining to the drugs effectiveness early in the course of therapy, so that side effects and expenses can be reduced substantially. PET has been used to measure changes in drug induced metabolism, cellular proliferation and tissue perfusion. Also changes induced by immuno-modulating drugs such as apoptosis, telomere activity, growth factor levels and many more can be studied using specific radiolabelled PET tracers whereas conventional imaging modalities which detect changes in tumor size and residual tissue histopathology may not prove useful in such scenario. In future, most PET scanners will be replaced by Hybrid PET-CT scanners, which provide functional and structural information in the same setting. In addition, PET-CT improves characterization of equivocal lesions and decreases interobserver variability. The most important recent patents concerning role of PET in drug development have been presented.
One-third of the global population lacks access to medications; the situation is worse in poor countries, where up to 50% of the population lacks access. The failure of current incentive systems based in intellectual property to offer the necessary pharmaceutical products, especially in the global south, is a call to action. Problems related to drug access cannot be solved solely through improvements or modifications in the existing incentive models. The intellectual property system model does not offer sufficient innovation for developing countries; new mechanisms that effectively promote innovation and drug access simultaneously are needed. A binding international agreement on research and development, negotiated under the auspices of the World Health Organization, could provide an adequate framework for guaranteeing priority-setting, coordination, and sustainable financing of drugs at reasonable prices for developing countries.
Under the Biologics Price Competition and Innovation Act (BPCI Act), a biological product may be demonstrated to be “biosimilar” if data show that, among other things, the product is “highly similar” to an already-approved biological product. Biosimilar insulins have the potential to reduce ever growing costs associated with insulin treatment by allowing competition. In this article, we describe the current drug development and regulatory paths for biosimilar insulins. Most likely basis of market approval for biosimilar insulins by the US Food and Drug Administration (FDA) and guidance for developing insulin biosimilars by European Medicines Agency (EMA) are discussed in detail. Currently, no product specific biosimilar FDA guidance for insulin biosimilarity assessment exists. We propose efficient and cost-effective drug development and potential regulatory paths based on scientific justification. In addition, novel trial designs for demonstrating interchangeability between the biosimilar and the reference insulin products are presented. PMID:24876531
Ho, Dean; Wang, Chung-Huei Katherine; Chow, Edward Kai-Hua
The implementation of nanomedicine in cellular, preclinical, and clinical studies has led to exciting advances ranging from fundamental to translational, particularly in the field of cancer. Many of the current barriers in cancer treatment are being successfully addressed using nanotechnology-modified compounds. These barriers include drug resistance leading to suboptimal intratumoral retention, poor circulation times resulting in decreased efficacy, and off-target toxicity, among others. The first clinical nanomedicine advances to overcome these issues were based on monotherapy, where small-molecule and nucleic acid delivery demonstrated substantial improvements over unmodified drug administration. Recent preclinical studies have shown that combination nanotherapies, composed of either multiple classes of nanomaterials or a single nanoplatform functionalized with several therapeutic agents, can image and treat tumors with improved efficacy over single-compound delivery. Among the many promising nanomaterials that are being developed, nanodiamonds have received increasing attention because of the unique chemical-mechanical properties on their faceted surfaces. More recently, nanodiamond-based drug delivery has been included in the rational and systematic design of optimal therapeutic combinations using an implicitly de-risked drug development platform technology, termed Phenotypic Personalized Medicine–Drug Development (PPM-DD). The application of PPM-DD to rapidly identify globally optimized drug combinations successfully addressed a pervasive challenge confronting all aspects of drug development, both nano and non-nano. This review will examine various nanomaterials and the use of PPM-DD to optimize the efficacy and safety of current and future cancer treatment. How this platform can accelerate combinatorial nanomedicine and the broader pharmaceutical industry toward unprecedented clinical impact will also be discussed. PMID:26601235
Brooks, W H; Guida, W C; Daniel, K G
Proteins are often enantioselective towards their binding partners. When designing small molecules to interact with these targets, one should consider stereoselectivity. As considerations for exploring structure space evolve, chirality is increasingly important. Binding affinity for a chiral drug can differ for diastereomers and between enantiomers. For the virtual screening and computational design stage of drug development, this problem can be compounded by incomplete stereochemical information in structure libraries leading to a "coin toss" as to whether or not the "ideal" chiral structure is present. Creating every stereoisomer for each chiral compound in a structure library leads to an exponential increase in the number of structures resulting in potentially unmanageable file sizes and screening times. Therefore, only key chiral structures, enantiomeric pairs based on relative stereochemistry need be included, and lead to a compromise between exploration of chemical space and maintaining manageable libraries. In clinical environments, enantiomers of chiral drugs can have reduced, no, or even deleterious effects. This underscores the need to avoid mixtures of compounds and focus on chiral synthesis. Governmental regulations emphasizing the need to monitor chirality in drug development have increased. The United States Food and Drug Administration issued guidelines and policies in 1992 concerning the development of chiral compounds. These guidelines require that absolute stereochemistry be known for compounds with chiral centers and that this information should be established early in drug development in order that the analysis can be considered valid. From exploration of structure space to governmental regulations it is clear that the question of chirality in drug design is of vital importance.
All, Anissa; Van Looy, Jan; Castellar, Elena Patricia Nuñez
This study explores the added value of co-design in addition to other innovation research methods in the process of developing a serious game design document for a road safety game. The sessions aimed at exploring 4 aspects of a location-based game experience: themes, game mechanics, mobile phone applications and locations for mini-games. In…
Tsaioun, Katya; Bottlaender, Michel; Mabondzo, Aloise
The advent of early absorption, distribution, metabolism, excretion, and toxicity (ADMET) screening has increased the attrition rate of weak drug candidates early in the drug-discovery process, and decreased the proportion of compounds failing in clinical trials for ADMET reasons. This paper reviews the history of ADMET screening and its place in pharmaceutical development, and central nervous system drug discovery in particular. Assays that have been developed in response to specific needs and improvements in technology that result in higher throughput and greater accuracy of prediction of human mechanisms of absorption and toxicity are discussed. The paper concludes with the authors' forecast of new models that will better predict human efficacy and toxicity. PMID:19534730
Frederick, Aliya L; Stanwood, Gregg D
Defects in the development of the brain have a profound impact on mature brain functions and underlying psychopathology. Classical neurotransmitters and neuromodulators, such as dopamine, serotonin, norepinephrine, acetylcholine, glutamate and GABA, have pleiotropic effects during brain development. In other words, these molecules produce multiple diverse effects to serve as regulators of distinct cellular functions at different times in neurodevelopment. These systems are impacted upon by abuse of a variety of illicit drugs, neurotherapeutics and environmental contaminants. In this review, we describe the impact of drugs and chemicals on brain formation and function in animal models and in human populations, highlighting sensitive periods and effects that may not emerge until later in life.
Roiser, Jonathan P.; Nathan, Pradeep J.; Mander, Adrian P.; Adusei, Gabriel; Zavitz, Kenton H.; Blackwell, Andrew D.
Cognitive impairment is increasingly recognised as an important potential adverse effect of medication. However, many drug development programmes do not incorporate sensitive cognitive measurements. Here, we review the rationale for cognitive safety assessment, and explain several basic methodological principles for measuring cognition during clinical drug development, including study design and statistical analysis, from Phase I through to postmarketing. The crucial issue of how cognition should be assessed is emphasized, especially the sensitivity of measurement. We also consider how best to interpret the magnitude of any identified effects, including comparison with benchmarks. We conclude by discussing strategies for the effective communication of cognitive risks. PMID:26610416
Hmed, Bennasr; Serria, Hammami Turky; Mounir, Zeghal Khaled
Several peptides contained in scorpion fluids showed diverse array of biological activities with high specificities to their targeted sites. Many investigations outlined their potent effects against microbes and showed their potential to modulate various biological mechanisms that are involved in immune, nervous, cardiovascular, and neoplastic diseases. Because of their important structural and functional diversity, it is projected that scorpion-derived peptides could be used to develop new specific drugs. This review summarizes relevant findings improving their use as valuable tools for new drugs development.
Kraus, Carl N
Cost estimates for developing new molecular entities (NME) are reaching non-sustainable levels and coupled with increasing regulatory requirements and oversight have led many pharmaceutical sponsors to divest their anti-microbial development portfolios [Projan SJ: Why is big Pharma getting out of anti-bacterial drug discovery?Curr Opin Microbiol 2003, 6:427-430] [Spellberg B, Powers JH, Brass EP, Miller LG, Edwards JE, Jr: Trends in antimicrobial drug development: implications for the future.Clin Infect Dis 2004, 38:1279-1286]. Operational issues such as study planning and execution are significant contributors to the overall cost of drug development that can benefit from the leveraging of pre-randomization data in an evidence-based approach to protocol development, site selection and patient recruitment. For non-NME products there is even greater benefit from available data resources since these data may permit smaller and shorter study programs. There are now many available open source intelligence (OSINT) resources that are being integrated into drug development programs, permitting an evidence-based or 'operational epidemiology' approach to study planning and execution.
Vaz, Julius A; Patnaik, Ashis
Diabetes mellitus has reached epidemic proportions and continues to be a major burden on society globally. The International Diabetes Federation (IDF) estimated the global burden of diabetes to be 366 million in 2011 and predicted that by 2030 this will have risen to 552 million. In spite of newer and effective treatment options, newer delivery and diagnostic devices, stricter glycaemic targets, better treatment guidelines and increased awareness of the disease, baseline glycosylated hemoglobin remains relatively high in subjects diagnosed and treated with type 2 diabetes. The search continues for an ideal anti diabetic drug that will not only normalize blood glucose but also provide beta cell rest and possibly restoration of beta cell function. The development of anti diabetic drugs is riddled with fundamental challenges. The concept of beta cell rest and restoration is yet to be completely understood and proven on a long term. The ideal therapeutic approach to treating type 2 diabetes is not yet determined. Our understanding of drug safety in early clinical development is primarily limited to "Type A" reactions. Until marketing authorization most drugs are approved based on the principle of confirming non-inferiority with an existing gold standard or determining superiority to a placebo. The need to obtain robust pharmaco-economic data prior to marketing authorization in order to determine appropriate pricing of a new drug remains a major challenge. The present review outlines some of the challenges in drug development of anti-diabetic drugs citing examples of pulmonary insulin, insulin analogues, thiazolidinediones and the GLP1 analogues.
Shaw, Daniel L.
Traditional drug development models are widely perceived as opaque and inefficient, with the cost of research and development continuing to rise even as production of new drugs stays constant. Searching for strategies to improve the drug discovery process, the biomedical research field has begun to embrace open strategies. The resulting changes are starting to reshape the industry. Open science—an umbrella term for diverse strategies that seek external input and public engagement—has become an essential tool with researchers, who are increasingly turning to collaboration, crowdsourcing, data sharing, and open sourcing to tackle some of the most pressing problems in medicine. Notable examples of such open drug development include initiatives formed around malaria and tropical disease. Open practices have found their way into the drug discovery process, from target identification and compound screening to clinical trials. This perspective argues that while open science poses some risks—which include the management of collaboration and the protection of proprietary data—these strategies are, in many cases, the more efficient and ethical way to conduct biomedical research. PMID:28356902
Ramos-Cabrer, Pedro; Campos, Francisco
Neurological diseases represent a medical, social, and economic problem of paramount importance in developed countries. Although their etiology is generally known, developing therapeutic interventions for the central nervous system is challenging due to the impermeability of the blood–brain barrier. Thus, the fight against neurological diseases usually struggles “at the gates” of the brain. Flooding the bloodstream with drugs, where only a minor fraction reaches its target therapeutic site, is an inefficient, expensive, and dangerous procedure, because of the risk of side effects at nontargeted sites. Currently, advances in the field of nanotechnology have enabled development of a generation of multifunctional molecular platforms that are capable of transporting drugs across the blood–brain barrier, targeting specific cell types or functional states within the brain, releasing drugs in a controlled manner, and enabling visualization of processes in vivo using conventional imaging systems. The marriage between drug delivery and molecular imaging disciplines has resulted in a relatively new discipline, known as theranostics, which represents the basis of the concept of personalized medicine. In this study, we review the concepts of the blood–brain barrier and the strategies used to traverse/bypass it, the role of nanotechnology in theranostics, the wide range of nanoparticles (with emphasis on liposomes) that can be used as stealth drug carriers, imaging probes and targeting devices for the treatment of neurological diseases, and the targets and targeting strategies envisaged in the treatment of different types of brain pathology. PMID:23486739
Shaw, Daniel L
Traditional drug development models are widely perceived as opaque and inefficient, with the cost of research and development continuing to rise even as production of new drugs stays constant. Searching for strategies to improve the drug discovery process, the biomedical research field has begun to embrace open strategies. The resulting changes are starting to reshape the industry. Open science-an umbrella term for diverse strategies that seek external input and public engagement-has become an essential tool with researchers, who are increasingly turning to collaboration, crowdsourcing, data sharing, and open sourcing to tackle some of the most pressing problems in medicine. Notable examples of such open drug development include initiatives formed around malaria and tropical disease. Open practices have found their way into the drug discovery process, from target identification and compound screening to clinical trials. This perspective argues that while open science poses some risks-which include the management of collaboration and the protection of proprietary data-these strategies are, in many cases, the more efficient and ethical way to conduct biomedical research.
Amarelle, Luciano; Lecuona, Emilia; Sznajder, Jacob I
Influenza is a very common contagious disease that carries significant morbidity and mortality. Treatment with antiviral drugs is available, which if administered early, can reduce the risk of severe complications. However, many virus types develop resistance to those drugs, leading to a notable loss of efficacy. There has been great interest in the development of new drugs to combat this disease. A wide range of drugs has shown anti-influenza activity, but they are not yet available for use in the clinic. Many of these target viral components, which others are aimed at elements in the host cell which participate in the viral cycle. Modulating host components is a strategy which minimizes the development of resistance, since host components are not subject to the genetic variability of the virus. The main disadvantage is the risk of treatment-related side effects. The aim of this review is to describe the main pharmacological agents currently available and new drugs in the pipeline with potential benefit in the treatment of influenza.
Declercq, Lieven D.; Vandenberghe, Rik; Van Laere, Koen; Verbruggen, Alfons; Bormans, Guy
Clinical trials aiming to develop disease-altering drugs for Alzheimer’s disease (AD), a neurodegenerative disorder with devastating consequences, are failing at an alarming rate. Poorly defined inclusion-and outcome criteria, due to a limited amount of objective biomarkers, is one of the major concerns. Non-invasive molecular imaging techniques, positron emission tomography and single photon emission (computed) tomography (PET and SPE(C)T), allow visualization and quantification of a wide variety of (patho)physiological processes and allow early (differential) diagnosis in many disorders. PET and SPECT have the ability to provide biomarkers that permit spatial assessment of pathophysiological molecular changes and therefore objectively evaluate and follow up therapeutic response, especially in the brain. A number of specific PET/SPECT biomarkers used in support of emerging clinical therapies in AD are discussed in this review. PMID:27065872
Bertucci, Carlo; Pistolozzi, Marco; De Simone, Angela
Chirality plays a fundamental role in determining the pharmacodynamic and pharmacokinetic properties of drugs, and contributes significantly to our understanding of the mechanisms that lie behind biorecognition phenomena. Circular dichroism spectroscopy is the technique of choice for determining the stereochemistry of chiral drugs and proteins, and for monitoring and characterizing molecular recognition phenomena in solution. The role of chirality in our understanding of recognition phenomena at the molecular level is discussed here via several selected systems of interest in the drug discovery and development area. The examples were selected in order to underline the utility of circular dichroism in emerging studies of protein-protein interactions in biological context. In particular, the following aspects are discussed here: the relationship between stereochemistry and pharmacological activity--stereochemical characterization of new leads and drugs; stereoselective binding of leads and drugs to target proteins--the binding of drugs to serum albumins; conformational transitions of peptides and proteins of physiological relevance, and the stereochemical characterization of therapeutic peptides.
FitzGerald, Garret A
New-drug approvals have remained roughly constant since 1950, while the cost of drug development has soared. It seems likely that a more modular approach to drug discovery and development will evolve, deriving some features from the not-for-profit sector. For this to occur, we must address the deficit in human capital with expertise in both translational medicine and therapeutics and also in regulatory science; utilize regulatory reform to incentivize innovation and the expansion of the precompetitive space; and develop an informatics infrastructure that permits the global, secure, and compliant sharing of heterogeneous data across academic and industry sectors. These developments, likely prompted by the perception of crisis rather than opportunity, will require linked initiatives among academia, the pharmaceutical industry, the US National Institutes of Health, and the US Food and Drug Administration, along with a more adventurous role for venture capital. A failure to respond threatens the United States' lead in biomedical science and in the development and regulation of novel therapeutics.
Shimizu, Yoshimi; Nagase, Shotaro; Yagi, Kiyohito; Kondoh, Masuo
Epithelium plays pivotal roles in biological barrier separating the inside of body and the outside environment. Ninety percent of malignant tumors are derived from epithelium. Most pathological microorganisms invade into the body from mucosal epithelium. Thus, epithelium is potential targets for drug development. Claudins (CLs), a family of tetra-transmembrane protein consisting of over 20 members, are structural and functional components of tight junction-seals in epithelium. Modulation of CL-seals enhanced mucosal absorption of drugs. CLs are often over-expressed in malignant tumors. CL-4 expression is increased in the epithelial cells covering the mucosal immune tissues. Very recently, CLs are also expected to be targets for traumatic brain injury and regenerative therapy. In this review, we overview the past, the present and the future of CLs-targeted drug development.
Ortiz, Ernesto; Gurrola, Georgina B; Schwartz, Elisabeth Ferroni; Possani, Lourival D
Scorpions are well known for their dangerous stings that can result in severe consequences for human beings, including death. Neurotoxins present in their venoms are responsible for their toxicity. Due to their medical relevance, toxins have been the driving force in the scorpion natural compounds research field. On the other hand, for thousands of years, scorpions and their venoms have been applied in traditional medicine, mainly in Asia and Africa. With the remarkable growth in the number of characterized scorpion venom components, several drug candidates have been found with the potential to tackle many of the emerging global medical threats. Scorpions have become a valuable source of biologically active molecules, from novel antibiotics to potential anticancer therapeutics. Other venom components have drawn attention as useful scaffolds for the development of drugs. This review summarizes the most promising candidates for drug development that have been isolated from scorpion venoms.
Sobieraj, Diana M.; White, C. Michael; Saulsberry, Whitney J.; Kohn, Christine G.; Doleh, Yunes; Zaccaro, Eric
Introduction When first line therapy with metformin is insufficient for patients with type 2 diabetes (T2D), the optimal adjunctive therapy is unclear. We assessed the efficacy and safety of adjunctive antidiabetic agents in patients with inadequately controlled T2D on metformin alone. Materials and Methods A search of MEDLINE and CENTRAL, clinicaltrials.gov, regulatory websites was performed. We included randomized controlled trials of 3–12 months duration, evaluating Food and Drug Administration or European Union approved agents (noninsulin and long acting, once daily basal insulins) in patients experiencing inadequate glycemic control with metformin monotherapy (≥1500 mg daily or maximally tolerated dose for ≥4 weeks). Random-effects network meta-analyses were used to compare the weighted mean difference for changes from baseline in HbA1c, body weight (BW) and systolic blood pressure (SBP), and the risk of developing hypoglycemia, urinary (UTI) and genital tract infection (GTI). Results Sixty-two trials evaluating 25 agents were included. All agents significantly reduced HbA1c vs. placebo; albeit not to the same extent (range, 0.43% for miglitol to 1.29% for glibenclamide). Glargine, sulfonylureas (SUs) and nateglinide were associated with increased hypoglycemia risk vs. placebo (range, 4.00–11.67). Sodium glucose cotransporter-2 (SGLT2) inhibitors, glucagon-like peptide-1 analogs, miglitol and empagliflozin/linagliptin significantly reduced BW (range, 1.15–2.26kg) whereas SUs, thiazolindinediones, glargine and alogliptin/pioglitazone caused weight gain (range, 1.19–2.44kg). SGLT2 inhibitors, empagliflozin/linagliptin, liraglutide and sitagliptin decreased SBP (range, 1.88–5.43mmHg). No therapy increased UTI risk vs. placebo; however, SGLT2 inhibitors were associated with an increased risk of GTI (range, 2.16–8.03). Conclusions Adding different AHAs to metformin was associated with varying effects on HbA1c, BW, SBP, hypoglycemia, UTI and GTI
Chau, Cindy H; Rixe, Olivier; McLeod, Howard; Figg, William D
The role of biomarkers in drug discovery and development has gained precedence over the years. As biomarkers become integrated into drug development and clinical trials, quality assurance and, in particular, assay validation become essential with the need to establish standardized guidelines for analytic methods used in biomarker measurements. New biomarkers can revolutionize both the development and use of therapeutics but are contingent on the establishment of a concrete validation process that addresses technology integration and method validation as well as regulatory pathways for efficient biomarker development. This perspective focuses on the general principles of the biomarker validation process with an emphasis on assay validation and the collaborative efforts undertaken by various sectors to promote the standardization of this procedure for efficient biomarker development.
...: Developing Drugs for Treatment; Availability AGENCY: Food and Drug Administration, HHS. ACTION: Notice... entitled ``Acute Bacterial Sinusitis: Developing Drugs for Treatment.'' This guidance addresses FDA's... an indication for the treatment of acute bacterial sinusitis (ABS). This guidance finalizes...
... Infections: Developing Drugs for Treatment; Availability AGENCY: Food and Drug Administration, HHS. ACTION... guidance for industry entitled ``Complicated Urinary Tract Infections: Developing Drugs for Treatment... treatment of complicated urinary tract infections (cUTIs). Specifically, this guidance addresses...
Gerevich, Jozsef; Bacskai, Erika
Examines the relationship of 2 dimensions of the theory of social development--vulnerability and protectivity--in 2 samples, schoolchildren aged 10 to 15 (n=1,454) and addictive drug users (n=170). Finds that the most important protective factors act against substance use. Finds that among the predictors of the addicts some forms of escape from…
Wells, Timothy N C; Willis, Paul; Burrows, Jeremy N; Hooft van Huijsduijnen, Rob
There is a growing consensus that drug discovery thrives in an open environment. Here, we describe how the malaria community has embraced four levels of open data - open science, open innovation, open access and open source - to catalyse the development of new medicines, and consider principles that could enable open data approaches to be applied to other disease areas.
Carrier, Felix; Banayan, David; Boley, Randy; Karnik, Niranjan
As the classification of mental disorders advances towards a disease model as promoted by the National Institute of Mental Health (NIMH) Research Domain Criteria (RDoC), there is hope that a more thorough neurobiological understanding of mental illness may allow clinicians and researchers to determine treatment efficacy with less diagnostic variability. This paradigm shift has presented a variety of ethical issues to be considered in the development of psychiatric drugs. These challenges are not limited to informed consent practices, industry funding, and placebo use. The consideration for alternative research models and quality of research design also present ethical challenges in the development of psychiatric drugs. The imperatives to create valid and sound research that justify the human time, cost, risk and use of limited resources must also be considered. Clinical innovation, and consideration for special populations are also important aspects to take into account. Based on the breadth of these ethical concerns, it is particularly important that scientific questions regarding the development of psychiatric drugs be answered collaboratively by a variety of stakeholders. As the field expands, new ethical considerations will be raised with increased focus on genetic markers, personalized medicine, patient-centered outcomes research, and tension over funding. We suggest that innovation in trial design is necessary to better reflect practices in clinical settings and that there must be an emphasized focus on expanding the transparency of consent processes, regard for suicidality, and care in working with special populations to support the goal of developing sound psychiatric drug therapies.
Itil, Turan M.; Itil, Kurt Z.
Quantification of standard electroencephalogram (EEG) by digital computers [computer-analyzed EEG (CEEG)] has transformed the subjective analog EEG into an objective scientific method. Until a few years ago, CEEG was only used to assist in the development of psychotropic drugs by means of the quantitative pharmaco EEG. Thanks to the computer revolution and the accompanying reductions in cost of quantification, CEEG can now also be applied in psychiatric practice. CEEG can assist the physician in confirming clinical diagnoses, selecting psychotropic drugs for treatment, and drug treatment monitoring. Advancements in communications technology allow physicians and researchers to reduce the costs of acquiring a high-technology CEEG brain mapping system by utilizing the more economical telephonic services.
Pardridge, William M
As human longevity increases, the likelihood of the onset of diseases of the brain (and other organs) also increases. Clinical therapeutics offer useful long-term treatments, if not cures, if drugs can be delivered appropriately and effectively. Unfortunately, research in drug transport to the brain has not advanced very far. Through better characterization of the transport systems utilized within the blood-brain barrier, a greater understanding of how to exploit these systems will lead to effective treatments for brain disorders. Pardridge reviews the functions of the various known transport systems in the brain and discusses how the development of BBB drug-targeting programs in pharmaceutical and academic settings may lead to more efficacious treatments.
Williams, Kevin; Bilsland, Elizabeth; Sparkes, Andrew; Aubrey, Wayne; Young, Michael; Soldatova, Larisa N; De Grave, Kurt; Ramon, Jan; de Clare, Michaela; Sirawaraporn, Worachart; Oliver, Stephen G; King, Ross D
There is an urgent need to make drug discovery cheaper and faster. This will enable the development of treatments for diseases currently neglected for economic reasons, such as tropical and orphan diseases, and generally increase the supply of new drugs. Here, we report the Robot Scientist 'Eve' designed to make drug discovery more economical. A Robot Scientist is a laboratory automation system that uses artificial intelligence (AI) techniques to discover scientific knowledge through cycles of experimentation. Eve integrates and automates library-screening, hit-confirmation, and lead generation through cycles of quantitative structure activity relationship learning and testing. Using econometric modelling we demonstrate that the use of AI to select compounds economically outperforms standard drug screening. For further efficiency Eve uses a standardized form of assay to compute Boolean functions of compound properties. These assays can be quickly and cheaply engineered using synthetic biology, enabling more targets to be assayed for a given budget. Eve has repositioned several drugs against specific targets in parasites that cause tropical diseases. One validated discovery is that the anti-cancer compound TNP-470 is a potent inhibitor of dihydrofolate reductase from the malaria-causing parasite Plasmodium vivax.
Benet, Leslie Z
Biopharmaceutics Classification System and Biopharmaceutics Drug Distribution Classification System are complimentary, not competing, classification systems that aim to improve, simplify, and speed drug development. Although both systems are based on classifying drugs and new molecular entities into four categories using the same solubility criteria, they differ in the criterion for permeability and have different purposes. Here, the details and applications of both systems are reviewed with particular emphasis of their role in drug development.
Blair, Wade; Perros, Manos
The 5th Antiviral Drug Discovery and Development Summit provided an up-to-date snapshot of the ongoing developments in the area. The topics covered ranged from updates on recently launched drugs (Kaletra), Fuzeon) and new investigational inhibitors (T-1249, Reverset, UK-427857, L-870810, PA-457, remofovir, VX-950), to the discovery of new antiviral targets and advances in technologies that may provide the substrate for the next generation of therapeutics. It is apparent from the range of presentations that much of today's efforts are focused on developing new classes of HIV inhibitors (gp41, integrase), while there is also considerable progress in hepatitis C, where a number of inhibitors have or should reach proof-of-concept studies in the coming months. Here we provide the highlights of this meeting, with particular emphasis on the new developments in HIV and hepatitis C virus.
Marsh, Eric D; Brooks-Kayal, Amy R; Porter, Brenda E
Seizures and antiepileptic drugs (AEDs) affect brain development and have long-term neurological consequences. The specific molecular and cellular changes, the precise timing of their influence during brain development, and the full extent of the long-term consequences of seizures and AEDs exposure have not been established. This review critically assesses both the basic and clinical science literature on the effects of seizures and AEDs on the developing brain and finds that evidence exists to support the hypothesis that both seizures and antiepileptic drugs influence a variety of biological process, at specific times during development, which alter long-term cognition and epilepsy susceptibility. More research, both clinical and experimental, is needed before changes in current clinical practice, based on the scientific data, can be recommended.
Mah, Robert; Thomas, Jason R; Shafer, Cynthia M
In recent years, the number of drug candidates with a covalent mechanism of action progressing through clinical trials or being approved by the FDA has increased significantly. And as interest in covalent inhibitors has increased, the technical challenges for characterizing and optimizing these inhibitors have become evident. A number of new tools have been developed to aid this process, but these have not gained wide-spread use. This review will highlight a number of methods and tools useful for prosecuting covalent inhibitor drug discovery programs.
US FDA approval of two serotonin-selective reuptake inhibitor (SSRI) agents for post-traumatic stress disorder (PTSD) has created new opportunities for drug development. This follows many years of exploring the potential utility of several classes of psychotropic agents for this very common, yet under-recognized and under-treated disorder. This review examines some of the basic neurobiological abnormalities observed in PTSD and summarizes open and controlled drug trials for major classes of medications, including SSRIs, other antidepressants, atypical neuroleptics, noradrenergic modulators and anticonvulsants, while critically evaluating the extent of effectiveness of these agents and reviewing unmet gaps in therapeutic need.
Janero, David R
Research universities continue to produce new scientists capable of generating knowledge with the potential to inform disease etiology and treatment. Mounting interest of doctoral-level experimental science students in therapeutics-related research careers is discordant with the widespread lack of direct drug-discovery and development experience, let alone commercialization success, among university faculty and administrators. Likewise, the archetypical publication- and grant-fueled, principal investigator (PI)-focused academic system ("PI-stan") risks commoditization of science students pursuing their doctorates as a labor source, rendering them ill-prepared for career options related to therapeutics innovation by marginalizing their development of "beyond-the-bench" professional skills foundational to modern drug-discovery campaigns and career fluency. To militate against professionalization deficits in doctoral drug-discovery researchers, the author--a scientist-administrator-consultant with decades of discovery research and development (R&D), business, and educator experience in commercial and university settings--posits a critical need for pluridimensionality in graduate education and mentorship that extends well beyond thesis-related scientific domains/laboratory techniques to instill transferable operational-intelligence, project/people-management, and communication competencies. Specific initiatives are advocated to help enhance the doctoral science student's market competitiveness, adaptability, and navigation of the significant research, commercial, and occupational challenges associated with contemporary preclinical drug-discovery R&D.
Thudium, Karen; Bilic, Sanela
American Association of Pharmaceutical Scientists National Biotechnology Conference Sheraton San Diego Hotel and Marina, San Diego, CA, USA, 19-23 May 2013 The National Biotechnology Conference, is a premier meeting for biotechnology professionals covering a broad range of hot topics in the biotechnology industry. Attracting participants from academia, industry and regulatory, this meeting features sessions that aim to address emerging subjects of interest and allows for open exchange between scientists. The 2013 conference featured leading researchers in the fields of antibody-drug conjugates (ADCs) and immunogenicity. Herein, we present a summary of the ADC hot topics, including bioanalytical and PK considerations, quantitative evaluation of the impact of immunogenicity and ADME to understand ADC drug-drug interactions, and clinical considerations for ADC development. This article aims to summarize the recommendations that were made by the speakers during various sessions throughout the conference.
Shafaie, Sara; Hutter, Victoria; Cook, Michael T.; Brown, Marc B.; Chau, David Y.S.
Abstract Tissue engineering is a rapidly expanding field that aims to establish feasible techniques to fabricate biologically equivalent replacements for diseased and damaged tissues/organs. Emerging from this prospect is the development of in vitro representations of organs for drug toxicity assessment. Due to the ever-increasing interest in ocular drug delivery as a route for administration as well as the rise of new ophthalmic therapeutics, there is a demand for physiologically accurate in vitro models of the eye to assess drug delivery and safety of new ocular medicines. This review summarizes current existing ocular models and highlights the important factors and limitations that need to be considered during their use. PMID:27158563
Dunlop, John; Brandon, Nicholas J
Current therapeutics for schizophrenia, the typical and atypical antipsychotic class of drugs, derive their therapeutic benefit predominantly by antagonism of the dopamine D2 receptor subtype and have robust clinical benefit on positive symptoms of the disease with limited to no impact on negative symptoms and cognitive impairment. Driven by these therapeutic limitations of current treatments and the recognition that transmitter systems beyond the dopaminergic system in particular glutamatergic transmission contribute to the etiology of schizophrenia significant recent efforts have focused on the discovery and development of novel treatments for schizophrenia with mechanisms of action that are distinct from current drugs. Specifically, compounds selectively targeting the metabotropic glutamate receptor 2/3 subtype, phosphodiesterase subtype 10, glycine transporter subtype 1 and the alpha7 nicotinic acetylcholine receptor have been the subject of intense drug discovery and development efforts. Here we review recent clinical experience with the most advanced drug candidates targeting each of these novel mechanisms and discuss whether these new agents are living up to expectations.
DiMasi, J A; Feldman, L; Seckler, A; Wilson, A
This study utilizes both public and private data sources to estimate clinical phase transition and clinical approval probabilities for drugs in the development pipelines of the 50 largest pharmaceutical firms (by sales). The study examined the development histories of these investigational compounds from the time point at which they first entered clinical testing (1993-2004) through June 2009. The clinical approval success rate in the United States was 16% for self-originated drugs (originating from the pharmaceutical company itself) during both the 1993-1998 and the 1999-2004 subperiods. For all compounds (including licensed-in and licensed-out drugs in addition to self-originated drugs), the clinical approval success rate for the entire study period was 19%. The estimated clinical approval success rates and phase transition probabilities differed significantly by therapeutic class. The estimated clinical approval success rate for self-originated compounds over the entire study period was 32% for large molecules and 13% for small molecules. The estimated transition probabilities were also higher for all clinical phases with respect to large molecules.
Vellozo, Augusto F.; Véron, Amélie S.; Baa-Puyoulet, Patrice; Huerta-Cepas, Jaime; Cottret, Ludovic; Febvay, Gérard; Calevro, Federica; Rahbé, Yvan; Douglas, Angela E.; Gabaldón, Toni; Sagot, Marie-France; Charles, Hubert; Colella, Stefano
In recent years, genomes from an increasing number of organisms have been sequenced, but their annotation remains a time-consuming process. The BioCyc databases offer a framework for the integrated analysis of metabolic networks. The Pathway tool software suite allows the automated construction of a database starting from an annotated genome, but it requires prior integration of all annotations into a specific summary file or into a GenBank file. To allow the easy creation and update of a BioCyc database starting from the multiple genome annotation resources available over time, we have developed an ad hoc data management system that we called Cyc Annotation Database System (CycADS). CycADS is centred on a specific database model and on a set of Java programs to import, filter and export relevant information. Data from GenBank and other annotation sources (including for example: KAAS, PRIAM, Blast2GO and PhylomeDB) are collected into a database to be subsequently filtered and extracted to generate a complete annotation file. This file is then used to build an enriched BioCyc database using the PathoLogic program of Pathway Tools. The CycADS pipeline for annotation management was used to build the AcypiCyc database for the pea aphid (Acyrthosiphon pisum) whose genome was recently sequenced. The AcypiCyc database webpage includes also, for comparative analyses, two other metabolic reconstruction BioCyc databases generated using CycADS: TricaCyc for Tribolium castaneum and DromeCyc for Drosophila melanogaster. Linked to its flexible design, CycADS offers a powerful software tool for the generation and regular updating of enriched BioCyc databases. The CycADS system is particularly suited for metabolic gene annotation and network reconstruction in newly sequenced genomes. Because of the uniform annotation used for metabolic network reconstruction, CycADS is particularly useful for comparative analysis of the metabolism of different organisms. Database URL: http
Vellozo, Augusto F; Véron, Amélie S; Baa-Puyoulet, Patrice; Huerta-Cepas, Jaime; Cottret, Ludovic; Febvay, Gérard; Calevro, Federica; Rahbé, Yvan; Douglas, Angela E; Gabaldón, Toni; Sagot, Marie-France; Charles, Hubert; Colella, Stefano
In recent years, genomes from an increasing number of organisms have been sequenced, but their annotation remains a time-consuming process. The BioCyc databases offer a framework for the integrated analysis of metabolic networks. The Pathway tool software suite allows the automated construction of a database starting from an annotated genome, but it requires prior integration of all annotations into a specific summary file or into a GenBank file. To allow the easy creation and update of a BioCyc database starting from the multiple genome annotation resources available over time, we have developed an ad hoc data management system that we called Cyc Annotation Database System (CycADS). CycADS is centred on a specific database model and on a set of Java programs to import, filter and export relevant information. Data from GenBank and other annotation sources (including for example: KAAS, PRIAM, Blast2GO and PhylomeDB) are collected into a database to be subsequently filtered and extracted to generate a complete annotation file. This file is then used to build an enriched BioCyc database using the PathoLogic program of Pathway Tools. The CycADS pipeline for annotation management was used to build the AcypiCyc database for the pea aphid (Acyrthosiphon pisum) whose genome was recently sequenced. The AcypiCyc database webpage includes also, for comparative analyses, two other metabolic reconstruction BioCyc databases generated using CycADS: TricaCyc for Tribolium castaneum and DromeCyc for Drosophila melanogaster. Linked to its flexible design, CycADS offers a powerful software tool for the generation and regular updating of enriched BioCyc databases. The CycADS system is particularly suited for metabolic gene annotation and network reconstruction in newly sequenced genomes. Because of the uniform annotation used for metabolic network reconstruction, CycADS is particularly useful for comparative analysis of the metabolism of different organisms. Database URL: http://www.cycadsys.org.
Khalid, Nauman; Kobayashi, Isao; Nakajima, Mitsutoshi
Microelectromechanical systems (MEMS) and micro total analysis systems (μTAS) revolutionized the biochemical and electronic industries, and this miniaturization process became a key driver for many markets. Now, it is a driving force for innovations in life sciences, diagnostics, analytical sciences, and chemistry, which are called 'lab-on-a-chip, (LOC)' devices. The use of these devices allows the development of fast, portable, and easy-to-use systems with a high level of functional integration for applications such as point-of-care diagnostics, forensics, the analysis of biomolecules, environmental or food analysis, and drug development. In this review, we report on the latest developments in fabrication methods and production methodologies to tailor LOC devices. A brief overview of scale-up strategies is also presented together with their potential applications in drug delivery and discovery. The impact of LOC devices on drug development and discovery has been extensively reviewed in the past. The current research focuses on fast and accurate detection of genomics, cell mutations and analysis, drug delivery, and discovery. The current research also differentiates the LOC devices into new terminology of microengineering, like organ-on-a-chip, stem cells-on-a-chip, human-on-a-chip, and body-on-a-chip. Key challenges will be the transfer of fabricated LOC devices from lab-scale to industrial large-scale production. Moreover, extensive toxicological studies are needed to justify the use of microfabricated drug delivery vehicles in biological systems. It will also be challenging to transfer the in vitro findings to suitable and promising in vivo models. For further resources related to this article, please visit the WIREs website.
Mikulskis, Alvydas; Yeung, Dave; Subramanyam, Meena; Amaravadi, Lakshmi
Humanized monoclonal antibody therapeutics are in many ways indistinguishable from the anti-therapeutic/anti-drug antibodies generated in humans. Therefore, immunogenicity assessments to such therapeutics pose unique challenges in clinical trials especially when significant drug interference is encountered. There are several technology platforms based on the bridging immunogenicity assay format, which have been successfully used for detection and quantification of anti-drug antibodies (ADA) in serum or plasma samples. Enzyme-Linked Immunosorbent Assay (ELISA) and Electrochemiluminescent (ECL) immunoassay formats are among the most popular technology platforms. Pretreatment of samples with acid can also be used to lower drug interference. While ECL technology platform offered many advantages over traditional solid-phase ELISA methods, reliance on a single (or limited) vendor source became a significant concern within the biopharmaceutical industry especially for immunogenicity assays that need to be implemented over a period of many years in support of a single drug development program. We describe herein a systematic evaluation of solid-phase ELISA, GYROS, AlphaLISA, ECL Immunoassay, and solution ELISA platforms for detection of anti-drug antibodies with the goal of selection and development of a robust technology platform that meets the desired performance characteristics for most immunogenicity assays and can be easily implemented in a typical immunoassay laboratory. As part of this effort the Design of Experiments (DOE) approach was utilized in optimization of sample acid treatment conditions in order to improve drug tolerance in the evaluated assay platforms. After the initial evaluation of various technology platforms, a solution ELISA format was chosen for further development to support clinical trials for a humanized therapeutic antibody. As part of the assay development, flexible use of digoxigenin and 6-(2,4-dinitrophenyl) aminohexanoic acid (DNP) for
Kitchen, Lynn W; Vaughn, David W; Skillman, Donald R
US military physicians and researchers helped identify the optimum treatment dose of the naturally occurring compound quinine and collaborated with the pharmaceutical industry in the development and eventual US Food and Drug Administration approval of the synthetic antimalarial drugs chloroquine, primaquine, chloroquine-primaquine, sulfadoxine-pyrimethamine, mefloquine, doxycycline, halofantrine, and atovaquone-proguanil. Because malaria parasites develop drug resistance, the US military must continue to support the creation and testing of new drugs to prevent and treat malaria until an effective malaria vaccine is developed. New antimalarial drugs also benefit civilians residing in and traveling to malarious areas.
Garbayo, E; Ansorena, E; Blanco-Prieto, M J
Current treatments for Parkinson's disease (PD) are aimed at addressing motor symptoms but there is no therapy focused on modifying the course of the disease. Successful treatment strategies have been so far limited and brain drug delivery remains a major challenge that restricts its treatment. This review provides an overview of the most promising emerging agents in the field of PD drug discovery, discussing improvements that have been made in brain drug delivery for PD. It will be shown that new approaches able to extend the length of the treatment, to release the drug in a continuous manner or to cross the blood-brain barrier and target a specific region are still needed. Overall, the results reviewed here show that there is an urgent need to develop both symptomatic and disease-modifying treatments, giving priority to neuroprotective treatments. Promising perspectives are being provided in this field by rasagiline and by neurotrophic factors like glial cell line-derived neurotrophic factor. The identification of disease-relevant genes has also encouraged the search for disease-modifying therapies that function by identifying molecularly targeted drugs. The advent of new molecular and cellular targets like α-synuclein, leucine-rich repeat serine/threonine protein kinase 2 or parkin, among others, will require innovative delivery therapies. In this regard, drug delivery systems (DDS) have shown great potential for improving the efficacy of conventional and new PD therapy and reducing its side effects. The new DDS discussed here, which include microparticles, nanoparticles and hydrogels among others, will probably open up possibilities that extend beyond symptomatic relief. However, further work needs to be done before DDS become a therapeutic option for PD patients.
Kimchi-Sarfaty, Chava; Schiller, Tal; Hamasaki-Katagiri, Nobuko; Khan, Mansoor A; Yanover, Chen; Sauna, Zuben E
Most native proteins do not make optimal drugs and thus a second- and third-generation of therapeutic proteins, which have been engineered to improve product attributes or to enhance process characteristics, are rapidly becoming the norm. There has been unprecedented progress, during the past decade, in the development of platform technologies that further these ends. Although the advantages of engineered therapeutic proteins are considerable, the alterations can affect the safety and efficacy of the drugs. We discuss both the key technological innovations with respect to engineered therapeutic proteins and advancements in the underlying basic science. The latter would permit the design of science-based criteria for the prediction and assessment of potential risks and the development of appropriate risk management plans. This in turn holds promise for more predictable criteria for the licensure of a class of products that are extremely challenging to develop but represent an increasingly important component of modern medical practice.
Several diseases are characterized by alterations in the molecular distribution of vascular structures, presenting the opportunity to use monoclonal antibodies for clinical therapies. This pharmaceutical strategy, often referred to as "vascular targeting", has promise in promoting the discovery and development of selective biological drugs to regulate angiogenesis-related diseases such as cancer. Various experimental approaches have been utilized to discover accessible vascular markers of health and disease at the protein level. Our group has developed a new chemical proteomics technology to identify and quantify accessible vascular proteins in normal organs and at disease sites. Our developed methodology relies on the perfusion of animal models with suitable ester derivatives of biotin, which react with the primary amine groups of proteins as soon as the molecules are attached. This presentation reports biomedical applications based on vascular targeting strategies, as well as methodologies that have been used to discover new vascular targets. The identification of antigens located in the stromal tissue of pathological blood vessels may provide attractive targets for the development of antibody drugs. This method will also provide an efficient discovery target that could lead to the development of novel antibody drugs.
Silva, Honorio; Stonier, Peter; Buhler, Fritz; Deslypere, Jean-Paul; Criscuolo, Domenico; Nell, Gerfried; Massud, Joao; Geary, Stewart; Schenk, Johanna; Kerpel-Fronius, Sandor; Koski, Greg; Clemens, Norbert; Klingmann, Ingrid; Kesselring, Gustavo; van Olden, Rudolf; Dubois, Dominique
Professional groups, such as IFAPP (International Federation of Pharmaceutical Physicians and Pharmaceutical Medicine), are expected to produce the defined core competencies to orient the discipline and the academic programs for the development of future competent professionals and to advance the profession. On the other hand, PharmaTrain, an Innovative Medicines Initiative project, has become the largest public-private partnership in biomedicine in the European Continent and aims to provide postgraduate courses that are designed to meet the needs of professionals working in medicines development. A working group was formed within IFAPP including representatives from PharmaTrain, academic institutions and national member associations, with special interest and experience on Quality Improvement through education. The objectives were: to define a set of core competencies for pharmaceutical physicians and drug development scientists, to be summarized in a Statement of Competence and to benchmark and align these identified core competencies with the Learning Outcomes (LO) of the PharmaTrain Base Course. The objectives were successfully achieved. Seven domains and 60 core competencies were identified and aligned accordingly. The effective implementation of training programs using the competencies or the PharmaTrain LO anywhere in the world may transform the drug development process to an efficient and integrated process for better and safer medicines. The PharmaTrain Base Course might provide the cognitive framework to achieve the desired Statement of Competence for Pharmaceutical Physicians and Drug Development Scientists worldwide. PMID:23986704
The progress, status, and results of ongoing Research and Development (R and D) within the Geothermal Drilling and Completion Technology Development Program are described. The program emphasizes the development of geothermal drilling hardware, drilling fluids, and completion technology. Advanced drilling systems are also under development. The goals of the program are to develop the technology required to reduce well costs by 25% by 1982 and by 50% by 1986.
Esch, Mandy B.; Smith, Alec; Prot, Jean-Matthieu; Sancho, Carlotta Oleaga; Hickman, James; Shuler, Michael L.
Multi-organ microdevices can mimic tissue-tissue interactions that occur as a result of metabolite travel from one tissue to other tissues in vitro. These systems are capable of simulating human metabolism, including the conversion of a pro-drug to its effective metabolite as well as its subsequent therapeutic actions and toxic side effects. Since tissue-tissue interactions in the human body can play a significant role in determining the success of new pharmaceuticals, the development and use of multi-organ microdevices presents an opportunity to improve the drug development process. The goals are to predict potential toxic side effects with higher accuracy before a drug enters the expensive phase of clinical trials as well as to estimate efficacy and dose response. Multi-organ microdevices also have the potential to aid in the development of new therapeutic strategies by providing a platform for testing in the context of human metabolism (as opposed to animal models). Further, when operated with human biopsy samples, the devices could be a gateway for the development of individualized medicine. Here we review studies in which multi-organ microdevices have been developed and used in a ways that demonstrate how the devices’ capabilities can present unique opportunities for the study of drug action. We also discuss the challenges that are inherent in the development of multi-organ microdevices. Among these are how to design the devices, and how to create devices that mimic the human metabolism with high authenticity. Since single organ devices are testing platforms for tissues that can later be combined with other tissues within multi-organ devices, we will also mention single organ devices where appropriate in the discussion. PMID:24412641
Esch, Mandy B; Smith, Alec S T; Prot, Jean-Matthieu; Oleaga, Carlota; Hickman, James J; Shuler, Michael L
Multi-organ microdevices can mimic tissue-tissue interactions that occur as a result of metabolite travel from one tissue to other tissues in vitro. These systems are capable of simulating human metabolism, including the conversion of a pro-drug to its effective metabolite as well as its subsequent therapeutic actions and toxic side effects. Since tissue-tissue interactions in the human body can play a significant role in determining the success of new pharmaceuticals, the development and use of multi-organ microdevices present an opportunity to improve the drug development process. The devices have the potential to predict potential toxic side effects with higher accuracy before a drug enters the expensive phase of clinical trials as well as to estimate efficacy and dose response. Multi-organ microdevices also have the potential to aid in the development of new therapeutic strategies by providing a platform for testing in the context of human metabolism (as opposed to animal models). Further, when operated with human biopsy samples, the devices could be a gateway for the development of individualized medicine. Here we review studies in which multi-organ microdevices have been developed and used in a ways that demonstrate how the devices' capabilities can present unique opportunities for the study of drug action. We will also discuss challenges that are inherent in the development of multi-organ microdevices. Among these are how to design the devices, and how to create devices that mimic the human metabolism with high authenticity. Since single organ devices are testing platforms for tissues that can later be combined with other tissues within multi-organ devices, we will also mention single organ devices where appropriate in the discussion.
NUMBER(O LTG Robert Lunn (US Army Ret), Dr. Barbara Glacel, Ms. Naomi J. McAfee, Mr. John Moore, Mr. Edward A. Miller, Dr. Leon Riebman, Mr. Harrison H...Comments on Terms of Reference and Panel Questions 11. Paper dated 20 Jun 88 submitted by Mr. John R. Moore, Subject: Considerations and Issues... Sculley Assistant Secretary of the Army (Research, Development and Acquisition) I September 1987 PARTICIPANTS LIST ARMY SCIENCE BOARD AD HOC SUBGROUP ON
prominently expressed in androgen independent prostate cancers . The goal of this research is to develop a novel therapeutic agent, Ad-IU-1, using PSES...better killing activity than TK against prostate cancer cells. We are on the process of constructing FCYttk-armed prostate restricted replicative...S RY( - ) S RY( - ) S RY( - ) LN 1 7 LN 1 8 LN 1 9 INTRODUCTION Metastatic human prostate cancer (PC) is commonly treated by hormone, radiation
Vandamme, Th F; Ellis, K J
Ruminants have a specialised digestive system that contains anaerobic bacteria and protozoa capable of digesting the cellulosic materials that are so common in plant materials. In addition, their distinct digestive system can change the metabolism and mode of action of some nutrients, medicines or other bioactive materials when delivered orally or may provide opportunities for alternative oral dosing strategies. In particular, there is interest in administering a relatively large depot of some drugs into the rumen, which then provides for a prolonged and sustained release of small quantities of these drugs over time. Any strategy to develop a new ruminal drug delivery system must take into account the characteristics of the digestive system of ruminants and its specific bioactive application. For example, in the case of products to control parasitic infections, the development of the host's immunity against the nematodes, which can be acquired during the pasture season, must be considered; likewise, where pharmacologically active materials are used to manipulate a particular metabolic or biochemical process, one must always be aware of interactions with other processes, which might eventuate. This article reviews the necessary concepts, the issues and the challenges to construct ruminal drug delivery systems.
Sharma, S B; Gupta, Richa
Modern research in drug discovery from medicinal plants involves a multidimensional approach combining botanical, phytochemical, biochemical combinatorial chemistry and bioassay-guided fractionation approaches. Natural sources continue to provide an alternative as pharmacological leads against various devastating diseases such as diabetes, CVD, cancer etc. Nowadays, there is enormous requirement of safe and effective drugs in the world. This has prompted scientists to revert back towards natural resources as a potential source of therapeutics for treatment and management of such chronic and fatal diseases. However, there are certain serious challenges and limitations in this field including scale up and commercialization of active compounds which allow only one in thousand lead molecules to be developed as drug. A systematic and scientific approach is an essential requirement for drug development from natural resource. This mini review provides an overview of the methods involved in natural product research starting from crude plant extract to bioactive pharmacological lead. Moreover, it also discusses the limitations of working concerning the bioactivity of medicinal plants.
Ulrich-Merzenich, Gudrun; Panek, D; Zeitler, H; Vetter, H; Wagner, H
Drug development in phytomedicine has been focused in the past on the discovery and analysis of new structures from natural products. The search aimed at the determination of the single "active principle" in plants, based on the assumption that a plant has one or a few ingredients which determine its therapeutic effects. But traditional systems of medicines like Ayurveda, traditional Chinese medicine or the European phytotherapy generally assume that a synergy of all ingredients of the plants will bring about the maximum of therapeutic efficacy. This approach has for long been impossible to investigate since adequate methods to standardize complex plant mixtures as well as to rationalize complex mode of actions were lacking. The introduction of high throughput technologies provides the opportunity to determine profiles of plants and to systematically explore the mode of action of combinatory drug regimes. The present review highlights the concept of synergy and gives examples of synergistic effects of plant constituents. It elaborates on how the high throughput technologies can be used in drug development from natural products with the aim of creating evidence-based plant medications in prevention and treatment of different diseases in the form of new single treatments or new combinatory drug regimes while exploiting synergy-effects.
Olliaro, Piero; Seiler, Jürg; Kuesel, Annette; Horton, John; Clark, Jeffrey N.; Don, Robert; Keiser, Jennifer
Background Few drugs are available for soil-transmitted helminthiasis (STH); the benzimidazoles albendazole and mebendazole are the only drugs being used for preventive chemotherapy as they can be given in one single dose with no weight adjustment. While generally safe and effective in reducing intensity of infection, they are contra-indicated in first-trimester pregnancy and have suboptimal efficacy against Trichuris trichiura. In addition, drug resistance is a threat. It is therefore important to find alternatives. Methodology We searched the literature and the animal health marketed products and pipeline for potential drug development candidates. Recently registered veterinary products offer advantages in that they have undergone extensive and rigorous animal testing, thus reducing the risk, cost and time to approval for human trials. For selected compounds, we retrieved and summarised publicly available information (through US Freedom of Information (FoI) statements, European Public Assessment Reports (EPAR) and published literature). Concomitantly, we developed a target product profile (TPP) against which the products were compared. Principal Findings The paper summarizes the general findings including various classes of compounds, and more specific information on two veterinary anthelmintics (monepantel, emodepside) and nitazoxanide, an antiprotozoal drug, compiled from the EMA EPAR and FDA registration files. Conclusions/Significance Few of the compounds already approved for use in human or animal medicine qualify for development track decision. Fast-tracking to approval for human studies may be possible for veterinary compounds like emodepside and monepantel, but additional information remains to be acquired before an informed decision can be made. PMID:21695247
Sakakibara, Noriko; Yoshioka, Ryuzo; Matsumoto, Kazuo
In 1970s, the material patent system was introduced in Japan. Since then, many Japanese pharmaceutical companies have endeavored to create original in-house products. From 1980s, many of the innovative products were small molecular drugs and were developed using powerful medicinal-chemical technologies. Among them were antibiotics and effective remedies for the digestive organs and circulatory organs. During this period, Japanese companies were able to launch some blockbuster drugs. At the same time, the pharmaceutical market, which had grown rapidly for two decades, was beginning to level off. From the late 1990s, drug development was slowing down due to the lack of expertise in biotechnology such as genetic engineering. In response to the circumstances, the research and development on biotechnology-based drugs such as antibody drugs have become more dynamic and popular at companies than small molecule drugs. In this paper, the writers reviewed in detail the transitions in drug discovery and development between 1980 and 2010.
Buscher, Brigitte; Laakso, Sirpa; Mascher, Hermann; Pusecker, Klaus; Doig, Mira; Dillen, Lieve; Wagner-Redeker, Winfried; Pfeifer, Thomas; Delrat, Pascal; Timmerman, Philip
Plasma protein binding (PPB) is an important parameter for a drug's efficacy and safety that needs to be investigated during each drug-development program. Even though regulatory guidance exists to study the extent of PPB before initiating clinical studies, there are no detailed instructions on how to perform and validate such studies. To explore how PPB studies involving bioanalysis are currently executed in the industry, the European Bioanalysis Forum (EBF) has conducted three surveys among their member companies: PPB studies in drug discovery (Part I); in vitro PPB studies in drug development (Part II); and in vivo PPB studies in drug development. This paper reflects the outcome of the three surveys, which, together with the team discussions, formed the basis of the EBF recommendation. The EBF recommends a tiered approach to the design of PPB studies and the bioanalysis of PPB samples: 'PPB screening' experiments in (early) drug discovery versus qualified/validated procedures in drug development.
Shapiro, Rebecca S.; Robbins, Nicole; Cowen, Leah E.
Summary: Pathogenic fungi have become a leading cause of human mortality due to the increasing frequency of fungal infections in immunocompromised populations and the limited armamentarium of clinically useful antifungal drugs. Candida albicans, Cryptococcus neoformans, and Aspergillus fumigatus are the leading causes of opportunistic fungal infections. In these diverse pathogenic fungi, complex signal transduction cascades are critical for sensing environmental changes and mediating appropriate cellular responses. For C. albicans, several environmental cues regulate a morphogenetic switch from yeast to filamentous growth, a reversible transition important for virulence. Many of the signaling cascades regulating morphogenesis are also required for cells to adapt and survive the cellular stresses imposed by antifungal drugs. Many of these signaling networks are conserved in C. neoformans and A. fumigatus, which undergo distinct morphogenetic programs during specific phases of their life cycles. Furthermore, the key mechanisms of fungal drug resistance, including alterations of the drug target, overexpression of drug efflux transporters, and alteration of cellular stress responses, are conserved between these species. This review focuses on the circuitry regulating fungal morphogenesis and drug resistance and the impact of these pathways on virulence. Although the three human-pathogenic fungi highlighted in this review are those most frequently encountered in the clinic, they represent a minute fraction of fungal diversity. Exploration of the conservation and divergence of core signal transduction pathways across C. albicans, C. neoformans, and A. fumigatus provides a foundation for the study of a broader diversity of pathogenic fungi and a platform for the development of new therapeutic strategies for fungal disease. PMID:21646428
Hollingsworth, Simon J; Biankin, Andrew V
The drivers of precision medicine are clear: for patients (and physicians)--more options, durable clinical benefit, reduced exposure to non-effective drugs and potential to leverage current scientific and technological advances; for the pharmaceutical industry--the potential to tackle core challenges in discovering and developing better and more efficacious medicines, to reduce rates of attrition in drug development and to reduce development costs; for healthcare systems and payers--improved efficiency through the provision of effective care and avoiding ineffective treatments. Oncology has been at the vanguard, the improvements gained in patient survival notable. However, the increasing number of molecular subgroups requires an equally increasing number (and new generation) of highly selective agents targeting inevitably lower incidence molecular segments. Innovative trial designs (umbrella/basket studies) are emerging as a patient-centric approach to drug development, and the rise in public-private partnerships, cross-industry, government and non-profit sector collaborations is enabling implementation of complex clinical trial designs. This poses significant challenges for healthcare systems and regulatory approval. Further substantial evolution of policy and processes, particularly regulatory requirements for approval for new therapeutics, are required.
Uchida, Shinya; Hiraoka, Shogo; Namiki, Noriyuki
About half of patients with schizophrenia have poor adherence to taking medication, so many have recurrence, therefore, providing formulations that enable patients to continue their medication without interruption is important. We aimed to develop a gummi drug that contains aripiprazole (which can reduce schizophrenia and manic symptoms in bipolar disorder). We were able to develop gummi drugs (OD-G, PW-G and OS-G) using three commercially available aripiprazole products (Abilify® orally disintegrating tablets, powder formulation, and oral solutions, respectively) as hospital formulations. Furthermore, we developed improved OD-G (iOD-G), which contained high aripiprazole content. Pharmaceutical characteristics of iOD-G were demonstrated to be suitable for hospital formulations, and iOD-G could be stored for ≤1 month. No significant differences in the dissolution and pharmacokinetics of divided portions of iOD-G were observed when compared with commercially available aripiprazole products. This study confirmed that new dosage forms of aripiprazole in gummi drugs can be developed as hospital formulations, which will contribute to improve medication adherence of patients.
Enlow, M L
The Joint Commission definition of drug-usage evaluation (DUE) also applies to DUE by disease state. The criteria for disease process selection, key processes being evaluated, methods to develop initial DUE protocols, and DUE validation and approval processes are reviewed. The treatment of community-acquired pneumonia is a disease state DUE performed at Saint Joseph Health Center in Kansas City, Missouri. The preliminary protocol was developed by a collaborative network of clinical pharmacists in the metropolitan area. Outcome measures were included in the evaluation. The results were used as baseline data in the development of a pneumonia clinical pathway.
Thomas, Simon; Wolstencroft, Katherine; de Bono, Bernard; Hunter, Peter J
The goal of developing therapies and dosage regimes for characterized subgroups of the general population can be facilitated by the use of simulation models able to incorporate information about inter-individual variability in drug disposition (pharmacokinetics), toxicity and response effect (pharmacodynamics). Such observed variability can have multiple causes at various scales, ranging from gross anatomical differences to differences in genome sequence. Relevant data for many of these aspects, particularly related to molecular assays (known as '-omics'), are available in online resources, but identification and assignment to appropriate model variables and parameters is a significant bottleneck in the model development process. Through its efforts to standardize annotation with consequent increase in data usability, the human physiome project has a vital role in improving productivity in model development and, thus, the development of personalized therapy regimes. Here, we review the current status of personalized medicine in clinical practice, outline some of the challenges that must be overcome in order to expand its applicability, and discuss the relevance of personalized medicine to the more widespread challenges being faced in drug discovery and development. We then review some of (i) the key data resources available for use in model development and (ii) the potential areas where advances made within the physiome modelling community could contribute to physiologically based pharmacokinetic and physiologically based pharmacokinetic/pharmacodynamic modelling in support of personalized drug development. We conclude by proposing a roadmap to further guide the physiome community in its on-going efforts to improve data usability, and integration with modelling efforts in the support of personalized medicine development.
Pankevich, Diana E.; Altevogt, Bruce M.; Dunlop, John; Gage, Fred H.; Hyman, Steve E.
Advances in the neurosciences have placed the field in the position where it is poised to significantly reduce the burden of nervous system disorders. However, drug discovery, development and translation for nervous system disorders still pose many unique challenges. The key scientific challenges can be summarized as follows: mechanisms of disease, target identification and validation, predictive models, biomarkers for patient stratification and as endpoints for clinical trials, clear regulatory pathways, reliability and reproducibility of published data, and data sharing and collaboration. To accelerate nervous system drug development the Institute of Medicine’s Forum on Neuroscience and Nervous System Disorders has hosted a series of public workshops that brought together representatives of industry, government (including both research funding and regulatory agencies), academia, and patient groups to discuss these challenges and offer potential strategies to improve the translational neuroscience. PMID:25442933
Anabalón, Andrés; Astefanesei, Dumitru; Choque, David
We construct exact hairy AdS soliton solutions in Einstein-dilaton gravity theory. We examine their thermodynamic properties and discuss the role of these solutions for the existence of first order phase transitions for hairy black holes. The negative energy density associated to hairy AdS solitons can be interpreted as the Casimir energy that is generated in the dual filed theory when the fermions are antiperiodic on the compact coordinate.
... HUMAN SERVICES Food and Drug Administration Lung Cancer Patient-Focused Drug Development; Extension of... lung cancer patient-focused drug development. In the Federal Register of June 5, 2013 (78 FR 33581... comment on lung cancer patient- focused drug development and explained that the comment period would...
...: Developing Drugs for Treatment; Availability AGENCY: Food and Drug Administration, HHS. ACTION: Notice... industry entitled ``Pulmonary Tuberculosis: Developing Drugs for Treatment.'' The purpose of the draft guidance is to assist sponsors in the development of antimycobacterial drugs for the treatment of...
Sewell, William F.; Borenstein, Jeffrey T.; Chen, Zhiqiang; Fiering, Jason; Handzel, Ophir; Holmboe, Maria; Kim, Ernest S.; Kujawa, Sharon G.; McKenna, Michael J.; Mescher, Mark M.; Murphy, Brian; Leary Swan, Erin E.; Peppi, Marcello; Tao, Sarah
Background Direct delivery of drugs and other agents into the inner ear will be important for many emerging therapies, including the treatment of degenerative disorders and guiding regeneration. Methods We have taken a microfluidics/MEMS (MicroElectroMechanical Systems) technology approach to develop a fully implantable reciprocating inner-ear drug-delivery system capable of timed and sequenced delivery of agents directly into perilymph of the cochlea. Iterations of the device were tested in guinea pigs to determine the flow characteristics required for safe and effective delivery. For these tests, we used the glutamate receptor blocker DNQX, which alters auditory nerve responses but not cochlear distortion product otoacoustic emissions. Results We have demonstrated safe and effective delivery of agents into the scala tympani. Equilibration of the drug in the basal turn occurs rapidly (within tens of minutes) and is dependent on reciprocating flow parameters. Conclusion We have described a prototype system for the direct delivery of drugs to the inner ear that has the potential to be a fully implantable means for safe and effective treatment of hearing loss and other diseases. PMID:19923811
Yu, Dan-dan; Wu, Ying; Shen, Hong-yu; Lv, Meng-meng; Chen, Wei-xian; Zhang, Xiao-hui; Zhong, Shan-liang; Tang, Jin-hai; Zhao, Jian-hua
Transport through the cell membrane can be divided into active, passive and vesicular types (exosomes). Exosomes are nano-sized vesicles released by a variety of cells. Emerging evidence shows that exosomes play a critical role in cancers. Exosomes mediate communication between stroma and cancer cells through the transfer of nucleic acid and proteins. It is demonstrated that the contents and the quantity of exosomes will change after occurrence of cancers. Over the last decade, growing attention has been paid to the role of exosomes in the development of breast cancer, the most life-threatening cancer in women. Breast cancer could induce salivary glands to secret specific exosomes, which could be used as biomarkers in the diagnosis of early breast cancer. Exosome-delivered nucleic acid and proteins partly facilitate the tumorigenesis, metastasis and resistance of breast cancer. Exosomes could also transmit anti-cancer drugs outside breast cancer cells, therefore leading to drug resistance. However, exosomes are effective tools for transportation of anti-cancer drugs with lower immunogenicity and toxicity. This is a promising way to establish a drug delivery system.
Salvadori, Piero A.
The research for the identification and development of new drugs represents a very complex process implying long times and massive investments. This process was not able to parallel the rate of discoveries made in the field of genomic and molecular biology and a gap created between demand of new drugs and the ability of pharmaceutical companies to select good candidates. Positron Emission Tomography, among the different Molecular Imaging modalities, could represent a new tool for the early assessment and screening of new drug candidates and, due to its physical performances and the characteristics of positron-labeled tracers, gain the role of "Biomarker" accepted by the Companies and the Regulatory Bodies of Drug Agencies. To fulfil this task PET has to exploit all of its special features such as data absolute quantification and modelling, high spatial resolution and dynamic imaging. Relevant efforts need to be directed to the careful design and validation of experimental protocols with the main goal of achieving consistency in multi- centric trials.
... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration Fibromyalgia Public Meeting on Patient-Focused Drug... public meeting entitled ``Fibromyalgia Public Meeting on Patient-Focused Drug Development''...
... HUMAN SERVICES Food and Drug Administration Human Immunodeficiency Virus Patient-Focused Drug Development and Human Immunodeficiency Virus Cure Research: Public Meeting AGENCY: Food and Drug... Administration (FDA) is announcing a public meeting and an opportunity for public comment on...
Marsh, Karen R.; Giffin, Bruce F.; Lowrie, Donald J., Jr.
The purpose of this project was to develop Web-based learning modules that combine (1) animated 3D graphics; (2) 3D models that a student can manipulate independently; (3) passage of time in embryonic development; and (4) animated 2D graphics, including 2D cross-sections that represent different "slices" of the embryo, and animate in…
Misiak, Majus; Mantegazza, Francesco; Beretta, Giovanni L
DNA damaging agents including anthracyclines, camptothecins and platinum drugs are among most frequently used drugs in the chemotherapeutic routine. Due to their relatively low selectivity for cancer cells, administration of these drugs is associated with adverse side effects, inherent genotoxicity with risk of developing secondary cancers. Development of new drugs, which could be spared of these drawbacks and characterize by improved antitumor efficacy, remains challenging yet vitally important task. These properties are in large part dictated by the selectivity of interaction between the drug and DNA and in this way the studies aimed at elucidating the complex interactions between ligand and DNA represent a key step in the drug development. Studies of the drug-DNA interactions encompass determination of DNA sequence specificity and mode of DNA binding as well as kinetic, dynamic and structural parameters of binding. Here, we consider the types of interactions between small molecule ligands and polynucleotides, how they are affected by DNA sequence and structure, and what is their significance for the antitumor activity. Based on this knowledge, we discuss the wide array of experimental techniques available to researchers for studying drug-DNA interactions, which include absorption and emission spectroscopies, NMR, magnetic and optical tweezers or atomic force microscopy. We show, using the clinical and experimental anticancer drugs as examples, how these methods provide various types of information and at the same time complement each other to provide full picture of drug- DNA interaction and aid in the development of new drugs.
Gad, Shayne C
As our recognition and understanding of diseases and disorders of the central nervous system (CNS) become more insightful, and society's concerns for the safety, efficacy, and use of such drugs become more acute, the regulatory requirements and expectations around assessing potential safety of the drug have continued to become more complex. Currently, these concerns and requirements are addressed in a time phased manner, attempting to match the advance of spending rate on assessing safety issues in alignment with advancing the moiety through development of the therapeutics. This article seeks to communicate all the critical but frequently overlooked aspects of current and pending regulatory requirements including the lesser known parts associated with impurities, active metabolites, and distribution of active components to (and subsequent clearance from) the population brain. While there are some exciting developments in treating CNS diseases with stem cells and some protein based therapies (Aboody et al., 2011), drugs meant to favorably effect, prevent, or cure a disease process within the central nervous system (CNS) are primarily small molecule and must meet a number of regulatory and scientifically mandated criteria to establish that their safety in clinical use is acceptable. This is initially done in in vivo animals or in in vitro preparations. The starting place for such nonclinical safety assessment requires some fundamental assumptions about the potential therapeutic (Ball et al., 2007; Gad, 2009; ICH S6, 2004; ICH M3 (R2), 2008). The first assumption is that the primary intended route of therapeutic administration is oral, as is indeed the case for the vast majority of both current and for most potential new drugs. Most aspects of nonclinical safety assessment do not depend on route, and we will consider the situations where the use of other routes influences requirements for nonclinical safety assessment, and why. A second general case assumption in the
Xu, Zhijian; Yang, Zhuo; Liu, Yingtao; Lu, Yunxiang; Chen, Kaixian; Zhu, Weiliang
Halogen bond has attracted a great deal of attention in the past years for hit-to-lead-to-candidate optimization aiming at improving drug-target binding affinity. In general, heavy organohalogens (i.e., organochlorines, organobromines, and organoiodines) are capable of forming halogen bonds while organofluorines are not. In order to explore the possible roles that halogen bonds could play beyond improving binding affinity, we performed a detailed database survey and quantum chemistry calculation with close attention paid to (1) the change of the ratio of heavy organohalogens to organofluorines along the drug discovery and development process and (2) the halogen bonds between organohalogens and nonbiopolymers or nontarget biopolymers. Our database survey revealed that (1) an obviously increasing trend of the ratio of heavy organohalogens to organofluorines was observed along the drug discovery and development process, illustrating that more organofluorines are worn and eliminated than heavy organohalogens during the process, suggesting that heavy halogens with the capability of forming halogen bonds should have priority for lead optimization; and (2) more than 16% of the halogen bonds in PDB are formed between organohalogens and water, and nearly 20% of the halogen bonds are formed with the proteins that are involved in the ADME/T process. Our QM/MM calculations validated the contribution of the halogen bond to the binding between organohalogens and plasma transport proteins. Thus, halogen bonds could play roles not only in improving drug-target binding affinity but also in tuning ADME/T property. Therefore, we suggest that albeit halogenation is a valuable approach for improving ligand bioactivity, more attention should be paid in the future to the application of the halogen bond for ligand ADME/T property optimization.
Veiby, Gyri; Daltveit, Anne Kjersti; Schjølberg, Synnve; Stoltenberg, Camilla; Øyen, Anne-Siri; Vollset, Stein Emil; Engelsen, Bernt A.; Gilhus, Nils Erik
Summary Purpose Antiepileptic drugs may cause congenital malformations. Less is known about the effect on development in infancy and childhood. The aim of this study was to examine whether exposure to antiepileptic drugs during pregnancy has an impact on early child development. Methods From mid-year 1999 through December 2008, children of mothers recruited at 13–17 weeks of pregnancy were studied in the ongoing prospective Norwegian Mother and Child Cohort Study. Information on birth outcomes were obtained from the Medical Birth Registry (108,264 –children), and mothers reported on their child’s motor development, language, social skills, and autistic traits using items from standardized screening tools at 18 months (61,351 children) and 36 months of age (44,147 children). The relative risk of adverse outcomes in children according to maternal or paternal epilepsy with and without prenatal exposure to antiepileptic drugs was estimated as odds ratios (ORs), using logistic regression with adjustment for maternal age, parity, education, smoking, depression/anxiety, folate-supplementation, and child congenital malformation or low birth weight. Key findings A total of 333 children were exposed to antiepileptic drugs in utero. At 18 months, the exposed children had increased risk of abnormal scores for gross motor skills (7.1 % vs. 2.9 %; OR, 2.0; 95 % Confidence Interval [CI], 1.1–3.7) and autistic traits (3.5 % vs. 0.9 %; OR, 2.7; CI, 1.1–6.7) compared to children of parents without epilepsy. At 36 months, the exposed children had increased risk of abnormal score for gross motor skills (7.5 % vs. 3.3 %; OR, 2.2; CI, 1.1–4.2), sentence skills (11.2 % vs. 4.8 %; OR, 2.1; CI, 1.2–3.6), and autistic traits (6.0 % vs. 1.5 %; OR, 3.4; CI, 1.6–7.0). The drug-exposed children also had increased risk of congenital malformations (6.1 % vs. 2.9 %; OR, 2.1; CI, 1.4–3.4), but exclusion of congenital malformations did not affect the risk of adverse development
Kunz, Meik; Liang, Chunguang; Nilla, Santosh; Cecil, Alexander; Dandekar, Thomas
The drug-minded protein interaction database (DrumPID) has been designed to provide fast, tailored information on drugs and their protein networks including indications, protein targets and side-targets. Starting queries include compound, target and protein interactions and organism-specific protein families. Furthermore, drug name, chemical structures and their SMILES notation, affected proteins (potential drug targets), organisms as well as diseases can be queried including various combinations and refinement of searches. Drugs and protein interactions are analyzed in detail with reference to protein structures and catalytic domains, related compound structures as well as potential targets in other organisms. DrumPID considers drug functionality, compound similarity, target structure, interactome analysis and organismic range for a compound, useful for drug development, predicting drug side-effects and structure-activity relationships.Database URL:http://drumpid.bioapps.biozentrum.uni-wuerzburg.de.
Kunz, Meik; Liang, Chunguang; Nilla, Santosh; Cecil, Alexander; Dandekar, Thomas
The drug-minded protein interaction database (DrumPID) has been designed to provide fast, tailored information on drugs and their protein networks including indications, protein targets and side-targets. Starting queries include compound, target and protein interactions and organism-specific protein families. Furthermore, drug name, chemical structures and their SMILES notation, affected proteins (potential drug targets), organisms as well as diseases can be queried including various combinations and refinement of searches. Drugs and protein interactions are analyzed in detail with reference to protein structures and catalytic domains, related compound structures as well as potential targets in other organisms. DrumPID considers drug functionality, compound similarity, target structure, interactome analysis and organismic range for a compound, useful for drug development, predicting drug side-effects and structure–activity relationships. Database URL: http://drumpid.bioapps.biozentrum.uni-wuerzburg.de PMID:27055828
The proteasome is the primary site for protein degradation in mammalian cells, and proteasome inhibitors have been invaluable tools in clarifying its cellular functions. The anticancer agent bortezomib inhibits the major peptidase sites in the proteasome’s 20S core particle. It is a “blockbuster drug” that has led to dramatic improvements in the treatment of multiple myeloma, a cancer of plasma cells. The development of proteasome inhibitors illustrates the unpredictability, frustrations, and potential rewards of drug development but also emphasizes the dependence of medical advances on basic biological research. PMID:23148232
Levitzki, Alexander; Gazit, Aviv
Protein tyrosine kinases (PTKs) regulate cell proliferation, cell differentiation, and signaling processes in the cells of the immune system. Uncontrolled signaling from receptor tyrosine kinases and intracellular tyrosine kinases can lead to inflammatory responses and to diseases such as cancer, atherosclerosis, and psoriasis. Thus, inhibitors that block the activity of tyrosine kinases and the signaling pathways they activate may provide a useful basis for drug development. This article summarizes recent progress in the development of PTK inhibitors and demonstrates their potential use in the treatment of disease.
Wan, Jian-bo; He, Chengwei; Hu, Yuanjia
Despite the existence of available therapies, the Hepatitis B virus infection continues to be one of the most serious threats to human health, especially in developing countries such as China and India. To shed light on the improvement of current therapies and development of novel anti-HBV drugs, we thoroughly investigated 212 US patents of anti-HBV drugs and analyzed the technology flow in research and development of anti-HBV drugs based on data from IMS LifeCycle databases. Moreover, utilizing the patent citation method, which is an effective indicator of technology flow, we constructed patent citation network models and performed network analysis in order to reveal the features of different technology clusters. As a result, we identified the stagnant status of anti-HBV drug development and pointed the way for development of domestic pharmaceuticals in developing countries. We also discussed about therapeutic vaccines as the potential next generation therapy for HBV infection. Lastly, we depicted the cooperation between entities and found that novel forms of cooperation added diversity to the conventional form of cooperation within the pharmaceutical industry. In summary, our study provides inspiring insights for investors, policy makers, researchers, and other readers interested in anti-HBV drug development. PMID:27727319
El Mouelhi, Mohamed
Drug development process faces many challenges, including those encountered in clinical trials for neuromuscular diseases. Drug development is a lengthy and highly costly process. Out of 10 compounds entering first study in man (phase 1), only one compound reaches the market after an average of 14 years with a cost of $2.7 billion. Nevertheless, according to the Centers for Medicare and Medicaid services, prescription drugs constituted only 9 % of each health care dollar spent in USA in 2013. Examples of challenges encountered in neuromuscular clinical trials include lack of validated patient-reported outcome tools, blinding issues, and the use of placebo in addition to lack of health authority guidance for orphan diseases. Patient enrollment challenge is the leading cause of missed clinical trial deadlines observed in about 80 % of clinical trials, resulting in delayed availability of potentially life-saving therapies. Another specific challenge introduced by recent technology is the use of social media and risk of bias. Sharing personal experiences while in the study could easily introduce bias among patients that would interfere with accurate interpretation of collected data. To minimize this risk, recent neuromuscular studies incorporate as an inclusion criterion the patient's agreement not to share any of study experiences through social media with other patients during the study conduct. Consideration of these challenges will allow timely response to the high unmet medical needs for many neuromuscular diseases.
Mendell, Jerry R; Csimma, Cristina; McDonald, Craig M; Escolar, Diana M; Janis, Scott; Porter, John D; Hesterlee, Sharon E; Howell, R Rodney
Current treatment benefits for patients with muscle disease are limited, but progress in legislative and scientific initiatives have set the stage for the development of new therapies. The MD-CARE Act (Public Law 107-84), which allocates federal resources to muscular dystrophy, was approved by Congress and signed into law by the President of the United States in 2001. This has shifted the emphasis toward translational research. To facilitate a push toward therapy for muscle disorders, the Muscular Dystrophy Association (MDA) sponsored a meeting with representatives from industry, the Food and Drug Administration (FDA), the National Institutes of Health (NIH), and other government agencies and academia. Each contributed in different ways. The FDA helped define the necessary data to support investigational new drug (IND) applications including the design of proof-of-principle studies, outcome measures for clinical trials, and the pathway for developing surrogate measures for fast-tracking promising new drugs. The NIH, other government agencies, and the MDA described potential funding sources for translational research. Industry delineated a complementary role with academia, and academic investigators elucidated the current strengths and weaknesses of available clinical endpoints. The meeting provided a format for communication for diverse disciplines that usually have no common meeting ground, helping to lay the foundation for bringing products to market in a timely fashion.
Mayer, E A; Bradesi, S; Chang, L; Spiegel, B M R; Bueller, J A; Naliboff, B D
Despite considerable efforts by academic researchers and by the pharmaceutical industry, the development of novel pharmacological treatments for irritable bowel syndrome (IBS) and other functional gastrointestinal (GI) disorders has been slow and disappointing. The traditional approach to identifying and evaluating novel drugs for these symptom-based syndromes has relied on a fairly standard algorithm using animal models, experimental medicine models and clinical trials. In the current article, the empirical basis for this process is reviewed, focusing on the utility of the assessment of visceral hypersensitivity and GI transit, in both animals and humans, as well as the predictive validity of preclinical and clinical models of IBS for identifying successful treatments for IBS symptoms and IBS-related quality of life impairment. A review of published evidence suggests that abdominal pain, defecation-related symptoms (urgency, straining) and psychological factors all contribute to overall symptom severity and to health-related quality of life. Correlations between readouts obtained in preclinical and clinical models and respective symptoms are small, and the ability to predict drug effectiveness for specific as well as for global IBS symptoms is limited. One possible drug development algorithm is proposed which focuses on pharmacological imaging approaches in both preclinical and clinical models, with decreased emphasis on evaluating compounds in symptom-related animal models, and more rapid screening of promising candidate compounds in man. PMID:17965064
EBOLA hemorrhagic fever, a typical emerging infectious disease, began in December 2013 in the southern part of Guinea, and killed more than 11000 people by the end of June, 2015. In addition to emerging/re-emerging diseases and the 3 major infectious diseases i.e. HIV/AIDS, tuberculosis and malaria, neglected tropical diseases (NTDs) have recently become important tropical diseases of the poor. It is remarkable that Japan succeeded in the eradication of malaria and other tropical diseases, which include lymphatic filariasis and schistosomiasis. However, despite these achievements, it is important to sustain our efforts when we consider global health. This review highlights the significance of elimination and/or control of NTDs, and then introduces the current situation of drug development activities in Japan, which are aimed towards combating tropical infectious diseases. They include studies on a novel drug target, the "mitochondrial NADH-fumarate reductase system (Fumarate respiration)" composed of complex I, rhodoquinone and complex II, which plays an important role in the anaerobic energy metabolism of many helminths such as Ascaris suum. An additional interesting finding highlighted herein is that ascofuranone, a recently developed anti-African trypanosome drug, shows specific inhibition of fumarate respiration in Echinococcus multilocularis mitochondria.
Pierce, Christopher G.; Lopez-Ribot, Jose L.
Introduction Targeting pathogenetic mechanisms rather than essential processes represents a very attractive alternative for the development of new antibiotics. This may be particularly important in the case of antimycotics, due to the urgent need for novel antifungal drugs and the paucity of selective fungal targets. The opportunistic pathogenic fungus Candida albicans is the main etiological agent of candidiasis, the most common human fungal infection. These infections carry unacceptably high mortality rates, a clear reflection of the many shortcomings of current antifungal therapy, including the limited armamentarium of antifungal agents, their toxicity, and the emergence of resistance. Moreover the antifungal pipeline is mostly dry. Areas covered This review covers some of the most recent progress towards understanding C. albicans pathogenetic processes and how to harness this information for the development of anti-virulence agents. The two principal areas covered are filamentation and biofilm formation, as C. albicans pathogenicity is intimately linked to its ability to undergo morphogenetic conversions between yeast and filamentous morphologies and to its ability to form biofilms. Expert opinion We argue that filamentation and biofilm formation represent high value targets, yet clinically unexploited, for the development of novel anti-virulence approaches against candidiasis. Although this has proved a difficult task despite increasing understanding at the molecular level of C. albicans virulence, we highlight new opportunities and prospects for antifungal drug development targeting these two important biological processes. PMID:23738751
Ong, Voon S.; Cook, Kevin L.; Kosara, Christine M.; Brubaker, William F.
An integrated approach to quantitative bioanalysis, incorporating turbulent flow chromatography (TFC) with mass spectrometric detection, was developed to support in-house drug discovery and development efforts. Activities such as metabolic stability screening and pharmacokinetic characterization support are carried out on a single unified platform. Two different TFC column-switching configurations, parallel and serial, are presented. The first, a parallel TFC column configuration, is capable of high-throughput analysis but carryover can reach as high as 0.24%. The characteristics of the instrument operating in the parallel configuration are provided for analysis of samples generated during in vitro metabolic stability assessments, a key screen during the lead optimization phase of drug discovery. Operating in this configuration, the system has the capability of performing on-line solid phase extraction and analysis of approximately 400 samples containing phosphate-buffered saline in approximately 14 h. The second, a serial TFC column configuration, was used to perform direct plasma injection analysis. The advantage of the serial configuration is the relatively low carryover (<0.040%) observed due to increased number of valve washes; however these extra washes lead to increased injection cycle times. A method developed using the serial TFC column configuration for the determination of dihydropyridines in plasma samples is given as an example. Analytical performance criteria examined during method development and validation included linearity, accuracy, precision, and recovery. The robustness of the technique was demonstrated by applying the method in the analysis of over 2500 plasma samples generated during preclinical drug development studies. Further, combined analysis of plasma and brain tissue was performed using acetonitrile precipitation as sample pretreatment for both matrices.
Hara, Michikazu; Nakajima, Kiyotaka; Kamata, Keigo
In recent decades, the substitution of non-renewable fossil resources by renewable biomass as a sustainable feedstock has been extensively investigated for the manufacture of high value-added products such as biofuels, commodity chemicals, and new bio-based materials such as bioplastics. Numerous solid catalyst systems for the effective conversion of biomass feedstocks into value-added chemicals and fuels have been developed. Solid catalysts are classified into four main groups with respect to their structures and substrate activation properties: (a) micro- and mesoporous materials, (b) metal oxides, (c) supported metal catalysts, and (d) sulfonated polymers. This review article focuses on the activation of substrates and/or reagents on the basis of groups (a)-(d), and the corresponding reaction mechanisms. In addition, recent progress in chemocatalytic processes for the production of five industrially important products (5-hydroxymethylfurfural, lactic acid, glyceraldehyde, 1,3-dihydroxyacetone, and furan-2,5-dicarboxylic acid) as bio-based plastic monomers and their intermediates is comprehensively summarized.
Hara, Michikazu; Nakajima, Kiyotaka; Kamata, Keigo
In recent decades, the substitution of non-renewable fossil resources by renewable biomass as a sustainable feedstock has been extensively investigated for the manufacture of high value-added products such as biofuels, commodity chemicals, and new bio-based materials such as bioplastics. Numerous solid catalyst systems for the effective conversion of biomass feedstocks into value-added chemicals and fuels have been developed. Solid catalysts are classified into four main groups with respect to their structures and substrate activation properties: (a) micro- and mesoporous materials, (b) metal oxides, (c) supported metal catalysts, and (d) sulfonated polymers. This review article focuses on the activation of substrates and/or reagents on the basis of groups (a)-(d), and the corresponding reaction mechanisms. In addition, recent progress in chemocatalytic processes for the production of five industrially important products (5-hydroxymethylfurfural, lactic acid, glyceraldehyde, 1,3-dihydroxyacetone, and furan-2,5-dicarboxylic acid) as bio-based plastic monomers and their intermediates is comprehensively summarized.
Bauer, Armin; Brönstrup, Mark
Covering: up to March 2013. In addition to their prominent role in basic biological and chemical research, natural products are a rich source of commercial products for the pharmaceutical and other industries. Industrial natural product chemistry is of fundamental importance for successful product development, as the vast majority (ca. 80%) of commercial drugs derived from natural products require synthetic efforts, either to enable economical access to bulk material, and/or to optimize drug properties through structural modifications. This review aims to illustrate issues on the pathway from lead to product, and how they have been successfully addressed by modern natural product chemistry. It is focused on natural products of current relevance that are, or are intended to be, used as pharmaceuticals.
Different epigenetic alterations (DNA methylation, histone modifications, chromatin remodeling, noncoding RNA dysregulation) are associated with the phenotypic expression of complex disorders in which genomic, epigenomic, proteomic, and metabolomic changes, in conjunction with environmental factors, are involved. As epigenetic modifications are reversible and can be potentially targeted by pharmacological and dietary interventions, a series of epigenetic drugs have been developed, including DNA methyltransferase inhibitors (nucleoside analogs, small molecules, bioproducts, antisense oligonucleotides, miRNAs), histone deacetylase inhibitors (short-chain fatty acids, hydroxamic acids, cyclic peptides, benzamides, ketones, sirtuin inhibitors, sirtuin activators), histone acetyltransferase modulators, histone methyltransferase inhibitors, histone demethylase inhibitors, and noncoding RNAs (miRNAs), with potential effects against myelodysplastic syndromes, different types of cancer, and neurodegenerative disorders. Pharmacogenetic and pharmacoepigenetic studies are required for the proper evaluation of efficacy and safety issues in clinical trials with epigenetic drugs.
Fabiilli, Mario L.; Sebastian, Ian E.; Fowlkes, J. Brian
Many therapeutic applications of ultrasound (US) include the use of pefluorocarbon (PFC) microbubbles or emulsions. These colloidal systems can be activated in the presence of US, which in the case of emulsions, results in the production of bubbles—a process known as acoustic droplet vaporization (ADV). ADV can be used as a drug delivery mechanism, thereby yielding the localized release of toxic agents such a chemotherapeutics. In this work, emulsions that contain PFC and chlorambucil, a chemotherapy drug, are formulated using albumin or lipid shells. For albumin droplets, the oil phase—which contained CHL—clearly enveloped the PFC phase. The albumin emulsion also displayed better retention of CHL in the absence of US, which was evaluated by incubating Chinese hamster ovary cells with the various formulations. Thus, the developed emulsions are suitable for further testing in ADV-induced release of CHL.
Gough, H G
Psychological measurement in regard to using drugs, alcohol, or other substances should attend to personological, attitudinal, and informational factors. Standardized tests are available for assessing personological and attitudinal variables, but not for knowledge. To develop a test of information, 45 multiple-choice items were correlated with total and part scores in samples of 132 men and 71 women; 35 items with significant (p less than .05) coefficients and other desirable properties were retained for a Drug and Alcohol Information Survey (DAIS). For 33 male and 36 female college students participating in an intensive psychological assessment program, scores on the DAIS were positively associated with (1) ratings of modernity, sensation seeking, originality, and nonorderliness; (2) personality scales for status propensity, sociability, social presence, and rebelliousness; and (3) a nonverbal test of field-independent cognitive ability. High scorers on the DAIS also reported more frequent use of marijuana, alcohol, and tobacco than did students with low scores.
Gericke, C A; Riesberg, A; Busse, R
This essay outlines the moral dilemma of funding orphan drug research and development. To date, ethical aspects of priority setting for research funding have not been an issue of discussion in the bioethics debate. Conflicting moral obligations of beneficence and distributive justice appear to demand very different levels of funding for orphan drug research. The two types of orphan disease, rare diseases and tropical diseases, however, present very different ethical challenges to questions about allocation of research funds. The dilemma is analysed considering utilitarian and rights based theories of justice and moral obligations of non-abandonment and a professional obligation to advance medical science. The limitations of standard economic evaluation tools and other priority setting tools used to inform health policy decision makers on research funding decisions are outlined.
Heldenbrand, Lois; Simms, Michael S.
Long-term care is a key public issue that affects all of us in some way at some time of our lives. Nowhere is performance improvement and quality management more imperative. Through an 8-month field study and follow-up case study, we discuss how using an integrated approach to individual leadership development, employee engagement, and customer…
It is our desire to develop new crosslinking agents for cotton textiles that afford useful flame protection regardless of fabric construction. Herein we present the synthesis and the application of the triazine and piperazine derivatives as flame retardant on cotton. Novel phosphorus-nitrogen contai...
... need sugar to function properly. Added sugars contribute zero nutrients but many added calories that can lead to extra pounds or even obesity, thereby reducing heart health. If you think of your daily calorie needs as a budget, you want to “spend” ...
UCLA IDEA, 2012
Value added measures (VAM) uses changes in student test scores to determine how much "value" an individual teacher has "added" to student growth during the school year. Some policymakers, school districts, and educational advocates have applauded VAM as a straightforward measure of teacher effectiveness: the better a teacher,…
DOE Award # EE0000393 was awarded to fund research into the development of beneficial uses of surplus algal biomass and the byproducts of biofuel production. At the time of award, Sapphire’s intended fuel production pathway was a fairly conventional extraction of lipids from biomass, resulting in a defatted residue which could be processed using anaerobic digestion. Over the lifetime of the award, we conducted extensive development work and arrived at the conclusion that anaerobic digestion presented significant technical challenges for this high-nitrogen, high-ash, and low carbon material. Over the same timeframe, Sapphire’s fuel production efforts came to focus on hydrothermal liquefaction. As a result of this technology focus, the residue from fuel production became unsuitable for either anaerobic digestion (or animal feed uses). Finally, we came to appreciate the economic opportunity that the defatted biomass could represent in the animal feed space, as well as understanding the impact of seasonal production on a biofuels extraction plant, and sought to develop uses for surplus biomass produced in excess of the fuel production unit’s capacity.
Koval, Mary; And Others
This study developed a Drug Involvement Classification for a general population. The classification took into consideration the following: type of drug used, legality, frequency and recency of drug use, number and combinations of drug used. The classification was developed from a New York State survey conducted in 1970. (Author)
... HUMAN SERVICES Food and Drug Administration Human Immunodeficiency Virus Patient-Focused Drug Development and Human Immunodeficiency Virus Cure Research; Reopening of Comment Period AGENCY: Food and Drug... Virus (HIV) Patient-Focused Drug Development and HIV Cure Research,'' published in the Federal...
... HUMAN SERVICES Food and Drug Administration Fibromyalgia Public Meeting on Patient-Focused Drug... public comment on Patient-Focused Drug Development for fibromyalgia. Patient-Focused Drug Development is... fibromyalgia on daily life as well as the available therapies for fibromyalgia. DATES: The public meeting...
Wang, Hongjie; Ducournau, Corinne; Saydaminova, Kamola; Richter, Maximilian; Yumul, Roma; Ho, Martin; Carter, Darrick; Zubieta, Chloé
knob domain and triggers intracellular signaling that culminates in the cleavage of the extracellular domain of DSG2, thereby disrupting DSG2 homodimers between epithelial cells. We confirmed this pathway with a second DSG2-interacting serotype, Ad14, and its recently emerged strain Ad14P1. These new insights in basic adenovirus biology can be employed to develop novel drugs to treat adenovirus infection as well as be used as tools for gene delivery into epithelial tissues or epithelial tumors. PMID:26292319
Knowles, Richard Graham
The research and development process for novel drugs to treat inflammatory diseases is described, and several current issues and debates relevant to this are raised: the decline in productivity, attrition, challenges and trends in developing anti-inflammatory drugs, the poor clinical predictivity of experimental models of inflammatory diseases, heterogeneity within inflammatory diseases, 'improving on the Beatles' in treating inflammation, and the relationships between big pharma and biotechs. The pharmaceutical research and development community is responding to these challenges in multiple ways which it is hoped will lead to the discovery and development of a new generation of anti-inflammatory medicines.
Ochoa-Cortes, Fernando; Liñán-Rico, Andromeda; Jacobson, Kenneth A.; Christofi, Fievos L.
Treatments for IBD, IBS, FD or motility disorders are not adequate, and purinergic drugs offer exciting new possibilities. GI symptoms that could be targeted for therapy include visceral pain, inflammatory pain, dysmotility, constipation and diarrhea. The focus of this review is on potential for developing purinergic drugs for clinical trials to treat GI symptoms. Purinergic receptors are divided into adenosine P1 (A1,A2A,A2B,A3), ionotropic ATP-gated P2X ion channel (P2X1–7) or metabotropic P2Y1,2,4,6,11–14 receptors. There is good experimental evidence for targeting A2A, A2B, A3, P2X7, P2X3 receptors or increasing endogenous adenosine levels to treat IBD, inflammatory pain, IBS/visceral pain, inflammatory-diarrhea and motility disorders. Purine genes are also potential biomarkers of disease. Advances in medicinal-chemistry have an accelerated pace toward clinical trials: Methotrexate and sulfasalazine, used to treat IBD, act by stimulating CD73-dependent adenosine production. ATP protects against NSAID-induced enteropathy and has pain-relieving properties in humans. A P2X7R antagonist AZD9056 is in clinical trials for CD. A3 AR drugs target inflammatory diseases (e.g. CF101; CF102). Dipyridamole, a nucleoside uptake-inhibitor, is in trials for endotoxemia. Drugs for pain in clinical-trials include P2X3/P2X2/3(AF-219) and P2X7(GSK1482160) antagonists and A1(GW493838) or A2A(BVT.115959) agonists. IberogastR is a phytopharmacon targeting purine-mechanisms with efficacy in IBS and FD. Purinergic drugs have excellent safety/efficacy profile for prospective clinical trials in IBD, IBS, FD and inflammatory-diarrhea. Genetic polymorphisms and caffeine consumption may affect susceptibility to treatment. Further studies in animals can clarify mechanisms and test new-generation drugs. Finally, there is still a huge gap in our knowledge of human pathophysiology of purinergic signaling. PMID:24859298
Dobchev, Dimitar A; Pillai, Girinath G; Karelson, Mati
Machine learning (ML) computational methods for predicting compounds with pharmacological activity, specific pharmacodynamic and ADMET (absorption, distribution, metabolism, excretion and toxicity) properties are being increasingly applied in drug discovery and evaluation. Recently, machine learning techniques such as artificial neural networks, support vector machines and genetic programming have been explored for predicting inhibitors, antagonists, blockers, agonists, activators and substrates of proteins related to specific therapeutic targets. These methods are particularly useful for screening compound libraries of diverse chemical structures, "noisy" and high-dimensional data to complement QSAR methods, and in cases of unavailable receptor 3D structure to complement structure-based methods. A variety of studies have demonstrated the potential of machine-learning methods for predicting compounds as potential drug candidates. The present review is intended to give an overview of the strategies and current progress in using machine learning methods for drug design and the potential of the respective model development tools. We also regard a number of applications of the machine learning algorithms based on common classes of diseases.
Lee, Andrew M.; Pasquato, Antonella; Kunz, Stefan
Hemorrhagic fevers caused by arenaviruses are among the most devastating emerging human diseases. Considering the number of individuals affected, the current lack of a licensed vaccine, and the limited therapeutic options, arenaviruses are arguably among the most neglected tropical pathogens and the development of efficacious anti-arenaviral drugs is of high priority. Over the past years significant efforts have been undertaken to identify novel potent inhibitors of arenavirus infection. High throughput screening of small molecule libraries employing pseudotype platforms led to the discovery of several potent and broadly active inhibitors of arenavirus cell entry that are effective against the major hemorrhagic arenaviruses. Mechanistic studies revealed that these novel entry inhibitors block arenavirus membrane fusion and provided novel insights into the unusual mechanism of this process. The success of these approaches highlights the power of small molecule screens in antiviral drug discovery and establishes arenavirus membrane fusion as a robust drug target. These broad screenings have been complemented by strategies targeting cellular factors involved in productive arenavirus infection. Approaches targeting the cellular protease implicated in maturation of the fusion-active viral envelope glycoprotein identified the proteolytic processing of the arenavirus glycoprotein precursor as a novel and promising target for anti-arenaviral strategies.
Walker, Chad; Baxter, Jamie; Ouellette, Danielle
Though historically dismissed as not-in-my-backyard (NIMBY) attitudes, reports of psychosocial stress linked to wind energy developments have emerged in Ontario, Canada. While the debate and rhetoric intensify concerning whether wind turbines 'actually' cause 'health' effects, less sincere attention has been given to the lived experience and mental well-being of those near turbines. Drawing on theories of environmental stress, this grounded theory, mixed-method (n = 26 interviews; n = 152 questionnaires) study of two communities in 2011 and 2012 traces how and why some wind turbine community residents suffer substantial changes to quality of life, develop negative perceptions of 'the other' and in some cases, experience intra-community conflict. Policy-related forces, along with existing community relationships may help explain much of these differences between communities. We suggest a move beyond debating simply whether or not 'annoyance' represents a 'health impact' and instead focus on ways to minimize and attenuate these feelings of threat (risk) and stress at the community level.
Developmental pharmacodynamics is the study of age-related maturation of the structure and function of biologic systems and how this affects response to pharmacotherapy. This may manifest as a change in the potency, efficacy, or therapeutic range of a drug. The paucity of studies exploring developmental pharmacodynamics reflects the lack of suitable juvenile animal models and the ethical and practical constraints of conducting studies in children. However, where data from animal models are available, valuable insight has been gained into how response to therapy can change through the course of development. For example, animal neurodevelopmental models have revealed that temporal differences in the maturation of norepinephrine and serotonin neurotransmitter systems may explain the lack of efficacy of some antidepressants in children. GABA(A) receptors that switch from an excitatory to inhibitory mode during early development help to explain paradoxical seizures experienced by infants after exposure to benzodiazepines. The increased sensitivity of neonates to morphine may be due to increased postnatal expression of the mu opioid receptor. An age dependency to the pharmacokinetic-pharmacodynamic relationship has also been found in some clinical studies. For example, immunosuppressive effects of ciclosporin (cyclosporine) revealed markedly enhanced sensitivity in infants compared with older children and adults. A study of sotalol in the treatment of children with supraventricular tachycardia showed that neonates exhibited a higher sensitivity towards QTc interval prolongation compared with older children. However, the data are limited and efforts to increase and establish data on developmental pharmacodynamics are necessary to achieve optimal drug therapy in children and to ensure long-term success of pediatric drug development. This requires a dual 'bottom up' (ontogeny knowledge driven) and 'top down' (pediatric pharmacokinetic-pharmacodynamic studies) approach.
Bauman, P S; Dougherty, F E
The present study compared 15 mothers on methadone maintenance (MM) and their 15 preschool children to 15 non-drug-addicted mothers (NDA) and their 15 preschool children on mothers' personalities and parenting attitudes, the mother-child interaction, and on children's intelligence and developmental levels. Findings showed that in comparison to the control group, MM mothers performed less adaptively on measures of personality and parenting behavior. There were no differences between the two groups of mothers on their parenting attitudes. Children of MM mothers performed more poorly than children of NDA mothers on measures of intelligence, development, and socially adaptive behavior.
Orphan nuclear receptors regulate diverse biological processes. These important molecules are ligand-activated transcription factors that act as natural sensors for a wide range of steroid hormones and xenobiotic ligands. Because of their importance in regulating various novel signaling pathways, recent research has focused on identifying xenobiotics targeting these receptors for the treatment of multiple human diseases. In this review, we will highlight these receptors in several physiologic and pathophysiologic actions and demonstrate how their functions can be exploited for the successful development of newer drugs. PMID:20372994
Cross, S E; Roberts, M S
Advances in molecular biology have given us a wide range of protein and peptide-based drugs that are unsuitable for oral delivery because of their high degree of first-pass metabolism. Though parenteral delivery is the obvious answer, for the successful development of commercial chronic and self-administration usage formulations it is not the ideal choice. Transdermal delivery is emerging as the biggest application target for these agents, however, the skin is extremely efficient at keeping out such large molecular weight compounds and therapeutic levels are never going to be realistically achieved by passive absorption. Physical enhancement mechanisms including: iontophoresis, electroporation, ultrasound, photomechanical waves, microneedles and jet-propelled particles are emerging as solutions to this topical delivery dilemma. Adding proteins and peptides to the list of other large molecular weight drugs with insufficient passive transdermal fluxes to be therapeutically useful, we have a collection of pharmacological agents waiting for efficient delivery methods to be introduced. This article reviews the current state of physical transdermal delivery technology, assesses the pros and cons of each technique and summarises the evidence-base of their drug delivery capabilities.
Ashammakhi, N; Wimpenny, I; Nikkola, L; Yang, Y
It is clear that nanofibrous structures can be used as tools for many applications. It is already known that electrospinning is a highly versatile method of producing nanofibres and recent developments in the technique of electrospinning have led to the development of aligned nanofibres and biphasic, core-sheath fibres which can be used to encapsulate different materials from molecules to cells. Natural extracellular matrix (ECM) contains fibres in both micro and nano-scales and provides a structural scaffold which allows cells to localize, migrate, proliferate and differentiate. Polymer nanofibres can provide the structural cues of ECM. However, current literature gives new hope to further functionalising polymeric nanofibres by using them for drug delivery devices and improving their design to improve control of delivery. By encapsulating active agents within nanofibres (multifunctional nanofibres), a degree of control can be exerted over the release of encapsulated agents and therefore, the behaviour of cells can be manipulated for developing effective therapies and is extremely encouraging in the tissue engineering field by combining factors like fibre diameter, alignment and chemicals in new ways. Such multifunctional nanofibre-based systems are already being investigated in vivo. Experiments have shown the significant potential for treatments of disease and engineering of neural and bone tissues. Further, phase III clinical trials of nanofibrous patches for applications in wound treatment were encouraging. Hopefully, clinical applications of these drug delivery devices will follow, to enhance regenerative medicine applications.
Martin-Liberal, Juan; Hierro, Cinta; Ochoa de Olza, Maria; Rodon, Jordi
Clinical researchers in oncology face the difficulty of developing new drugs for treating cancer patients. This challenge nowadays extends towards new horizons since a high number of drugs are developed in each of the three paradigms: classical cytotoxics, new targeted agents, and emergent immunotherapeutic approaches. Over the last decade, there has been an unstoppable progress in this third paradigm, to the extent that in 2013 immunotherapy was granted the scientific breakthrough of the year. However, the novel mechanisms of action of these immunotherapeutic agents entail a whole new series of concepts, resulting in a number of unresolved questions to which clarification is crucial for their success: establishment of accurate preclinical models able to predict human toxicities, better selection of candidate populations, finding and validation of predictive biomarkers, definition of suitable endpoints, improvements in first-in-human study designs, proposal of more accurate radiological response criteria, management of novel immune-related toxicities and development of combinations based on a biological rationale. In this article, we review the major challenges to overcome in forthcoming years. The final role of immunotherapy in cancer will be determined by our capacity to shed some light on some of these key points.
Alday, P Holland; Doggett, Joseph Stone
Toxoplasma gondii causes fatal and debilitating brain and eye diseases. Medicines that are currently used to treat toxoplasmosis commonly have toxic side effects and require prolonged courses that range from weeks to more than a year. The need for long treatment durations and the risk of relapsing disease are in part due to the lack of efficacy against T. gondii tissue cysts. The challenges for developing a more effective treatment for toxoplasmosis include decreasing toxicity, achieving therapeutic concentrations in the brain and eye, shortening duration, eliminating tissue cysts from the host, safety in pregnancy, and creating a formulation that is inexpensive and practical for use in resource-poor areas of the world. Over the last decade, significant progress has been made in identifying and developing new compounds for the treatment of toxoplasmosis. Unlike clinically used medicines that were repurposed for toxoplasmosis, these compounds have been optimized for efficacy against toxoplasmosis during preclinical development. Medicines with enhanced efficacy as well as features that address the unique aspects of toxoplasmosis have the potential to greatly improve toxoplasmosis therapy. This review discusses the facets of toxoplasmosis that are pertinent to drug design and the advances, challenges, and current status of preclinical drug research for toxoplasmosis. PMID:28182168
Adedeji, Adeyemi O.; Sarafianos, Stefan G.
Coronaviruses are positive stranded RNA viruses that cause respiratory, enteric and central nervous system diseases in many species, including humans. Until recently, the relatively low burden of disease in humans caused by few of these viruses impeded the development of coronavirus specific therapeutics. However, the emergence of severe acute respiratory syndrome coronavirus (SARS-CoV), and more recently, Middle East respiratory syndrome coronavirus (MERS-CoV), has impelled the development of such drugs. This review focuses on some newly identified SARS-CoV inhibitors, with known mechanisms of action and their potential to inhibit the novel MERS-CoV. The clinical development of optimized versions of such compounds could be beneficial for the treatment and control of SARS-CoV, the current MERS-CoV and other future SARS-like epidemics. PMID:24997250
of a possible drug related SGPT elevation is required. 3. Optimal dose schedules for Sodium Stibogluconate can be...subject also had a nightmare following drug administration. The gastrointestinal signs and symptoms are considered drug related ...The neurologic symptoms are considered possibly drug related . No physical changes were observed. All subjects had two
Schrattenholz, André; Soskić, Vukić
regard to a new focus on agents that modulate multiple targets simultaneously. Targeting cellular function as a system rather than on the level of the single protein molecule significantly increases the size of the drugable proteome and is expected to introduce novel classes of multi-target drugs with fewer adverse effects and toxicity. Multiple target approaches have recently been used to design medications against atherosclerosis, cancer, depression, psychosis and neurodegenerative diseases. A focussed approach towards "systemic" drugs will certainly require the development of novel computational and mathematical concepts for appropriate modelling of complex data and extraction of "screenable" information from biological systems essentially ruled by deterministic chaotic processes on a background of individual stochasticity.
Wolffgramm, J; Heyne, A
The development of drug taking from controlled intake to drug addiction was studied by means of an animal model. Outbred rats had continuous free access to water and drinking fluids containing different concentrations of a drug for 7-9 months. After an abstinence period of 4-9 months, the drug was offered again (retest). Previous ethological classification of each rat and changes of housing conditions were used to study the modifiability of drug taking. With ethanol and the mu-agonistic opiate etonitazene, two stages followed each other. Controlled drug intake was adjusted to situational and individual variables. Social isolation of the rats raised the intake of ethanol and opiate. Dominant rats took less drugs than subordinate ones, but, in contrast to the latter, increased drug consumption after social disturbances. The adjustment of drug taking to social variables, was accompanied by changes in the dopaminergic and GABAA-ergic neurotransmission and by altered responses to acute drug administrations. Further, place preference, associated with reinforcing stimuli was modulated by subchronic sensitization/desensitization of dopaminergic transmission. Controlled drug intake lasted for 6-8 months, after which a spontaneous increase of drug consumption was found which latently continued during abstinence periods of 1 month. In the retest after abstinence, drug intake of these rats was strongly increased compared with both their previous consumption and that of drug-naive controls. Since drug taking could no longer be modulated by gustatory, environmental or individual factors (loss of control), it was considered as addictive. Addiction appeared to be specific to the kind of the drug. It persisted for the rest of the rat's life. After long periods of abstinence, ethanol-addicted rats revealed a completely altered pattern of response to self-administered alcohol compared with controlled drinkers. Their dopaminergic D1-transmission was irreversibly altered. Drug
Adam, G I
The potential of pharmacogenomic research to improve general healthcare, reduce morbidity and mortality resulting from treatment side effects, and to accelerate therapeutic compound discovery, design and development in the pharmaceutical industry, remains largely unfulfilled. Major contributory factors affecting progress in the field include: (i) the need for large clinical populations and control/placebo-treated cohorts to be studied; (ii) the difficulty in evaluating drug response in many instances with empirical or qualitative treatment response values often not available; (iii) interactions of underlying biochemical pathways are often not fully understood, both in terms of mode-of-action of a therapeutic compound itself and in the occurrence of side effects; (iv) population-specific frequency data for reported genetic variants and physically mapped genomic markers for evaluation in drug response studies are often not readily and/or publicly available; (v) accurate, high-throughput, cost-effective polymorphism detection and screening methods are required; and (vi) sophisticated biostatistical data analysis programs to perform the multi-parametric tests and permutation analyses necessary are still under development. With the recent human genome sequence draft release by both the public and commercial initiatives, in addition to the publication of locus and chromosome-specific polymorphism maps and TSC (The SNP Consortium) SNP map information expected in late-2001, it is hoped that at least some of the inherent difficulties in pharmacogenomics research will soon be alleviated.
The use of microelectromechanical systems (MEMS) technology in medical and biological applications has increased dramatically in the past decade due to the potential for enhanced sensitivity, functionality, and performance associated with the miniaturization of devices, as well as the market potential for low-cost, personalized medicine. However, the utility of such devices in clinical medicine is ultimately limited due to factors associated with prevailing micromachined materials such as silicon, as it poses concerns of safety and reliability due to its intrinsically brittle properties, making it prone to catastrophic failure. Recent advances in titanium (Ti) micromachining provides an opportunity to create devices with enhanced safety and performance due to its proven biocompatibility and high fracture toughness, which causes it to fail by means of graceful, plasticity-based deformation. Motivated by this opportunity, we discuss our efforts to advance Ti MEMS technology in two ways: 1) Through the development of titanium-based microneedles (MNs) that seek to provide a safer, simpler, and more efficacious means of ocular drug delivery, and 2) Through the advancement of Ti anodic bonding for future realization of robust microfluidic devices for photocatalysis applications. As for the first of these thrusts, we show that MN devices with in-plane geometry and through-thickness fenestrations that serve as drug reservoirs for passive delivery via diffusive transport from fast-dissolving coatings can be fabricated utilizing Ti deep reactive ion etching (Ti DRIE). Our mechanical testing and finite element analysis (FEA) results suggest that these devices possess sufficient stiffness for reliable corneal insertion. Our MN coating studies show that, relative to solid MNs of identical shank dimension, fenestrated devices can increase drug carrying capacity by 5-fold. Furthermore, we demonstrate that through-etched fenestrations provide a protective cavity for delivering
Yan, Juan; Hu, Chongya; Liu, Xunwei; Zhong, Jian; Sun, Gang; He, Dannong
DNA origami technique was first introduced in 2006 by Rothemund, it has gained widespread research interest and led to explosive achievements, in which long single-stranded DNA (ssDNA) is folded into a designed nanostructure, in either two dimensions (2D) or three dimensions (3D), with the aid of many shorter staple strands. A series of methods for new design principles for DNA origami nanostructures have already been proposed, ranging from the preparation of scaffold to the folding mechanisms. After that, novel strategies in functionalizing DNA origami nanostructures and their practical applications are gradually becoming research hotspots. This review focuses on the development in the new scaffold design approaches, folding conditions, various nano objects functionalized on DNA origami nanostructures, and their applications as drug carriers in the recent five years. We anticipate more exploratory and extendible work developed based on the summary of progress obtained previously.
Rimann, Markus; Graf-Hausner, Ursula
Since the 1970s, the limitations of two dimensional (2D) cell culture and the relevance of appropriate three dimensional (3D) cell systems have become increasingly evident. Extensive effort has thus been made to move cells from a flat world to a 3D environment. While 3D cell culture technologies are meanwhile widely used in academia, 2D culture technologies are still entrenched in the (pharmaceutical) industry for most kind of cell-based efficacy and toxicology tests. However, 3D cell culture technologies will certainly become more applicable if biological relevance, reproducibility and high throughput can be assured at acceptable costs. Most recent innovations and developments clearly indicate that the transition from 2D to 3D cell culture for industrial purposes, for example, drug development is simply a question of time.
da Silva, F B; Cassiani, S H; Zem-Mascarenhas, S H
This study identified existent sites in the internet about Administration of Medications and developed and evaluated a specific site of this thematic. Of the 158 existent and available sites in the database of the Alta Vista search, 17 of these presented some relationship with pharmacology, marketing and information about drugs, technologies and rules of the medication. After that a site was developed and named The process of Administration of Medications in focus which goal was to present investigations conducted by a group about the following topics: errors, technology, complications, study group and the team. The evaluation of this site was made by 2 analyst of systems, 2 computer science technicians and 4 nursing professors and it showed that the quality of the pages, the time of answer, the link, images and content were considered between excellent and satisfactory.
Martin-Moe, Sheryl; Lim, Fredric J; Wong, Rita L; Sreedhara, Alavattam; Sundaram, Jagannathan; Sane, Samir U
Quality by design (QbD) is a science- and risk-based approach to drug product development. Although pharmaceutical companies have historically used many of the same principles during development, this knowledge was not always formally captured or proactively submitted to regulators. In recent years, the US Food and Drug Administration has also recognized the need for more controls in the drug manufacturing processes, especially for biological therapeutics, and it has recently launched an initiative for Pharmaceutical Quality for the 21st Century to modernize pharmaceutical manufacturing and improve product quality. In the biopharmaceutical world, the QbD efforts have been mainly focused on active pharmaceutical ingredient processes with little emphasis on drug product development. We present a systematic approach to biopharmaceutical drug product development using a monoclonal antibody as an example. The approach presented herein leverages scientific understanding of products and processes, risk assessments, and rational experimental design to deliver processes that are consistent with QbD philosophy without excessive incremental effort. Data generated using these approaches will not only strengthen data packages to support specifications and manufacturing ranges but hopefully simplify implementation of postapproval changes. We anticipate that this approach will positively impact cost for companies, regulatory agencies, and patients, alike.
Brian, William; Tremaine, Larry M; Arefayene, Million; de Kanter, Ruben; Evers, Raymond; Guo, Yingying; Kalabus, James; Lin, Wen; Loi, Cho-Ming; Xiao, Guangqing
Genetic variants of drug metabolism enzymes and transporters can result in high pharmacokinetic and pharmacodynamic variability, unwanted characteristics of efficacious and safe drugs. Ideally, the contributions of these enzymes and transporters to drug disposition can be predicted from in vitro experiments and in silico modeling in discovery or early development, and then be utilized during clinical development. Recently, regulatory agencies have provided guidance on the preclinical investigation of pharmacogenetics, for application to clinical drug development. This white paper summarizes the results of an industry survey conducted by the Industry Pharmacogenomics Working Group on current practice and challenges with using in vitro systems and in silico models to understand pharmacogenetic causes of variability in drug disposition.
Hara, Michikazu; Nakajima, Kiyotaka; Kamata, Keigo
In recent decades, the substitution of non-renewable fossil resources by renewable biomass as a sustainable feedstock has been extensively investigated for the manufacture of high value-added products such as biofuels, commodity chemicals, and new bio-based materials such as bioplastics. Numerous solid catalyst systems for the effective conversion of biomass feedstocks into value-added chemicals and fuels have been developed. Solid catalysts are classified into four main groups with respect to their structures and substrate activation properties: (a) micro- and mesoporous materials, (b) metal oxides, (c) supported metal catalysts, and (d) sulfonated polymers. This review article focuses on the activation of substrates and/or reagents on the basis of groups (a)–(d), and the corresponding reaction mechanisms. In addition, recent progress in chemocatalytic processes for the production of five industrially important products (5-hydroxymethylfurfural, lactic acid, glyceraldehyde, 1,3-dihydroxyacetone, and furan-2,5-dicarboxylic acid) as bio-based plastic monomers and their intermediates is comprehensively summarized. PMID:27877800
Kapoor, Mamta; Lee, Sau L; Tyner, Katherine M
Research in the area of liposomes has grown substantially in the past few decades. Liposomes are lipid bilayer structures that can incorporate drug substances to modify the drug's pharmacokinetic profile thereby improving drug delivery. The agency has received over 400 liposomal drug product submissions (excluding combination therapies), and there are currently eight approved liposomal drug products on the US market. In order to identify the pain points in development and manufacturing of liposomal drug products, a retrospective analysis was performed from a quality perspective on submissions for new and generic liposomal drug products. General analysis on liposomal drug product submissions was also performed. Results indicated that 96% of the submissions were Investigational New Drug (IND) applications, 3% were New Drug Applications (NDAs), and the remaining 1% was Abbreviated New Drug Applications (ANDAs). Doxorubicin hydrochloride was the most commonly used drug substance incorporated into the liposomes (31%). The majority of the liposomal products were administered via intravenous route (84%) with cancer (various types) being the most common indication (63%). From a quality perspective, major challenges during the development of liposomal drug products included identification and (appropriate) characterization of critical quality attributes of liposomal drug products and suitable control strategies during product development. By focusing on these areas, a faster and more efficient development of liposomal drug products may be achieved. Additionally, in this way, the drug review process for such products can be streamlined.
... HUMAN SERVICES Food and Drug Administration Sickle Cell Disease Public Meeting on Patient-Focused Drug... public comment on Patient-Focused Drug Development for sickle cell disease. Patient-Focused Drug... impact of sickle cell disease on daily life and on available therapies for sickle cell disease....
Resnik, D B
This paper discusses the economic, legal, moral, and political difficulties in developing drugs for the developing world. It argues that large, global pharmaceutical companies have social responsibilities to the developing world, and that they may exercise these responsibilities by investing in research and development related to diseases that affect developing nations, offering discounts on drug prices, and initiating drug giveaways. However, these social responsibilities are not absolute requirements and may be balanced against other obligations and commitments in light of economic, social, legal, political, and other conditions. How a company decides to exercise its social responsibilities to the developing world depends on (1) the prospects for a reasonable profit and (2) the prospects for a productive business environment. Developing nations can either help or hinder the pharmaceutical industry's efforts to exercise social responsibility through various policies and practices. To insure that companies can make a reasonable profit, developing nations should honor pharmaceutical product patents and adhere to international intellectual property treaties, such as the Trade-Related Aspects of Intellectual Property Rights (TRIPS) agreement. To insure the companies have a good business environment, developing nations should try to promote the rule of law, ethical business practices, stable currencies, reliable banking systems, free and open markets, democracy, and other conditions conducive to business. Overall, this paper advocates for reciprocity and cooperation between pharmaceutical companies and developing nations to address the problem of developing drugs for the developing world. In pursuing this cooperative approach, developing nations may use a variety of other techniques to encourage pharmaceutical companies to act responsibly, such as subsidizing pharmaceutical research, helping to design and implement research protocols, providing a guaranteed market, and
Cheah, Phaik Yeong; Parker, Michael; Dondorp, Arjen M.
Over 90% of deaths attributable to malaria are in African children under 5 years old. Yet, new treatments are often tested primarily in adult patients and extrapolations have proven to be sometimes invalid, especially in dosing regimens. For studies in severe malaria an additional complication is that the decline in severe malaria in adult patients precludes sufficiently powered trials in adults, before the intervention can be tested in the ultimate target group, paediatric severe malaria. In this paper we propose an alternative pathway to the development of drugs for use in paediatric severe malaria. We argue that following the classical phase I and II studies, small safety and efficacy studies using well-chosen surrogate endpoints in adult severe malaria be conducted, instead of larger mortality endpoint trials. If the drug appears safe and promising small pilot studies in paediatric severe malaria using the same endpoints can follow. Finally, with carefully observed safeguards in place to ensure high ethical standards, promising candidate interventions can be taken forward into mortality endpoint, well-powered, large paediatric studies in African children with severe malaria. Given the available research capacity, limited numbers of prudently selected interventions can be studied in phase III trials, and adaptive designs should be considered. PMID:27620923
Kelly, Patrick; Anand, Prachi; Uvaydov, Alexander; Chakravartula, Srinivas; Sherpa, Chhime; Pires, Elena; O’Neil, Alison; Douglas, Trevor; Holford, Mandë
The potency, selectivity, and decreased side effects of bioactive peptides have propelled these agents to the forefront of pharmacological research. Peptides are especially promising for the treatment of neurological disorders and pain. However, delivery of peptide therapeutics often requires invasive techniques, which is a major obstacle to their widespread application. We have developed a tailored peptide drug delivery system in which the viral capsid of P22 bacteriophage is modified to serve as a tunable nanocontainer for the packaging and controlled release of bioactive peptides. Recent efforts have demonstrated that P22 nanocontainers can effectively encapsulate analgesic peptides and translocate them across blood-brain-barrier (BBB) models. However, release of encapsulated peptides at their target site remains a challenge. Here a Ring Opening Metathesis Polymerization (ROMP) reaction is applied to trigger P22 nanocontainer disassembly under physiological conditions. Specifically, the ROMP substrate norbornene (5-Norbornene-2-carboxylic acid) is conjugated to the exterior of a loaded P22 nanocontainer and Grubbs II Catalyst is used to trigger the polymerization reaction leading to nanocontainer disassembly. Our results demonstrate initial attempts to characterize the ROMP-triggered release of cargo peptides from P22 nanocontainers. This work provides proof-of-concept for the construction of a triggerable peptide drug delivery system using viral nanocontainers. PMID:26473893
Shitov, G G
The conjuncture and technological analysis was made of the current status and approaches to further development of the drugs--chondroprotectors on the basis of glycosaminoglycans. The concept of the goal-oriented search of the new type of drugs for the treatment of diseases of joints and other pathologies was worded on the basis of the systematization and summarization of the reported data and the results of own investigations. This concept rests on the current views of biochemistry of the nature of metabolism and the mechanisms of its regulation. The approach suggested lies in obtaining specific products--protein fragments (polypeptides) that contain oxidized functional groups not found, as a rule, under natural conditions in normal physiological state. The conversion of protein fragments to a higher degree of oxidation means the conversion to the metabolic state in which the possibility of regulating disturbed metabolism is provided. In order to realize the given approach, it is proposed that the oxidation-hydrolytic modification of human placenta may be performed with the aid of chlorine dioxide or direct synthesis. The results of studying the physicochemical and pharmacological properties of the products obtained are presented. Animal experiments have demonstrated a powerful hitherto unknown pharmacotherapeutic action in a dose of 0.3 mg/kg, namely chondroprotective, resolving, reparative, antiinflammatory, antioxidant, analgesic, antistress, and immunotropic. The regulatory mechanism of the action of the substances obtained is suggested.
Arnold, Renée J.G.; Bighash, Lida; Bryón Nieto, Alejandro; Tannus Branco de Araújo, Gabriela; Gay-Molina, Juan Gabriel; Augustovski, Federico
Compared to a decade ago, nearly three times as many drugs for rare diseases are slated for development. This article addresses the market access issues associated with orphan drug status in Europe and the United States in contrast to the legislation in five Latin American (LA) countries that have made strides in this regard--Mexico, Brazil, Colombia, Chile and Argentina. Based on the success of orphan drug legislation in the EU and US, LA countries should strive to adopt similar strategies with regard to rare diseases and drug development. With the implementation of new targeted regulations, reimbursement strategies, and drug approvals, accessibility to treatment will be improved for people afflicted with rare diseases in these developing countries. PMID:25844162
Arnold, Renée J G; Bighash, Lida; Bryón Nieto, Alejandro; Tannus Branco de Araújo, Gabriela; Gay-Molina, Juan Gabriel; Augustovski, Federico
Compared to a decade ago, nearly three times as many drugs for rare diseases are slated for development. This article addresses the market access issues associated with orphan drug status in Europe and the United States in contrast to the legislation in five Latin American (LA) countries that have made strides in this regard--Mexico, Brazil, Colombia, Chile and Argentina. Based on the success of orphan drug legislation in the EU and US, LA countries should strive to adopt similar strategies with regard to rare diseases and drug development. With the implementation of new targeted regulations, reimbursement strategies, and drug approvals, accessibility to treatment will be improved for people afflicted with rare diseases in these developing countries.
He, S-M; Zhou, Z-W; Li, X-T; Zhou, S-F
CYP2C9 metabolizes more than 100 clinically used drugs including phenytoin, S-warfarin, tolbutamide, glipizide, diclofenac, and losartan with varying contributions. CYP2C9 is considered one of the most important CYPs, with substrate specificity typical of many new chemical entities (i.e. lipophilic bases). A large interindividual variation has been identified for the CYP2C9 activity and for the clinical response to the therapeutics metabolised by the enzyme. So far, at least 33 variants of CYP2C9 (*2 through to *34) have been identified. CYP2C9 is one of the clinically significant drug metabolising enzymes that demonstrates genetic variants with significant phenotype and clinical outcomes. This review updates our current knowledge on the polymorphic metabolism of drugs by CYP2C9 and discusses its implications in drug development. The authors have searched through computer-based literatures by full text search in Medline (via Pubmed), ScienceDirect, Genetics Abstracts (CSA), SCOPUS, Chemical Abstracts, Current Contents Connect (ISI), Cochrance Library, CINAHL (EBSCO), CrossRef Search and Embase (all from inception to October 31 2010). A comprehensive literature search has identified 32 drugs that are subject to CYP2C9-mediated polymorphic metabolism. Drugs that are subject to polymorphic metabolism with clinical significance include nine nonsteroidal anti-inflammatory agents, six sulfonylurea antidiabetic drugs and, most critically, three oral coumarin anticoagulants. Polymorphisms in CYP2C9 have the potential to affect the clearance and clinical response of CYP2C9 substrate drugs with low therapeutic indices such as warfarin, phenytoin, and certain antidiabetic drugs. Warfarin has served as a model drug of how pharmacogenetics can be employed to achieve maximum efficacy and minimum toxicity. Minimizing interindividual variability in drug exposure due to CYP2C9 polymorphisms is an important goal in drug development and discovery.
Hu, Wenhui; Ralay Ranaivo, Hantamalala; Craft, Jeffrey M; Van Eldik, Linda J; Watterson, D Martin
The neuroinflammation cycle has been proposed as a potential therapeutic target in the development of new approaches to altering Alzheimer's disease (AD) progression. However, the efficacy and toxicological profile of compounds that focus only on classical NSAID targets have been disappointing to date. Therefore, we recently initiated an unbiased, integrative chemical biology approach that used a hierarchal set of cell-based screens, followed by efficacy analysis in a new AD-relevant animal model that more closely resembles human pathology endpoints in terms of neuroinflammation and neuronal loss. The prior investigations provided a proof of concept that targeting the neuroinflammation cycle may be a viable drug discovery approach for AD. However, recent informatics analyses of the high attrition rate in drug development have identified the need for starting drug development with lead compounds that are well below cut off values in computed molecular properties in order to facilitate late stage medicinal chemistry refinement to improve in vivo functions. We describe here how we are leveraging our novel, unbiased, integrative chemical biology approach for the rapid discovery of potential lead compounds for AD drug discovery. Specifically, we show that orally bioavailable compounds with the desired physical properties and in vivo functions can be identified in focused synthetic libraries composed of chemical diversifications of the inactive but privileged pyridazine molecular fragment.
Agung, Mochammad Anugrah; Basari
Electrocardiogram (ECG) devices measure electrical activity of the heart muscle to determine heart conditions. ECG signal quality is the key factor in determining the diseases of the heart. This paper presents the design of 3-lead acquistion on single channel wireless ECG device developed on AD8232 chip platform using microcontroller. To make the system different from others, monopole antenna 2.4 GHz is used in order to send and receive ECG signal. The results show that the system still can receive ECG signal up to 15 meters by line of sight (LOS) condition. The shape of ECG signals is precisely similar with the expected signal, although some delays occur between two consecutive pulses. For further step, the system will be applied with on-body antenna in order to investigate body to body communication that will give variation in connectivity from the others.
research working in concert with one another. The goal of this work is to use a molecular genetic approach both in the identification of new drug targets...analysis of critical genes in the Plasmodium falciparum for their role in drug resistance and as potential new drug targets using both the homologous P. falciparum system and the heterologous yeast system.
research working in concert with one another. The goal of this work is to use a molecular genetic approach both in the identification of new drug targets and...Plasmodium falciparum for their role in drug resistance and as potential new drug targets, including the analysis of gene expression in response to
Nau, Gerard J.; Ross, Ted M.; Evans, Thomas G.; Chakraborty, Krishnendu; Empey, Kerry M.; Flynn, JoAnne L.
Pulmonary diseases and infections are among the top contributors to human morbidity and mortality worldwide, and despite the successful history of vaccines and antimicrobial therapeutics, infectious disease still presents a significant threat to human health. Effective vaccines are frequently unavailable in developing countries, and successful vaccines have yet to be developed for major global maladies, such as tuberculosis. Furthermore, antibiotic resistance poses a growing threat to human health. The “Challenges and Future in Vaccines, Drug Development, and Immunomodulatory Therapy” session of the 2013 Pittsburgh International Lung Conference highlighted several recent and current studies related to treatment and prevention of antibiotic-resistant bacterial infections, highly pathogenic influenza, respiratory syncytial virus, and tuberculosis. Research presented here focused on novel antimicrobial therapies, new vaccines that are either in development or currently in clinical trials, and the potential for immunomodulatory therapies. These studies are making important contributions to the areas of microbiology, virology, and immunology related to pulmonary diseases and infections and are paving the way for improvements in the efficacy of vaccines and antimicrobials. PMID:25148426
Hansen, Sven Erik
The interplay of factors contributing to the development of adrenal cortical hormones into drugs is reviewed. Clinical research performed during long periods by the physicians T. Addison and P.S. Hench in a nearly obsessional way stimulated basic research in physiology and biochemistry of the adrenal glands. From about 1900 increasing public interest in the "new hormones"coincided with expansion in research and development in academic and industrial settings. Pharmaceutical companies developed skill by production of much demanded organ-extracts, both effective ones as insulin and preparations of questionable clinical value. In 1949 the powerful anti-inflammatory effect of the cortical hormone, cortisone was discovered. As the supply of that hormone was scanty, it had temporarily to be substituted by the adrenocorticotropic hormone (ACTH) from animal hypophyses. Thereafter development accelerated through the combined effect of many years' painstaking research on the adrenal cortical hormones, technological breakthroughs, a climate positive for bold clinical experimentation and vigorous competition among mainly American pharmaceutical companies. Within a decade prednisone, the successor of cortisone, was launched, its clinical use established and large-scale inexpensive production instituted.
Kling, Heather M; Nau, Gerard J; Ross, Ted M; Evans, Thomas G; Chakraborty, Krishnendu; Empey, Kerry M; Flynn, JoAnne L
Pulmonary diseases and infections are among the top contributors to human morbidity and mortality worldwide, and despite the successful history of vaccines and antimicrobial therapeutics, infectious disease still presents a significant threat to human health. Effective vaccines are frequently unavailable in developing countries, and successful vaccines have yet to be developed for major global maladies, such as tuberculosis. Furthermore, antibiotic resistance poses a growing threat to human health. The "Challenges and Future in Vaccines, Drug Development, and Immunomodulatory Therapy" session of the 2013 Pittsburgh International Lung Conference highlighted several recent and current studies related to treatment and prevention of antibiotic-resistant bacterial infections, highly pathogenic influenza, respiratory syncytial virus, and tuberculosis. Research presented here focused on novel antimicrobial therapies, new vaccines that are either in development or currently in clinical trials, and the potential for immunomodulatory therapies. These studies are making important contributions to the areas of microbiology, virology, and immunology related to pulmonary diseases and infections and are paving the way for improvements in the efficacy of vaccines and antimicrobials.
Ma, Cong; Yang, Xiao; Lewis, Peter J
Transcription, the first step of gene expression, is carried out by the enzyme RNA polymerase (RNAP) and is regulated through interaction with a series of protein transcription factors. RNAP and its associated transcription factors are highly conserved across the bacterial domain and represent excellent targets for broad-spectrum antibacterial agent discovery. Despite the numerous antibiotics on the market, there are only two series currently approved that target transcription. The determination of the three-dimensional structures of RNAP and transcription complexes at high resolution over the last 15 years has led to renewed interest in targeting this essential process for antibiotic development by utilizing rational structure-based approaches. In this review, we describe the inhibition of the bacterial transcription process with respect to structural studies of RNAP, highlight recent progress toward the discovery of novel transcription inhibitors, and suggest additional potential antibacterial targets for rational drug design.
Karathanasis, Sotirios K.
Despite the explosion of knowledge in basic biological processes controlling tissue regeneration and the growing interest in repairing/replacing diseased tissues and organs through various approaches (e.g., small and large molecule therapeutics, stem cell injection, tissue engineering), the pharmaceutical industry (pharma) has been reluctant to fully adopt these technologies into the traditional drug discovery and research and development (R&D) process. In this article, I discuss knowledge-base gaps and other possible factors that may delay full incorporation of these innovations in pharma R&D. I hope that this discussion will illuminate key issues that currently limit synergistic relationships between pharma and academic institutions and may even stimulate initiation of such collaborative research. PMID:25085955
Ma, Cong; Yang, Xiao
SUMMARY Transcription, the first step of gene expression, is carried out by the enzyme RNA polymerase (RNAP) and is regulated through interaction with a series of protein transcription factors. RNAP and its associated transcription factors are highly conserved across the bacterial domain and represent excellent targets for broad-spectrum antibacterial agent discovery. Despite the numerous antibiotics on the market, there are only two series currently approved that target transcription. The determination of the three-dimensional structures of RNAP and transcription complexes at high resolution over the last 15 years has led to renewed interest in targeting this essential process for antibiotic development by utilizing rational structure-based approaches. In this review, we describe the inhibition of the bacterial transcription process with respect to structural studies of RNAP, highlight recent progress toward the discovery of novel transcription inhibitors, and suggest additional potential antibacterial targets for rational drug design. PMID:26764017
Motabar, Omid; Sidransky, Ellen; Goldin, Ehud; Zheng, Wei
Fabry disease is a rare inherited lysosomal storage disorder caused by a partial or complete deficiency of α-galactosidase A (GLA), resulting in the storage of excess cellular glycosphingolipids. Enzyme replacement therapy is available for the treatment of Fabry disease, but it is a costly, intravenous treatment. Alternative therapeutic approaches, including small molecule chaperone therapy, are currently being explored. High throughput screening (HTS) technologies can be utilized to discover other small molecule compounds, including non-inhibitory chaperones, enzyme activators, molecules that reduce GLA substrate, and molecules that activate GLA gene promoters. This review outlines the current therapeutic approaches, emerging treatment strategies, and the process of drug discovery and development for Fabry disease.
Hong, S; Lee, J S; Park, J W; Nam, K; Choi, J; Lee, J C; Park, J K; Ko, Y P; Jo, Y H
An intrathecal drug infusion system has been designed, manufactured and tested. The system is composed of a drug reservoir and a pump/controller assembly. The drug reservoir made of SUS316L is a negative pressure gas chamber enclosing a bellows type drug chamber. The pump/controller assembly includes a bacterial filter, a controller circuit board, a battery and a micropump, and is connected to a catheter for intrathecal infusion. The micropump implements a peristaltic pumping of the drug by a sequential motion of three pairs of cam and cam-follower. In vitro performance tests were conducted with prototypes.
Orsini, Larry L.; Hudack, Lawrence R.; Zekan, Donald L.
The value-added statement (VAS), relatively unknown in the United States, is used in financial reports by many European companies. Saint Bonaventure University (New York) has adapted a VAS to make it appropriate for not-for-profit universities by identifying stakeholder groups (students, faculty, administrators/support personnel, creditors, the…
Li, Zhi Jie; Cho, Chi Hin
The development of more selective agents focused on targeted delivery of imaging probes and drugs to different tumor sites is the current trend in cancer diagnosis and therapies. Peptides are small amino acid sequences that can be isolated to bind to a predetermined target and are potentially capable of interfering with its function. These specific peptides isolated can inhibit individual signaling components, which are essential in cancer development and progression. Phage display is a powerful technology for selecting and cloning peptides displayed on the surface of bacteriophage. Billionclone-peptide libraries can be rapidly and simultaneously selected by phage biopanning, leading to large numbers of hits. Although peptides account for only a small part of current therapeutic agents, their potential is being improved by new technologies affecting their modification, delivery, stability and their application in preclinical settings. This review will highlight how to isolate peptides that target pivotal molecules in cancer development and progression through phage library biopanning and how to modify these peptides to enhance their anticancer efficacy.
Baldwin, Aaron David
The use of polymers as biomaterials has evolved over the past several decades, encompassing an expanding synthetic toolbox and many bio-mimetic approaches. Both synthetic and natural polymers have been used as components for biomaterials as their unique chemical structures can provide specific functions for desired applications. Of these materials, heparin, a highly sulfated naturally occurring polysaccharide, has been investigated extensively as a core component in drug delivery platforms and tissue engineering. The goal of this work was to further explore the use of heparin via conjugation with synthetic polymers for applications in drug delivery. We begin by investigating low molecular weight heparin (LMWH), a depolymerized heparin that is used medicinally in the prevention of thrombosis by subcutaneous injection or intravenous drip. Certain disease states or disorders require frequent administration with invasive delivery modalities leading to compliance issues for individuals on prolonged therapeutic courses. To address these issues, a long-term delivery method was developed for LMWH via subcutaneous injection of in situ hydrogelators. This therapy was accomplished by chemical modification of LMWH with maleimide functionality so that it may be crosslinked into continuous hydrogel networks with four-arm thiolated polyethylene glycol (PEG-SH). These hydrogels degrade via hydrolysis over a period of weeks and release bioactive LMWH with first-order kinetics as determined by in vitro and in vivo models, thus indicating the possibility of an alternative means of heparin delivery over current accepted methodologies. Evaluation of the maleimide-thiol chemistries applied in the LMWH hydrogels revealed reversibility for some conjugates under reducing conditions. Addition chemistries, such as maleimide-thiol reactions, are widely employed in biological conjugates and are generally accepted as stable. Here we show that the resulting succinimide thioether formed by the
Sprunk, Angela; Strachan, Clare J; Graf, Anja
The aims of this study were to formulate a self-microemulsifying drug delivery system (SMEDDS) by a rational formulation approach using mixture experimental design and to derive general concepts that make the development of such systems more feasible. Various types of oils and surfactants were systematically combined and the phase behaviour upon dilution with simulated gastric fluid examined by construction of phase diagrams. The systems solubilising the highest amount of simulated gastric fluid in the continuous microemulsion area were selected for investigation and optimisation of drug solubility. Simvastatin was added as a poorly water-soluble, lipophilic model drug. Two different mixture experimental designs using D-optimal design were set up and used to investigate the solubility of simvastatin in the SMEDDS before and after dilution with simulated gastric fluid respectively. The solubility in each mixture region was analysed by fitting quadratic models using partial least squares analysis. The established models revealed the influence of mixture components on phase behaviour and drug solubility and gave the rationale for formulation optimisation. This study demonstrated that the development of complex self-emulsifying formulations with sufficient solubilisation capacity for poorly water-soluble drugs upon oral administration can be more feasible when using experimental design.
Jensen, Kasper; Ni, Yueqiong; Panagiotou, Gianni; Kouskoumvekaki, Irene
Recent research has demonstrated that consumption of food -especially fruits and vegetables- can alter the effects of drugs by interfering either with their pharmacokinetic or pharmacodynamic processes. Despite the recognition of such drug-food associations as an important element for successful therapeutic interventions, a systematic approach for identifying, predicting and preventing potential interactions between food and marketed or novel drugs is not yet available. The overall objective of this work was to sketch a comprehensive picture of the interference of ∼ 4,000 dietary components present in ∼1800 plant-based foods with the pharmacokinetics and pharmacodynamics processes of medicine, with the purpose of elucidating the molecular mechanisms involved. By employing a systems chemical biology approach that integrates data from the scientific literature and online databases, we gained a global view of the associations between diet and dietary molecules with drug targets, metabolic enzymes, drug transporters and carriers currently deposited in DrugBank. Moreover, we identified disease areas and drug targets that are most prone to the negative effects of drug-food interactions, showcasing a platform for making recommendations in relation to foods that should be avoided under certain medications. Lastly, by investigating the correlation of gene expression signatures of foods and drugs we were able to generate a completely novel drug-diet interactome map.
Jensen, Kasper; Ni, Yueqiong; Panagiotou, Gianni; Kouskoumvekaki, Irene
Recent research has demonstrated that consumption of food -especially fruits and vegetables- can alter the effects of drugs by interfering either with their pharmacokinetic or pharmacodynamic processes. Despite the recognition of such drug-food associations as an important element for successful therapeutic interventions, a systematic approach for identifying, predicting and preventing potential interactions between food and marketed or novel drugs is not yet available. The overall objective of this work was to sketch a comprehensive picture of the interference of ∼ 4,000 dietary components present in ∼1800 plant-based foods with the pharmacokinetics and pharmacodynamics processes of medicine, with the purpose of elucidating the molecular mechanisms involved. By employing a systems chemical biology approach that integrates data from the scientific literature and online databases, we gained a global view of the associations between diet and dietary molecules with drug targets, metabolic enzymes, drug transporters and carriers currently deposited in DrugBank. Moreover, we identified disease areas and drug targets that are most prone to the negative effects of drug-food interactions, showcasing a platform for making recommendations in relation to foods that should be avoided under certain medications. Lastly, by investigating the correlation of gene expression signatures of foods and drugs we were able to generate a completely novel drug-diet interactome map. PMID:25668218
Ning, Yang-Min; Maher, V Ellen
Regulatory advice and assessment play an important role in the successful development of new drugs and radiopharmaceuticals for the treatment of urologic malignancies. Cooperation between the US Food and Drug Administration (FDA) and the pharmaceutical industry has led to the approval of more than 20 new urologic oncology products in the last 2 decades. Despite these advances, more effective treatments need to be developed and approved for the treatment of urologic malignancies. This review provides general information about the FDA's role in the development of investigational new drugs, with an emphasis on the regulatory process and the requirements for marketing approval. In addition, this review summarizes the products for the treatment of urologic malignancies that were approved by the FDA in the last 30 years and the key issues concerning urologic oncology products that were discussed publicly at Oncologic Drug Advisory Committee meetings in the past 10 years.
... HUMAN SERVICES Food and Drug Administration Draft Guidance for Industry on Rheumatoid Arthritis... guidance for industry entitled ``Rheumatoid Arthritis: Developing Drug Products for Treatment.'' This... of patients with rheumatoid arthritis (RA). It also addresses additional considerations for...
Pelkonen, Olavi; Pasanen, Markku; Tolonen, Ari; Koskinen, Mikko; Hakkola, Jukka; Abass, Khaled; Laine, Jaana; Hakkinen, Merja; Juvonen, Risto; Auriola, Seppo; Storvik, Markus; Huuskonen, Pasi; Rousu, Timo; Rahikkala, Maiju
Drug metabolism can result in the formation of highly reactive metabolites that are known to play a role in toxicity resulting in a significant proportion of attrition during drug development and clinical use. Thus, the earlier such reactivity was detected, the better. This review summarizes our multi-year project, together with pertinent literature, to examine a battery of in vitro tests capable of detecting the formation of reactive metabolites. Principal prerequisites for such tests were delineated: chemicals known/not known to cause tissue injury and produce reactive metabolites, activation system (mainly human-derived), small- and large-molecular targets (small-molecular trappers, peptides, proteins), analytical techniques (mass spectrometry), and cellular toxicity biomarkers. The current status of in vitro tools to detect reactive intermediates is the following: 1. Small-molecular trapping agents such glutathione or cyanide detect the production of reactive species with high sensitivity by proper MS technique. However, it seems that also putative "negatives" give rise to corresponding adducts. 2. Results from peptide and dG (DNA targeting) trapper studies are generally in line with those of small-molecular trappers, although also important differences exist. These two trapping platforms do not overlap. 3. It is anticipated that the in vitro adduct studies could be fully interpreted only in conjunction with toxicity biomarker (such as the Nrf2 pathway) information from whole cells or tissues. However, while there are tools to characterize the chemical liability and there are correlation between individual/integrated endpoints and toxicity, there are still severe gaps in understanding the mechanisms behind the link between reactive metabolites and adverse effects.
Fan, Teresa W-M.; Lorkiewicz, Pawel; Sellers, Katherine; Moseley, Hunter N.B.; Higashi, Richard M.; Lane, Andrew N.
Advances in analytical methodologies, principally nuclear magnetic resonance spectroscopy (NMR) and mass spectrometry (MS), during the last decade have made large-scale analysis of the human metabolome a reality. This is leading to the reawakening of the importance of metabolism in human diseases, particularly cancer. The metabolome is the functional readout of the genome, functional genome, and proteome; it is also an integral partner in molecular regulations for homeostasis. The interrogation of the metabolome, or metabolomics, is now being applied to numerous diseases, largely by metabolite profiling for biomarker discovery, but also in pharmacology and therapeutics. Recent advances in stable isotope tracer-based metabolomic approaches enable unambiguous tracking of individual atoms through compartmentalized metabolic networks directly in human subjects, which promises to decipher the complexity of the human metabolome at an unprecedented pace. This knowledge will revolutionize our understanding of complex human diseases, clinical diagnostics, as well as individualized therapeutics and drug response. In this review, we focus on the use of stable isotope tracers with metabolomics technologies for understanding metabolic network dynamics in both model systems and in clinical applications. Atom-resolved isotope tracing via the two major analytical platforms, NMR and MS, has the power to determine novel metabolic reprogramming in diseases, discover new drug targets, and facilitates ADME studies. We also illustrate new metabolic tracer-based imaging technologies, which enable direct visualization of metabolic processes in vivo. We further outline current practices and future requirements for biochemoinformatics development, which is an integral part of translating stable isotope-resolved metabolomics into clinical reality. PMID:22212615
Urbina, Julio A
This article presents an overview of the currently available drugs nifurtimox (NFX) and benznidazole (BZN) used against Trypanosoma cruzi, the aetiological agent of Chagas disease; herein we discuss their limitations along with potential alternatives with a focus on ergosterol biosynthesis inhibitors (EBI). These compounds are currently the most advanced candidates for new anti-T. cruzi agents given that they block de novo production of 24-alkyl-sterols, which are essential for parasite survival and cannot be replaced by a host's own cholesterol. Among these compounds, new triazole derivatives that inhibit the parasite's C14alpha sterol demethylase are the most promising, as they have been shown to have curative activity in murine models of acute and chronic Chagas disease and are active against NFX and BZN-resistant T. cruzi strains; among this class of compounds, posaconazole (Schering-Plough Research Institute) and ravuconazole (Eisai Company) are poised for clinical trials in Chagas disease patients in the short term. Other T. cruzi-specific EBI, with in vitro and in vivo potency, include squalene synthase, lanosterol synthase and squalene epoxidase-inhibitors as well as compounds with dual mechanisms of action (ergosterol biosynthesis inhibition and free radical generation), but they are less advanced in their development process. The main putative advantages of EBI over currently available therapies include their higher potency and selectivity in both acute and chronic infections, activity against NFX and BZN-resistant T. cruzi strains, and much better tolerability and safety profiles. Limitations may include complexity and cost of manufacture of the new compounds. As for any new drug, such compounds will require extensive clinical testing before being introduced for clinical use, and the complexity of such studies, particularly in chronic patients, will be compounded by the current limitations in the verification of true parasitological cures for T. cruzi
Bogan, Reinhard; Worek, Franz; Koller, Marianne; Klaubert, Bernd
HI-6 exhibits superior efficacy in the therapy of intoxication by different highly toxic organophosphorus nerve agents. Therefore HI-6 is a promising candidate for the development of new antidotes against nerve agents. For ethical and safety reasons antidotes containing HI-6 should get marketing authorization. Active pharmaceutical ingredients of medicinal products have to fulfil regulatory conditions in terms of purity and stability. Photostability is an essential parameter in this testing strategy. HI-6 was tested under conditions of ICH Q1B 'Photostability testing of new drug substances and products'. The data showed a marked degradation of HI-6 after exposure to daylight. The mechanism of degradation could be detected as photoisomerism. The light burden dependent rate of photoisomerism was followed quantitatively. Based on these quantitative results on the amount of light induced isomeric product a pharmacological qualification was made. A standardized in vitro test showed a decreased ability of light exposed HI-6 to reactivate sarin- and paraoxon-inhibited human acetylcholinesterase. These results have an impact on the further development of antidotes containing HI-6, as light protection will probably be necessary during handling, packaging, storage and application.
Zavyalova, Elena; Golovin, Andrey; Pavlova, Galina; Kopylov, Alexey
Blood hemostasis is attained with two sophisticated interconnected network systems, a coagulation cascade and a platelet activation system. Multiple inhibitors were developed to various components of both systems to prevent thrombosis-related morbid events that are of extremely high frequency in the human population. Antithrombotic inhibitors possess both positive and negative aspects. One of the essential modern requirements is a controllable mode of action for both anticoagulants and antiplatelets that could be achieved due to the high affinity and specificity of the inhibitor, as well as a possibility to apply an antidote, which quickly annihilates activity of the inhibitor and restores the proper hemostasis. Aptamers are DNA or RNA oligonucleotides with particular tertiary structure, such as DNA guanine quadruplex. Besides antibodies and other peptides/proteins, aptamers are one more example of the molecular recognizing elements that specifically bind to the target. Therefore, aptamers could be developed into a promising novel class of the drugs with high affinity, specificity, innate low toxicity, and rational antidote. Several aptamers with prospective antithrombotic activity have been reviewed; some of them are in preclinical and clinical trials.
Zhang, Jing; Fan, Wei; Li, Hong-Fa; Man, Shu-Li; Liu, Zhen; Gao, Wen-Yuan
Risk monitoring of new Chinese patent anti-hepatoma drugs is tracking recognized risks and residual risks, identifying emerging risk and ensure the implementation of the plan, estimating the process of reducing effectiveness. The paper is mainly through understanding the status of Chinese patent anti-hepatoma drugs, the content, characteristic and analysis method of dynamic risk monitoring, and then select the risk control indicators, collect risk information. Finally, puts forward the thought of anti-hepatoma drugs listed evaluation in our country, and try to establish the model of dynamic risk management of anti-hepatoma drugs.
Hoffmann, Georg F.
Background Epilepsy is a serious chronic health condition with a high morbidity impairing the life of patients and afflicted families. Many epileptic conditions, especially those affecting children, are rare disorders generating an urgent medical need for more efficacious therapy options. Therefore, we assessed the output of the US and European orphan drug legislations. Methods Quantitative analysis of the FDA and EMA databases for orphan drug designations according to STrengthening the Reporting of OBservational studies in Epidemiology (STROBE) criteria. Results Within the US Orphan Drug Act 40 designations were granted delivering nine approvals, i.e. clobazam, diazepam viscous solution for rectal administration, felbamate, fosphenytoin, lamotrigine, repository corticotropin, rufinamide, topiramate, and vigabatrin. Since 2000 the EMA granted six orphan drug designations whereof two compounds were approved, i.e. rufinamide and stiripentol. In the US, two orphan drug designations were withdrawn. Orphan drugs were approved for conditions including Lennox-Gastaut syndrome, infantile spasms, Dravet syndrome, and status epilepticus. Comparing time to approval for rufinamide, which was approved in the US and the EU to treat rare seizure conditions, the process seems faster in the EU (2.2 years) than in the US (4.3 years). Conclusion Orphan drug development in the US and in the EU delivered only few molecular entities to treat rare seizure disorders. The development programs focused on already approved antiepileptic drugs or alternative pharmaceutical formulations. Most orphan drugs approved in the US are not approved in the EU to treat rare seizures although some were introduced after 2000 when the EU adopted the Orphan Drug Regulation. PMID:27557111
Li, Albert P
Over the past decades, a number of drugs have been withdrawn or have required special labeling due to adverse effects observed post-marketing. Species differences in drug toxicity in preclinical safety tests and the lack of sensitive biomarkers and nonrepresentative patient population in clinical trials are probable reasons for the failures in predicting human drug toxicity. It is proposed that toxicology should evolve from an empirical practice to an investigative discipline. Accurate prediction of human drug toxicity requires resources and time to be spent in clearly defining key toxic pathways and corresponding risk factors, which hopefully, will be compensated by the benefits of a lower percentage of clinical failure due to toxicity and a decreased frequency of market withdrawal due to unacceptable adverse drug effects.
Löbler, Marian; Sternberg, Katrin; Stachs, Oliver; Allemann, Reto; Grabow, Niels; Roock, Anne; Kreiner, Christine F; Streufert, Detlef; Neffe, Axel T; Hanh, Bui Duc; Lendlein, Andreas; Schmitz, Klaus-Peter; Guthoff, Rudolf
Implantation of a glaucoma drainage system is an appropriate therapeutic intervention in some glaucoma patients. However, one drawback with this approach is the fibrotic tissue response to the implant material, leading to reduced flow of aqueous liquid or complete blockage of the drainage system. As a basis for developing an aqueous shunt we report here investigations with poly(3-hydroxybutyrate) (P(3HB)) and poly(4-hydroxybutyrate) (P(4HB)) as polymer matrices and with paclitaxel (PTX) and triamcinolone acetonide (TA) as drugs that might, in combination, delay or prevent the process of fibrosis by reducing fibroblast activity. P(3HB) and P(4HB) were fabricated into test prototypes with 500 μm outer and 200 μm inner diameter and ∼1 cm length. The antiproliferative agent PTX and the anti-inflammatory agent TA were incorporated into the polymer matrices and were released by diffusion. In vitro cell assays demonstrated that the polymers have the potential to reduce fibroblast viability, while TA showed differential inhibition of Tenon fibroblasts, but not cornea keratocytes. Implantation of polymer disks and prototype devices into rabbit eyes confirmed the good biocompatibility of the materials. The combined use of a poly(hydroxybutyrate) polymer with PTX or TA has the potential to reduce the fibrosis associated with conventional glaucoma drainage systems.
Bracken, Louise E.; Nunn, Anthony J.; Kirkham, Jamie J.; Peak, Matthew; Arnott, Janine; Smyth, Rosalind L.; Pirmohamed, Munir; Turner, Mark A.
Aim To develop and test a new tool to assess the avoidability of adverse drug reactions that is suitable for use in paediatrics but which is also applicable to a variety of other settings. Methods The study involved multiple phases. Preliminary work involved using the Hallas scale and a modification of the existing Hallas scale, to assess two different sets of adverse drug reaction (ADR) case reports. Phase 1 defined, modified and refined a new tool using multidisciplinary teams. Phase 2 involved the assessment of 50 ADR case reports from a prospective study of paediatric inpatients by individual assessors. Phase 3 compared assessments with the new tool for individuals and groups in comparison to the ‘gold standard’ (the avoidability outcome set by a panel of senior investigators: an experienced clinical pharmacologist, paediatrician and pharmacist). Main Outcome Measures Inter-rater reliability (IRR), measure of disagreement and utilization of avoidability categories. Results Preliminary work—Pilot phase: results for the original Hallas cases were fair and pairwise kappa scores ranged from 0.21 to 0.36. Results for the modified Hallas cases were poor, pairwise kappa scores ranged from 0.06 to 0.16. Phase 1: on initial use of the new tool, agreement between the two multidisciplinary groups was found on 13/20 cases with a kappa score of 0.29 (95% CI -0.04 to 0.62). Phase 2: the assessment of 50 ADR case reports by six individual reviewers yielded pairwise kappa scores ranging from poor to good 0.12 to 0.75 and percentage exact agreement (%EA) ranged from 52–90%. Phase 3: Percentage exact agreement ranged from 35–70%. Overall, individuals had better agreement with the ‘gold standard’. Conclusion Avoidability assessment is feasible but needs careful attention to methods. The Liverpool ADR avoidability assessment tool showed mixed IRR. We have developed and validated a method for assessing the avoidability of ADRs that is transparent, more objective than
Tu, Peng-fei; Jiang, Yong; Guo, Xiao-yu
Referring to the rapid developed life science and the higher requirements for the approval of innovative Chinese drugs in recent years, this paper described systematically the discovery, research and development (R&D) approaches for the innovative Chinese drugs under the new situation from the following five aspects, i. e., active components discovered from TCMs, the discovery of effective fractions of TCMs and their formulae, the R&D of TCM innovative drugs based on famous classic prescriptions and famous Chinese patent drugs, and the transformation of clinical effective prescriptions, on the basis of analysing the advantages of innovative drugs derived from natural products based on TCM theories and the problems existed in current R&D of new TCM drugs. Moreover, five suggestions are also given for the rapid development of TCM innovative drugs in China. All these will provide reference for the R&D of TCM innovative drugs.
Michelson, S; Joho, K
Drug development is a very expensive and inefficient process. Currently, it takes on average 15 years and costs approximately US $500 million to bring a new drug to market, with the pharmaceutical industry spending more than US $20 billion in identifying and developing drugs in 1998. Twenty-two percent of this total was spent on screening assays and toxicity testing. Yet the rapidly accelerating advances in high-throughput technologies, including screening and robotics, combinatorial chemistry, and genomics makes this an extremely data-rich environment. Add to that the new paradigms of pharmacogenomics and 'customized medicine', and the question is, are we helping or hurting our cause? Clearly, interpreting this flood of data and turning it into useful information is our next great hurdle. By extending the pharmacogenomic paradigm to the drug discovery process, this paper intends to put the scope of the problem into context.
Arkhipov, V I; Kapralova, M V
The review is devoted to experimental investigations of metabotropic glutamate receptors and the properties of drugs (ligands) belonging to agonists, antagonists, and modulators of the activity of these receptors. Possibilities of the treatment of neurodegenerative disorders, cognitive disturbances in schizophrenia patients, and narcotic dependency by using drugs of this class are considered.
Bhunu, C. P.
Homelessness and drug-misuse are known to exist like siamese twins. We present a model to capture the dynamics in the growth in the number of homeless (street kids and street adults) and drug misusers. The reproduction numbers of the model are determined and analyzed. Results from this study suggests that adult peer pressure plays a more significant role in the growth of drug-misuse and the number of street kids. This result suggests that in resource constrained settings intervention strategies should be tailor made to target adults whose behaviour influence others to misuse drugs and abuse children. Furthermore, numerical simulations show that homelessness and drug-misuse positively enhances, the growth of each other. Thus, to effectively control these two social problems require strategies targeting both of them.
Creeley, Catherine E.; Olney, John W.
Maternal ingestion of alcohol during pregnancy can cause a disability syndrome termed Fetal Alcohol Spectrum Disorder (FASD), which may include craniofacial malformations, structural pathology in the brain, and a variety of long-term neuropsychiatric disturbances. There is compelling evidence that exposure to alcohol during early embryogenesis (4th week of gestation) can cause excessive death of cell populations that are essential for normal development of the face and brain. While this can explain craniofacial malformations and certain structural brain anomalies that sometimes accompany FASD, in many cases these features are absent, and the FASD syndrome manifests primarily as neurobehavioral disorders. It is not clear from the literature how alcohol causes these latter manifestations. In this review we will describe a growing body of evidence documenting that alcohol triggers widespread apoptotic death of neurons and oligodendroglia (OLs) in the developing brain when administered to animals, including non-human primates, during a period equivalent to the human third trimester of gestation. This cell death reaction is associated with brain changes, including overall or regional reductions in brain mass, and long-term neurobehavioral disturbances. We will also review evidence that many drugs used in pediatric and obstetric medicine, including general anesthetics (GAs) and anti-epileptics (AEDs), mimic alcohol in triggering widespread apoptotic death of neurons and OLs in the third trimester-equivalent animal brain, and that human children exposed to GAs during early infancy, or to AEDs during the third trimester of gestation, have a significantly increased incidence of FASD-like neurobehavioral disturbances. These findings provide evidence that exposure of the developing human brain to GAs in early infancy, or to alcohol or AEDs in late gestation, can cause FASD-like neurodevelopmental disability syndromes. We propose that the mechanism by which alcohol, GAs and
Hurst, Hunter, Ed.; And Others
This document contains the third volume of "Today's Delinquent," an annual publication of the National Center for Juvenile Justice. This volume deals with the issue of drugs and includes articles by leading authorities in delinquency and substance abuse who share their views on causes and cures for the drug problem among youth in this country.…
Ozawa, Hikaru; Abiko, Yasushi; Akimoto, Takeshi
The developments and trends of hemostatic and antithrombotic drugs in Japan were investigated chronologically for the last 50 years after the 2nd World War. 1. Hemostatic drugs are classified into three groups ; capillary stabilizers, blood coagulants and antifibrinolytics. l) As to capillary stabilizers, flavonoid (rutin, 1949), adrenochrome derivative (carbazochrome, 1954) and conjugated estrogen (Premarin, 1964) were introduced therapeutically. Especially, the soluble types of adrenochrome compounds (Adona 1956, S-Adchnon, 1962) were devised and used widely in Japan. 2) Drugs concerning blood coagulation, thrombin, introduced in 1953, and hemocoagulase, a snake venom introduced in 1966, were used clinically. V.K. groups producing various coagulation factors were introduced as V.K1 (Phytonadione, 1962) and V.K2 (rnenatetrenone,1972), and they were admitted in "The Japanese Pharmacopoeia"editions 8 and 14, respectively). 3) Regarding antifibrinolytic drugs, Japanese researchers have made remarkable contributions. e-Aminocapronic acid (Ipsilon, 1962) and tranexamic acid (Transamin, 1965) were developed and used for various abnormal bleedings or hemorrhage associated with plasmin over-activation. tranexamic acid also proved to suppress inflammations of the throat such as tonsillitis, pharyngitis or laryngitis. 2. Antithrombotic drugs are also divided into three groups; anticoagulants, antiplatelet drugs and fibrinolytics.1) The anticoagulants used therapeutically by injection are heparins (Na-salt, 1951; Ca-salt, 1962) and low-molecular-weight heparins such as dalteparin (1992), parnaparin (1994) and reviparin (1999). The low molecule compounds are superior to the original heparins in reducing the risk of bleeding. As oral anticoagulants, coumarin derivatives, dicumarol (1950), ethylbiscoumacetate (1954), phenylindandione (1956) and warfarin (1962) are known. Warfarin potassium is the main drug for oral therapy of thromboembolism lately. Gabexate mesilate (1989) and
Burke, Amy C; Dron, Jacqueline S; Hegele, Robert A; Huff, Murray W
Proprotein convertase subtilisin/kexin type-9 (PCSK9) is a secreted zymogen expressed primarily in the liver. PCSK9 circulates in plasma, binds to cell surface low-density lipoprotein (LDL) receptors, is internalized, and then targets the receptors to lysosomal degradation. Studies of naturally occurring PCSK9 gene variants that caused extreme plasma LDL cholesterol (LDL-C) deviations and altered atherosclerosis risk unleashed a torrent of biological and pharmacological research. Rapid progress in understanding the physiological regulation of PCSK9 was soon translated into commercially available biological inhibitors of PCSK9 that reduced LDL-C levels and likely also cardiovascular outcomes. Here we review the swift evolution of PCSK9 from novel gene to drug target, to animal and human testing, and finally to outcome trials and clinical applications. In addition, we explore how the genetics-guided path to PCSK9 inhibitor development exemplifies a new paradigm in pharmacology. Finally, we consider some potential challenges as PCSK9 inhibition becomes established in the clinic.
Yildiz, Mustafa; Yildiz, Banu Sahin; Gursoy, Mustafa Ozan; Akin, Ibrahim
The interventional treatment of coronary artery disease was introduced in 1970`s by Andreas Grüntzig. The initial treatment strategy with plain old balloon angioplasty (POBA) was associated with high restenosis rates. The introduction of coronary stents, especially drug-eluting stents (DES) in 2002 has improved the results by lowering the rate of in-stent restenosis from 20-40% in the era of bare-metal stent (BMS) to 6-8%. However, in 2006 with the observation of late stent thrombosis the reputations of DES have decreased. However, improvements in stent design especially antiproliferative agents, polymeric agents as well as stent platforms improved newer generation DES. In controlled trials as well as registries the use of second-generation DES as compared to bare-metal stents (BMS) was associated with better clinical and angiographic results. A further development of these stents with use of biodegradable polymers, polymer-free stents, and biodegradable stents on the basis of poly L-lactide (PLLA) or magnesium resulted in third-generation DES and has been evaluated in preclinical and first clinical trials. However, to date, there is a lack of data comparing these third-generation DES with first- and second-generatrion DES in a large scale.
Yuan, Zhilong; Chen, Gang; Huang, Qin
Many methods have been proposed to account for the potential impact of ethnic/regional factors when extrapolating results from multiregional clinical trials (MRCTs) to targeted ethnic (TE) patients, i.e., "bridging." Most of them either focused on TE patients in the MRCT (i.e., internal bridging) or a separate local clinical trial (LCT) (i.e., external bridging). Huang et al. (2012) integrated both bridging concepts in their method for the Simultaneous Global Drug Development Program (SGDDP) which designs both the MRCT and the LCT prospectively and combines patients in both trials by ethnic origin, i.e., TE vs. non-TE (NTE). The weighted Z test was used to combine information from TE and NTE patients to test with statistical rigor whether a new treatment is effective in the TE population. Practically, the MRCT is often completed before the LCT. Thus to increase the power for the SGDDP and/or obtain more informative data in TE patients, we may use the final results from the MRCT to re-evaluate initial assumptions (e.g., effect sizes, variances, weight), and modify the LCT accordingly. We discuss various adaptive strategies for the LCT such as sample size reassessment, population enrichment, endpoint change, and dose adjustment. As an example, we extend a popular adaptive design method to re-estimate the sample size for the LCT, and illustrate it for a normally distributed endpoint.
The development of new models and tools has led to the discovery and clinical development of a large number of new anti-hepatitis C virus (HCV) drugs, including direct-acting antivirals and host-targeted agents. Surprisingly, curing HCV infection appears to be easy with these new drugs, provided that a potent drug combination with a high barrier to resistance is used. HCV infection cure rates can be optimized by combining drugs with synergistic antiviral effects, tailoring treatment duration to the patients' needs, and/or using ribavirin. Two HCV drugs have been approved in 2011--telaprevir and boceprevir, both first-wave, first-generation NS3-4A protease inhibitors, two others in 2013/2014--simeprevir, a second-wave, first-generation NS3-4A protease inhibitor, and sofosbuvir, a nucleotide analogue inhibitor of the viral polymerase. Numerous other drugs have reached phase II or III clinical development. From 2015 and onwards, interferon-containing regimens will disappear, replaced by interferon-free regimens yielding infection cure rates over 90%. These therapies will raise new issues, including the need for broad-scale screening and access to care.
Hadi, Pejman; Yeung, Kit Ying; Guo, Jiaxin; Wang, Huaimin; McKay, Gordon
This paper aims at the sustainable development of activated carbons for value-added applications from the waste tyre pyrolysis product, tyre char, in order to make pyrolysis economically favorable. Two activation process parameters, activation temperature (900, 925, 950 and 975 °C) and residence time (2, 4 and 6 h) with steam as the activating agent have been investigated. The textural properties of the produced tyre char activated carbons have been characterized by nitrogen adsorption-desorption experiments at -196 °C. The activation process has resulted in the production of mesoporous activated carbons confirmed by the existence of hysteresis loops in the N2 adsorption-desorption curves and the pore size distribution curves obtained from BJH method. The BET surface area, total pore volume and mesopore volume of the activated carbons from tyre char have been improved to 732 m(2)/g, 0.91 cm(3)/g and 0.89 cm(3)/g, respectively. It has been observed that the BET surface area, mesopore volume and total pore volume increased linearly with burnoff during activation in the range of experimental parameters studied. Thus, yield-normalized surface area, defined as the surface area of the activated carbon per gram of the precursor, has been introduced to optimize the activation conditions. Accordingly, the optimized activation conditions have been demonstrated as an activation temperature of 975 °C and an activation time of 4 h.
Thompson, Lorna J.; Kratochvil, Daniel W.
This report of the development of a drug-educational product which appears to have potential impact, is based upon published materials, documents in the files of the developing agency, and interviews with staff who were involved in the development of the product. The long-range goal of the drug program is to encourage young people to develop…
Wang, J; Avant, D; Green, D; Seo, S; Fisher, J; Mulberg, A E; McCune, S K; Burckart, G J
Conducting clinical trials in neonates is challenging, and knowledge gaps in neonatal clinical pharmacology exist. We surveyed the US Food and Drug Administration databases and identified 43 drugs studied in neonates or referring to neonates between 1998 and 2014. Twenty drugs were approved in neonates. For 10 drugs, approval was based on efficacy data in neonates, supplemented by pharmacokinetic data for four drugs. Approval for neonates was based on full extrapolation from older patients for six drugs, and partial extrapolation was the basis of approval for four drugs. Dosing recommendations differed from older patients for most drugs, and used body-size based adjustment in neonates. Trial failures were associated with various factors including inappropriate dose selection. Successful drug development in neonates could be facilitated by an improved understanding of the natural history and pathophysiology of neonatal diseases and identification and validation of clinically relevant biomarkers.
... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration Food and Drug Administration/American Academy of Ophthalmology Workshop on Developing Novel Endpoints for Premium Intraocular Lenses; Public Workshop AGENCY: Food and Drug Administration, HHS. ACTION:...
This article presents a re-conceptualization of moderate adolescent drug use. It is argued that experimentation with alcohol and other drugs during the teenage years may play an important role in the development of regulatory competency in relation to drug consumption in adulthood. When such regulatory skills fail to emerge in young people, during…
... disorder of the central nervous system caused by the brain's inability to control sleep-wake cycles and is... HUMAN SERVICES Food and Drug Administration Narcolepsy Public Meeting on Patient-Focused Drug Development AGENCY: Food and Drug Administration, HHS. ACTION: Notice of public meeting; request for...
Roberts, S A; Miya, T S; Schnell, R C
Cadmium administration potentiates the duration of hexobarbital-induced hypnosis and inhibits the rate of hepatic microsomal metabolism of this drug in the male rat. The threshold dose of cadmium required to produce these alterations in drug action is 0.84 mg Ck/kg. If subthreshold doses of cadmium (0.21 or 0.42 mg Cd/kg) are administered prior to the 0.84 mg Cd/kg dose, the cadmium-induced alterations in drug action are no longer observed.
Chen, Ang; Shi, Ye; Yan, Zhiqiang; Hao, Hongxun; Zhang, Yong; Zhong, Jian; Hou, Huiming
A large amount of new drug candidates are practically insoluble in aqueous solvents and are even simultaneously poorly soluble in organic solvents. Nanosuspension drug delivery system (DDS) was firstly developed in 1994 and has attracted more and more attention as a formation solution for the poorly soluble drugs. By nansizing the poorly soluble drugs, nanosuspensions have several outstanding advantages for drug delivery. Among many administration routes of drug delivery, oral administration is the most preferred route due to its advantages such as ease of ingestion, versatility to accommodate various types of drug candidates, low production cost, high safety, good patient compliance, and pain avoidance. Current marketed pharmaceutical nanosuspension DDS products are mostly for oral administration. This review is to systematically summarize the nanosuspension DDS dosage form developments of poorly soluble drugs for oral administration use.
Caprino, Luciano; Russo, Pierluigi
Assessment of drug innovation is a burning issue because it involves so many different perspectives, mainly those of patients, decision- and policy-makers, regulatory authorities and pharmaceutical companies. Moreover, the innovative value of a new medicine is usually an intrinsic property of the compound, but it also depends on the specific context in which the medicine is introduced and the availability of other medicines for treating the same clinical condition. Thus, a model designed to assess drug innovation should be able to capture the intrinsic properties of a compound (which usually emerge during R&D) and/or modification of its innovative value with time. Here we describe the innovation assessment algorithm (IAA), a simulation model for assessing drug innovation. IAA provides a score of drug innovation by assessing information generated during both the pre-marketing and the post-marketing authorization phase.
synthesis of CNS-targeted prodrug esters of ribavirin and selenazole, pharmacokinetic studies of drug distribution and sustained delivery of drug in the brain...The scope of the research program involves the synthesis of CNS-targeted prodrug esters of ribavirin and selenazole, pharmaco- kinetic, studies of...blood-brain barrier. Our initial efforts have been directed toward the synthesis of ribavirin prodrugs. Based upon the brain-specific delivery of, for
Du, Dongyi; Goldsmith, John; Aikin, Kathryn J; Encinosa, William E; Nardinelli, Clark
In 2007 the federal government began requiring drug makers to include in their print direct-to-consumer advertisements information for consumers on how to contact the Food and Drug Administration directly, either by phone or through the agency's website, to report any adverse events that they experienced after taking a prescription drug. Adverse events can range from minor skin problems like itching to serious injuries or illness that result in hospitalization, permanent disability, or even death. Even so, current rates of adverse event reporting are low. We studied adverse event reports about 123 drugs that came from patients before and after the enactment of the print advertising requirement and estimated that requirement's impact with model simulations. We found that if monthly spending on print direct-to-consumer advertising increased from zero to $7.7 million per drug, the presence of the Food and Drug Administration contact information tripled the increase in patient-reported adverse events, compared to what would have happened in the absence of the law. However, the absolute monthly increase was fewer than 0.24 reports per drug, suggesting that the public health impact of the increase was small and that the adverse event reporting rate would still be low. The study results suggest that additional measures, such as more publicity about the Adverse Event Reporting System or more consumer education, should be considered to promote patient reporting of adverse events.
Tell, Volkmar; Holzer, Max; Herrmann, Lydia; Mahmoud, Kazem Ahmed; Schächtele, Christoph; Totzke, Frank; Hilgeroth, Andreas
Alzheimer disease (AD) turned out to be a multifactorial process leading to neuronal decay. So far merely single target structures which attribute to the AD progression have been considered to develop specific drugs. However, such drug developments have been disappointing in clinical stages. Multitargeting of more than one target structure determines recent studies of developing novel lead compounds. Protein kinases have been identified to contribute to the neuronal decay with CDK1, GSK-3β and CDK5/p25 being involved in a pathological tau protein hyperphosphorylation. We discovered novel lead structures of the dihydroxy-1-aza-9-oxafluorene type with nanomolar activities against CDK1, GSK-3β and CDK5/p25. Structure-activity relationships (SAR) of the protein kinase inhibition are discussed within our first compound series. One nanomolar active compound profiled as selective protein kinase inhibitor. Bioanalysis of a harmless cellular toxicity and of the inhibition of tau protein phosphorylation qualifies the compound for further studies.
Kentucky State Dept. of Education, Frankfort. Div. of Program Development.
This guide is designed to provide teachers with concepts and instructional experiences for use in classroom drug education. Teachers are encouraged to develop additional student activities, audio-visuals, and evaluation tools. Activities have been developed to enable students to: (1) increase their knowledge of drugs; (2) develop skills in making…
Page, Richard C.; Berkow, Daniel N.
Describes group work designed to promote spiritual development with drug and alcohol abusers. Provides a definition of spirituality. Discusses research that relates to the spiritual development of members of drug and alcohol groups. Compares the ways that group work and Alcoholics Anonymous promote spiritual development. (Author/MKA)
De Clercq, Erik
Antiviral drug development has often followed a curious meandrous route, guided by serendipity rather than rationality. This will be illustrated by ten examples. The polyanionic compounds (i) polyethylene alanine (PEA) and (ii) suramin were designed as an antiviral agent (PEA) or known as an antitrypanosomal agent (suramin), before they emerged as, respectively, a depilatory agent, or reverse transcriptase inhibitor. The 2',3'-dideoxynucleosides (ddNs analogues) (iii) have been (and are still) used in the "Sanger" DNA sequencing technique, although they are now commercialized as nucleoside reverse transcriptase inhibitors (NRTIs) in the treatment of HIV infections. (E)-5-(2-Bromovinyl)-2'-deoxyuridine (iv) was discovered as a selective anti-herpes simplex virus compound and is now primarily used for the treatment of varicella-zoster virus infections. The prototype of the acyclic nucleoside phosphonates (ANPs), (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine [(S)-HPMPA], (v) was never commercialized, although it gave rise to several marketed products (cidofovir, adefovir, and tenofovir). 1-[2-(Hydroxyethoxy)methyl]-6-(phenylthio)thymine (vi) and TIBO (tetrahydroimidazo[4,5,1-jk][1,4-benzodiazepin-2(1H)]-one and -thione) (vii) paved the way to a number of compounds (i.e., nevirapine, delavirdine, etravirine, and rilpivirine), which are now collectively called non-NRTIs. The bicyclam AMD3100 (viii) was originally described as an anti-HIV agent before it became later marketed as a stem cell mobilizer. The S-adenosylhomocysteine hydrolase inhibitors (ix), while active against a broad range of (-)RNA viruses and poxviruses may be particularly effective against Ebola virus, and for (x) the O-ANP derivatives, the potential application range encompasses virtually all DNA viruses.
Festing, Michael F W
There is growing concern about the poor quality and lack of repeatability of many pre-clinical experiments involving laboratory animals. According to one estimate as much as $28 billion is wasted annually in the USA alone in such studies. A decade ago the FDA's "Critical path" white paper noted that "The traditional tools used to assess product safety-animal toxicology and outcomes from human studies-have changed little over many decades and have largely not benefited from recent gains in scientific knowledge. The inability to better assess and predict product safety leads to failures during clinical development and, occasionally, after marketing." Repeat-dose 28-days and 90-days toxicity tests in rodents have been widely used as part of a strategy to assess the safety of drugs and chemicals but their repeatability and power to detect adverse effects have not been formally evaluated.The guidelines (OECD TG 407 and 408) for these tests specify the dose levels and number of animals per dose but do not specify the strain of animals which should be used. In practice, almost all the tests are done using genetically undefined "albino" rats or mice in which the genetic variation, a major cause of inter-individual and strain variability, is unknown and uncontrolled. This chapter suggests that a better strategy would be to use small numbers of animals of several genetically defined strains of mice or rats instead of the undefined animals used at present. Inbred strains are more stable providing more repeatable data than outbred stocks. Importantly their greater phenotypic uniformity should lead to more powerful and repeatable tests. Any observed strain differences would indicate genetic variation in response to the test substance, providing key data. We suggest that the FDA and other regulators and funding organizations should support research to evaluate this alternative.
Sanders, Bryan K
Amateau and McCarthy's findings published in Nature Neuroscience (June 2004) are noteworthy for suggesting a role for prostaglandins in sexual development. However, evidence suggests that in manipulating PGE2, they unknowingly implicated 3alpha-hydroxysteroid dehydrogenase [E.C. 22.214.171.124], 3(or 17)alpha-hydroxysteroid dehydrogenase [E.C. 126.96.36.199] and their respective products, androsterone (ADT) and epitestosterone (EpiT), in the developmental masculinization of sex behavior. EpiT is generally regarded as a hormonally inactive 17alpha-epimer of testosterone (T). In rats, the kidney is the primary site of EpiT formation, whereas in humans it originates from the gonads, with only a small contribution secreted by the adrenals. Because the ratio of T to EpiT is nearly constant, it is presently used for assessing steroid abuse in competitive sports, where the World Anti-Doping Agency (WADA) considers a T/EpiT ratio >4 evidence of T doping. Despite its central role in the detection of illict anabolic steroid use, our knowledge of factors effecting EpiT production is poor. Clues in the literature, however, reveal that prostaglandin-mediated processes, such as LHRH release, may influence its production. Antimycotics, NSAIDs, and opioid analgesics used in sports medicine are all known to effect prostaglandin E2 synthesis. Primary PGs are potent inhibitors of ADT oxidation, while indomethacin, a prostaglandin blocker, powerfully inhibits 3alpha-HSD reduction and ADT oxidation. This is significant because ADT inhibits the oxidation of EpiT, and may modulate its antiandrogenic and neuroprotective effects. It is hypothesized that the T/EpiT ratio is increased by COX-2 inhibitors and opiod analgesics, and decreased by antimycotics that do not impair testosterone biosynthesis. Given the devastating personal and career consequences that may result from false positive drug tests, substantive research on the effects of PGE2 manipulations on EpiT is warranted.
Solfrizzi, Vincenzo; Imbimbo, Bruno P.; Lozupone, Madia; Santamato, Andrea; Zecca, Chiara; Barulli, Maria Rosaria; Bellomo, Antonello; Pilotto, Alberto; Daniele, Antonio; Greco, Antonio
The failure of several Phase II/III clinical trials in Alzheimer's disease (AD) with drugs targeting β-amyloid accumulation in the brain fuelled an increasing interest in alternative treatments against tau pathology, including approaches targeting tau phosphatases/kinases, active and passive immunization, and anti-tau aggregation. The most advanced tau aggregation inhibitor (TAI) is methylthioninium (MT), a drug existing in equilibrium between a reduced (leuco-methylthioninium) and oxidized form (MT+). MT chloride (methylene blue) was investigated in a 24-week Phase II clinical trial in 321 patients with mild to moderate AD that failed to show significant positive effects in mild AD patients, although long-term observations (50 weeks) and biomarker studies suggested possible benefit. The dose of 138 mg/day showed potential benefits on cognitive performance of moderately affected AD patients and cerebral blood flow in mildly affected patients. Further clinical evidence will come from the large ongoing Phase III trials for the treatment of AD and the behavioral variant of frontotemporal dementia on a new form of this TAI, more bioavailable and less toxic at higher doses, called TRx0237. More recently, inhibitors of tau acetylation are being actively pursued based on impressive results in animal studies obtained by salsalate, a clinically used derivative of salicylic acid. PMID:27429978
Fukunaga, Satoshi; Kusama, Makiko; Ono, Shunsuke
Pharmaceutical companies incorporate different features into the trials for new drug applications (NDAs) to render them efficient, making use of their experience. The objective of this analysis was to examine the associations between outcome and features related to study design and clinical development experience in commercially sponsored clinical trials. We collected data of phase 2 and phase 3 trials of all the drugs that obtained approval for depression, schizophrenia, asthma, hypertension, and diabetes in Japan from 1970 to 2011. In total, 145 trials from 90 test drugs were eligible for our study. We calculated the effect size, the standard mean of differences between test drug and comparator therapeutic effects, as the objective variable for use in our analysis. A linear mixed effect model with nested and crossed random effects was used in the analysis including variety of therapeutic area, test drugs and clinical trials. The analysis showed that trial features including sample size, subjective endpoints and active comparator of the same mode of action were negatively associated with effect size. In addition, sponsors' domestic clinical development experience with similar drugs seemed to have a positive association, but prior development experience in foreign countries did not. The accumulation of skills and knowledge within sponsors, and accumulated experience in domestic professionals who implement clinical trials under study contracts with sponsors would be of great importance for yielding clear outcomes. This study provides additional evidence with respect to possible sizes and directions of the influence of study design features that must be considered when planning and implementing trials for new drug applications, and when retrospectively comparing outcomes from trials with different designs and environments.
Kloster-Jensen, Kristine; Sahraoui, Afaf; Vethe, Nils Tore; Korsgren, Olle; Bergan, Stein; Foss, Aksel; Scholz, Hanne
Tacrolimus and sirolimus are important immunosuppressive drugs used in human islet transplantation; however, they are linked to detrimental effects on islets and reduction of long-term graft function. Few studies investigate the direct effects of these drugs combined in parallel with single drug exposure. Human islets were treated with or without tacrolimus (30 μg/L), sirolimus (30 μg/L), or a combination thereof for 24 hrs. Islet function as well as apoptosis was assessed by glucose-stimulated insulin secretion (GSIS) and Cell Death ELISA. Proinflammatory cytokines were analysed by qRT-PCR and Bio-Plex. Islets exposed to the combination of sirolimus and tacrolimus were treated with or without methylprednisolone (1000 μg/L) and the expression of the proinflammatory cytokines was investigated. We found the following: (i) No additive reduction in function and viability in islets existed when tacrolimus and sirolimus were combined compared to the single drug. (ii) Increased expression of proinflammatory cytokines mRNA and protein levels in islets took place. (iii) Methylprednisolone significantly decreased the proinflammatory response in islets induced by the drug combination. Although human islets are prone to direct toxic effect of tacrolimus and sirolimus, we found no additive effects of the drug combination. Short-term exposure of glucocorticoids could effectively reduce the proinflammatory response in human islets induced by the combination of tacrolimus and sirolimus. PMID:26885529
Sullivan, Helen W; Campbell, Miriam
Direct-to-consumer prescription drug advertising (DTCA) is a major source of consumer information about prescription drugs. The present study updates 2002 U.S. Food and Drug Administration phone survey questions that found that 44% and 61% of consumers thought that DTCA did not include enough information about benefits and risks, respectively. The present study was administered by mail using a nationally representative sample, and provides a more in-depth understanding of how these beliefs relate to demographic and health characteristics. Data collected from 3,959 respondents to the National Cancer Institute's 2011 Health Information National Trends Survey find results similar to the 2002 survey: 46% and 52% of respondents thought that DCTA did not include enough information about benefits and risks, respectively. Respondents fell into four groups: 23% agreed that DTCA tells enough about drug benefits and risks, 41% disagreed, 18% expressed no opinion, and 18% had discordant beliefs. DTCA attitudes were negatively associated with education, income, and whether respondents purchase prescription drugs; attitudes were positively associated with whether respondents understand prescription drug information. This study confirms that a plurality of Americans believe that DTCA does not include enough information about benefits and risks, suggesting that the educational effect of DTCA could be improved.
Lötsch, Jörn; Ultsch, Alfred
A novel functional-genomics based concept of pharmacology that uses artificial intelligence techniques for mining and knowledge discovery in "big data" providing comprehensive information about the drugs' targets and their functional genomics is proposed. In "process pharmacology", drugs are associated with biological processes. This puts the disease, regarded as alterations in the activity in one or several cellular processes, in the focus of drug therapy. In this setting, the molecular drug targets are merely intermediates. The identification of drugs for therapeutic or repurposing is based on similarities in the high-dimensional space of the biological processes that a drug influences. Applying this principle to data associated with lymphoblastic leukemia identified a short list of candidate drugs, including one that was recently proposed as novel rescue medication for lymphocytic leukemia. The pharmacological data science approach provides successful selections of drug candidates within development and repurposing tasks.
Sardar, Samra; Andersson, Åsa
Development of novel drugs for treatment of chronic inflammatory diseases is to a large extent dependent on the availability of good experimental in vivo models in order to perform preclinical tests of new drugs and for the identification of novel drug targets. Here, we review a number of existing rodent models for Rheumatoid Arthritis in the context of how these models have been utilized for developing established therapy in Rheumatoid Arthritis and, furthermore, the present use of animal models for studies of novel drug candidates. We have studied the literature in the field for the use of in vivo models during development of anti-rheumatic drugs; from Methotrexate to various antibody treatments, to novel drugs that are, or have recently been, in clinical trials. For novel drugs, we have explored websites for clinical trials. Although a single Rheumatoid Arthritis in vivo model cannot mirror the complexity of disease development, there exist a number of good animal models for Rheumatoid Arthritis, each defining some parts in disease development, which are useful for studies of drug response. We find that many of the established drugs were not tested in in vivo models before being used in the clinic, but rather animal models have been subsequently used to find mechanisms for efficacy. Finally, we report a number of novel drugs, tested in preclinical in vivo models, presently in clinical trials.
Borsook, D; Becerra, L; Fava, M
The use of novel brain biomarkers using nuclear magnetic resonance imaging holds potential of making central nervous system (CNS) drug development more efficient. By evaluating changes in brain function in the disease state or drug effects on brain function, the technology opens up the possibility of obtaining objective data on drug effects in the living awake brain. By providing objective data, imaging may improve the probability of success of identifying useful drugs to treat CNS diseases across all clinical phases (I–IV) of drug development. The evolution of functional imaging and the promise it holds to contribute to drug development will require the development of standards (including good imaging practice), but, if well integrated into drug development, functional imaging can define markers of CNS penetration, drug dosing and target engagement (even for drugs that are not amenable to positron emission tomography imaging) in phase I; differentiate objective measures of efficacy and side effects and responders vs non-responders in phase II, evaluate differences between placebo and drug in phase III trials and provide insights into disease modification in phase IV trials. PMID:23860483
Calabrese, Edward J; Staudenmayer, John W; Stanek, Edward J
This review proposes that the emerging acceptance of the hormetic dose-response model in toxicology and pharmacology has the potential to significantly change important aspects of drug development. Two situations where the hormesis concept may affect drug development are considered: one in which low-dose stimulation may represent an adverse/unwanted effect (eg, stimulation of tumor cell proliferation by antitumor drugs), the other in which low-dose stimulation defines the therapeutic zone (ie, a beneficial or intended effect; eg, cognition enhancement in Alzheimer's disease treatment). Examples are used to demonstrate that the hormetic dose-response model has implications for the definition of an ideal candidate for a therapeutic agent, as well as implications for study designs needed to assess the quantitative features of the dose-response relationship.
Mollenhauer, Hannes; Schima, Robert; Assing, Martin; Mollenhauer, Olaf; Dietrich, Peter; Bumberger, Jan
Due to the heterogeneity and dynamic of ecosystems, the observation and monitoring of natural processes necessitate a high temporal and spatial resolution. This also requires inexpensive and adaptive measurements as well as innovative monitoring strategies. To this end, the application of ad-hoc wireless sensor networks holds the potential of creating an adequate monitoring platform. In order to achieve a comprehensive monitoring in space and time with affordability, it is necessary to reduce the sensor costs. Common investigation methods, especially with regard to vegetation processes, are based on optical measurements. In particular, different wavelengths correspond to specific properties of the plants and preserve the possibility to derive information about the ecosystem, e.g. photosynthetic performance or nutrient content. In this context, photosynthetically active radiation (PAR) sensors and hyperspectral sensors are in major use. This work aims the development, evaluation and application of inexpensive but high performance optical sensors for the implementation in wireless sensor networks. Photosynthetically active radiation designates the spectral range from 400 to 700 nanometers that photosynthetic organisms are able to use in the process of photosynthesis. PAR sensors enable the detection of the reflected solar light of the vegetation in the whole PAR wave band. The amount of absorption indicates photosynthetic activity of the plant, with good approximation. Hyperspectral sensors observe specific parts or rather distinct wavelengths of the solar light spectrum and facilitate the determination of the main pigment classes, e.g. Chlorophyll, Carotenoid and Anthocyanin. Due to the specific absorption of certain pigments, a characteristic spectral signature can be seen in the visible part of the electromagnetic spectrum, known as narrow-band peaks. In an analogous manner, also the presence and concentration of different nutrients cause a characteristic spectral
Alomar, Muaed Jamal
Objectives To discuss the effect of certain factors on the occurrence of Adverse Drug Reactions (ADRs). Data Sources A systematic review of the literature in the period between 1991 and 2012 was made based on PubMed, the Cochrane database of systematic reviews, EMBASE and IDIS. Key words used were: medication error, adverse drug reaction, iatrogenic disease factors, ambulatory care, primary health care, side effects and treatment hazards. Summary Many factors play a crucial role in the occurrence of ADRs, some of these are patient related, drug related or socially related factors. Age for instance has a very critical impact on the occurrence of ADRs, both very young and very old patients are more vulnerable to these reactions than other age groups. Alcohol intake also has a crucial impact on ADRs. Other factors are gender, race, pregnancy, breast feeding, kidney problems, liver function, drug dose and frequency and many other factors. The effect of these factors on ADRs is well documented in the medical literature. Taking these factors into consideration during medical evaluation enables medical practitioners to choose the best drug regimen. Conclusion Many factors affect the occurrence of ADRs. Some of these factors can be changed like smoking or alcohol intake others cannot be changed like age, presence of other diseases or genetic factors. Understanding the different effects of these factors on ADRs enables healthcare professionals to choose the most appropriate medication for that particular patient. It also helps the healthcare professionals to give the best advice to patients. Pharmacogenomics is the most recent science which emphasizes the genetic predisposition of ADRs. This innovative science provides a new perspective in dealing with the decision making process of drug selection. PMID:24648818
Gao, Yue; Ma, Zengchun; Zhang, Boli
The research of new herbal drugs involves in new herbal drugs development and renew the old drugs. It is necessary to research new herbal drugs based on the theory of traditional Chinese medicine (TCM). The current development of famous TCM focuses on the manufacture process, quality control standards, material basis and clinical research. But system management of security evaluation is deficient, the relevant system for the safety assessment TCM has not been established. The causes of security problems, security risks, target organ of toxicity, weak link of safety evaluation, and ideas of safety evaluation are discussed in this paper. The toxicology research of chinese herbal drugs is necessary based on standard of good laboratory practices (GLP), the characteristic of Chinese herbal drugs is necessary to be fully integrated into safety evaluation. The safety of new drug research is necessary to be integrated throughout the entire process. Famous Chinese medicine safety research must be paid more attention in the future.
Leek, Hanna; Andersson, Shalini
The provision of pure enantiomers is of increasing importance not only for the pharmaceutical industry but also for agro-chemistry and biotechnology. In drug discovery and development, the enantiomers of a chiral drug depict unique chemical and pharmacological behaviors in a chiral environment, such as the human body, in which the stereochemistry of the chiral drugs determines their pharmacokinetic, pharmacodynamic and toxicological properties. We present a number of challenging case studies of up-to-kilogram separations of racemic or enriched isomer mixtures using preparative liquid chromatography and super critical fluid chromatography to generate individual enantiomers that have enabled the development of new candidate drugs within AstraZeneca. The combination of chromatography and racemization as well as strategies on when to apply preparative chiral chromatography of enantiomers in a multi-step synthesis of a drug compound can further facilitate accelerated drug discovery and the early clinical evaluation of the drug candidates.
Only four drugs are available for the chemotherapy of human African trypanosomiasis or sleeping sickness; Suramin, pentamidine, melarsoprol and eflornithine. The history of the development of these drugs is well known and documented. suramin, pentamidine and melarsoprol were developed in the first half of the last century by the then recently established methods of medicinal chemistry. Eflornithine, originally developed in the 1970s as an anti-cancer drug, became a treatment of sleeping sickness largely by accident. This review summarises the developmental processes which led to these chemotherapies from the discovery of the first bioactive lead compounds to the identification of the final drugs. PMID:20219092
Roses, Allen D; Saunders, Ann M; Lutz, Michael W; Zhang, Nanyin; Hariri, Ahmad R; Asin, Karen E; Crenshaw, Donna G; Budur, Kumar; Burns, Daniel K; Brannan, Stephen K
TOMMORROW is a Phase III delay of onset clinical trial to determine whether low doses of pioglitazone, a molecule that induces mitochondrial doubling, delays the onset of MCI-AD in normal subjects treated with low dose compared to placebo. BOLD imaging studies in rodents and man were used to find the dose that increases oxygen consumption at central regions of the brain in higher proportion than activation of large corticol regions. The trial is made practical by the use of a pharmacogenetic algorithm based on TOMM40 and APOE genotypes and age to identify normal subjects at high risk of MCI-AD between the ages of 65-83 years within a five year follow-up period.
Walker, D K
The pharmaceutical industry continues to look for ways to reduce drug candidate attrition throughout the drug discovery and development process. A significant cause of attrition is due to safety issues arising either as a result of animal toxicity testing or in the clinical programme itself. A factor in the assessment of safety during early drug development is the pharmacokinetic profile of the compound. This allows safety data to be considered in the light of systemic drug exposure and therefore permits a quantitative assessment. This is particularly applicable when assessing the risk of a new chemical entity (NCE) in relation to safety parameters such as QT interval prolongation, where free plasma concentrations have been shown to be predictive of this property in relation to potency in preclinical testing. Prior to actual human exposure it is therefore important to be able to predict reliably the pharmacokinetic behaviour of an NCE in order to place such safety findings into a quantitative risk context. The emerging science of pharmacogenetics is likely to further our ability to assess the risk of NCEs to populations and individuals due to genetic variance. The drug metabolizing enzyme CYP2D6 has been recognized as providing the potential to result in widely differing systemic drug exposure in the patient population due to polymorphic expression. Further knowledge is likely to add to our understanding of population differences in exposure and response and aid in the identification of risk factors. One potential strategy for improving the effectiveness of the drug discovery process is to obtain clinical pharmacokinetic data more rapidly in order to assess more accurately the potential for both efficacy and safety of an NCE. Whilst procedures and technologies are available that allow this on the microdose scale, it is important that we recognize potential limitations of these approaches in order that they can be applied beneficially. PMID:15563358
R176 274 MOLECULAR MODELING IN DRUG DESIGN FOR THE DEVELOPMENT 1/1OF ORGANOPI4OSPHORUS (U) AMERICA CYANAMID CO PEARL RIVER NY LEDERLE LAOS DIV R...MOLECULAR MODELING IN DRUG DESIGN FOR THE DEVELO ’"ENT OF ORGANOPHOSPHORUS ANTIDOTES/PROPHYLACTICS Final Report R. Venkataraghavan, Ph.D. June 1, 1986 I...Security Classification) (U) .Molecular Modeling in Drug Design for the Development of Organophosphorus Antidotes/Prophylactics 12 PERSONAL AUTHOR(S) R
Takano, Akihiro; Varrone, Andrea; Gulyás, Balázs; Salvadori, Piero; Gee, Antony; Windhorst, Albert; Vercouillie, Johnny; Bormans, Guy; Lammertsma, Adriaan A; Halldin, Christer
This guideline summarizes the current view of the European Association of Nuclear Medicine Drug Development Committee. The purpose of this guideline is to guarantee a high standard of PET studies that are aimed at measuring target occupancy in the brain within the framework of development programs of drugs that act within the central nervous system (CNS drugs). This guideline is intended to present information specifically adapted to European practice. The information provided should be applied within the context of local conditions and regulations.
Jardim, Denis Leonardo; Schwaederle, Maria; Hong, David S.; Kurzrock, Razelle
The effects of incorporating a biomarker-based (personalized or precision) selection strategy on drug development timelines for new oncology drugs merit investigation. Here we accessed documents from the Food and Drug Administration (FDA) database for anticancer agents approved between 09/1998 and 07/2014 to compare drugs developed with and without a personalized strategy. Sixty-three drugs were included (28 [44%] personalized and 35 [56%] non-personalized). No differences in access to FDA-expedited programs were observed between personalized and non-personalized drugs. A personalized approach for drug development was associated with faster clinical development (Investigational New Drug [IND] to New Drug Application [NDA] submission; median = 58.8 months [95% CI 53.8–81.8] vs. 93.5 months [95% CI 73.9–112.9], P =.001), but a similar approval time (NDA submission to approval; median=6.0 months [95% CI 5.5–8.4] vs. 6.1 months [95% CI 5.9–8.3], P = .756) compared to a non-personalized strategy. In the multivariate model, class of drug stratified by personalized status (targeted personalized vs. targeted non-personalized vs. cytotoxic) was the only independent factor associated with faster total time of clinical drug development (clinical plus approval phase, median = 64.6 vs 87.1 vs. 112.7 months [cytotoxic], P = .038). Response rates (RR) in early trials were positively correlated with RR in registration trials (r = 0.63, P = <.001), and inversely associated with total time of drug development (r = −0.29, P = .049). In conclusion, targeted agents were developed faster than cytotoxic agents. Shorter times to approval were associated, in multivariate analysis, with a biomarker-based clinical development strategy. PMID:27419632
Ji, Xun; Wang, Jiang; Zhang, Lei; Zhao, Lin-Xiang; Jiang, Hua-Liang; Liu, Hong
Based on the character of the molecular structure, the prodrugs of phosphates and phosphonates were divided into two categories. The first is the drug which contained the phosphate group, introducing protected groups to increase lipophilicity and improve bioavailability. The other one is the drug which had no phosphate group, introducing the phosphate group into molecules to enhance the solubility, regulate the distribution coefficient and enhance the drug-like property. This review focuses on the application of phosphates and phosphonates in drug research and development based on improvement of physico-chemical property, drug safety and the pharmacokinetics.
Kurimoto, Fuki; Hori, Satoko; Satoh, Hiroki; Miki, Akiko; Sawada, Yasufumi
For drug fostering and evolution, it is important to collect information directly from patients on the efficacy and safety of drugs as well as patient needs. At present, however, information gathered by healthcare professionals, pharmaceutical companies, or governments is not sufficient. There is concern that patients may fail to recognize the importance of providing information voluntarily. The present study was conducted to provide drug information to patients/consumers, to enlighten them on the importance of providing drug information by themselves, and to develop an Internet website, called "Minkusu," for collecting drug information from patients. This website is based on a registration system (free of charge). It is designed to provide information on proper drug use, and to collect opinions about drugs. As of May 31, 2012, a total of 1149 people had been registered. The male/female ratio of registered members was approximately 1:1, and patients/consumers accounted for 23%. According to the results of a questionnaire survey, several patient/consumer members appreciated the usefulness of the information service, and they took an opportunity to know of the concepts of drug development and evolution (Ikuyaku, in Japanese) through the information services provided by this site. In conclusion, the developed information system would contribute to the proper use of drugs by patients/consumers and to the promotion of drug development and evolution.
Sherman, Gerald P.; Lubawy, William C.
A multidisciplinary approach is taken in a college course intended for primary and secondary school teachers, school administrators, and others such as law enforcement officers and drug treatment personnel. The course is conducted informally with lectures and demonstration-discussion workshops, and supplemented by audio cassette tapes. (LBH)
Scherer, Michael; Furr-Holden, C. Debra; Voas, Robert B.
Background: Despite the ample interest in the measurement of substance abuse and dependence, obtaining biological samples from participants as a means to validate a scale is considered time and cost intensive and is, subsequently, largely overlooked. Objectives: To report the psychometric properties of the drug use disorder (DUD) questionnaire…
Scheier, Lawrence M.; Newcomb, Michael D.
Many questions about the associations between risk factors and drug use remain unanswered. Data originally obtained from seventh graders participating in a school-based prevention program were examined in terms of a theoretical model. A series of multiple regression analyses were then conducted to select those risk factors which contributed unique…
Strategy Alert, 1992
How community-based groups are confronting and preventing alcohol and other drug problems and related crime in their communities is the focus of this publication. A wide range of approaches and strategies, used by 10 nonprofit, community-based organizations representative of urban and rural areas, are presented. Case studies describe two community…
Griffin, Stephen O.; Keller, Adrienne; Cohn, Alan
Although employee drug testing is widespread among private employers, the development of programs in the public sector has been slower due to constitutional law constraints. A qualitative approach presenting various participant perspectives may aid in developing an employee drug testing program. (Contains 41 references/notes.) (JOW)
...; Formerly 2008N-0004] Guidance for Industry on Acute Bacterial Otitis Media: Developing Drugs for Treatment... Media: Developing Drugs for Treatment.'' This guidance addresses FDA's current thinking regarding the... treatment of acute bacterial otitis media (ABOM). This guidance finalizes the revised draft guidance of...
Pignatello, R.; Musumeci, T.; Basile, L.; Carbone, C.; Puglisi, G.
Contact with many different biological membranes goes along the destiny of a drug after its systemic administration. From the circulating macrophage cells to the vessel endothelium, to more complex absorption barriers, the interaction of a biomolecule with these membranes largely affects its rate and time of biodistribution in the body and at the target sites. Therefore, investigating the phenomena occurring on the cell membranes, as well as their different interaction with drugs in the physiological or pathological conditions, is important to exploit the molecular basis of many diseases and to identify new potential therapeutic strategies. Of course, the complexity of the structure and functions of biological and cell membranes, has pushed researchers toward the proposition and validation of simpler two- and three-dimensional membrane models, whose utility and drawbacks will be discussed. This review also describes the analytical methods used to look at the interactions among bioactive compounds with biological membrane models, with a particular accent on the calorimetric techniques. These studies can be considered as a powerful tool for medicinal chemistry and pharmaceutical technology, in the steps of designing new drugs and optimizing the activity and safety profile of compounds already used in the therapy. PMID:21430952
Bidwell, Gene L
Therapeutic peptides (TPs) are a class of peptide-based agents capable of eliciting a therapeutic response by modulation of targets within or on the surface of cells. TPs are advantageous because they are amenable to rational design, they have high specificity for their targets and can be made to target almost any protein of interest, including proteins for which we have no small-molecule drugs. Owing to this versatility, TPs have a great potential for cancer therapy in an age of personalized medicine, in which we need novel drugs to target the many novel pathways being discovered as tumor drivers. However, in order to utilize TPs as drugs, many obstacles must be overcome. TPs have short half-lives in systemic circulation, are easily degraded by proteases in plasma and target cells, are often cleared by the reticuloendothelial system and can be immunogenic. This article will discuss ways of overcoming many of these hurdles by utilizing macromolecular peptide delivery systems and tumor-targeting agents.
Wu, Duojiao; Wang, Diane C; Cheng, Yunfeng; Qian, Mengjia; Zhang, Miaomiao; Shen, Qi; Wang, Xiangdong
The drug resistance limits the optimal efficacy of drugs during target therapies for lung cancer and requires the development of precision medicine to identify and develop new highly selective drugs and more precise tailoring of medicine to the target population. Lung cancer heterogeneity as a potential cause of drug resistance to targeted therapy may foster tumor evolution and adaptation and fade personalized-medicine strategies. The present review elucidates the influence of tumor heterogeneity on drug efficacy and resistance, and discusses potential strategies to combat heterogeneity for cancer treatment. There is an urgent need to discover and develop disease- and biology-specific biomarkers for monitoring the existence and occurrence of lung cancer heterogeneity, testing targeted drugs in clinical trials, and implementing precision medicine for patients. Better understanding of lung cancer heterogeneity will strengthen therapeutic strategies and apply precision medicine to cure the disease.
Drug Development for Neurodegenerative Diseases--Second Annual marcus evans Conference. Advances in drug development for NDD and expediting discovery through novel compounds and sound clinical trials.
The Second Annual marcus evens Drug Development for Neurodegenerative Diseases Conference, held in Boston, included topics covering new therapeutic developments in the field of neurodegenerative diseases. This conference report highlights selected presentations on biomarkers for neurodegenerative diseases; novel approaches to therapy for neurodegenerative disorders, including targeting PKCepsilon in Alzheimer's disease, small-molecule therapeutics for neurogenesis, neureglins to promote neurorecovery, and updates on several investigational drugs; and progress in neurodegenerative disease research, including measuring microtubule dynamics in Parkinson's disease and drug delivery to the brain. Investigational drugs discussed include NNI-251 (NeuroNascent Inc), neuregulins including glial growth factor 2 (Acorda Therapeutics Inc), AL-108 (Allon Therapeutics Inc) and EVP-0962 (EnVivo Pharmaceuticals Inc).
Zhang, Ming; Schmitt-Ulms, Gerold; Sato, Christine; Xi, Zhengrui; Zhang, Yalun; Zhou, Ye; St George-Hyslop, Peter; Rogaeva, Ekaterina
Traditional drug development for Alzheimer's disease (AD) is costly, time consuming and burdened by a very low success rate. An alternative strategy is drug repositioning, redirecting existing drugs for another disease. The large amount of biological data accumulated to date warrants a comprehensive investigation to better understand AD pathogenesis and facilitate the process of anti-AD drug repositioning. Hence, we generated a list of anti-AD protein targets by analyzing the most recent publically available 'omics' data, including genomics, epigenomics, proteomics and metabolomics data. The information related to AD pathogenesis was obtained from the OMIM and PubMed databases. Drug-target data was extracted from the DrugBank and Therapeutic Target Database. We generated a list of 524 AD-related proteins, 18 of which are targets for 75 existing drugs-novel candidates for repurposing as anti-AD treatments. We developed a ranking algorithm to prioritize the anti-AD targets, which revealed CD33 and MIF as the strongest candidates with seven existing drugs. We also found 7 drugs inhibiting a known anti-AD target (acetylcholinesterase) that may be repurposed for treating the cognitive symptoms of AD. The CAD protein and 8 proteins implicated by two 'omics' approaches (ABCA7, APOE, BIN1, PICALM, CELF1, INPP5D, SPON1, and SOD3) might also be promising targets for anti-AD drug development. Our systematic 'omics' mining suggested drugs with novel anti-AD indications, including drugs modulating the immune system or reducing neuroinflammation that are particularly promising for AD intervention. Furthermore, the list of 524 AD-related proteins could be useful not only as potential anti-AD targets but also considered for AD biomarker development.
Brynne, Lena; Bresell, Anders; Sjögren, Niclas
Integrative understanding of preclinical and clinical data is imperative to enable informed decisions and reduce the attrition rate during drug development. The volume and variety of data generated during drug development have increased tremendously. A new information model and visualization tool was developed to effectively utilize all available data and current knowledge. The Knowledge Plot integrates preclinical, clinical, efficacy and safety data by adding two concepts: knowledge from the different disciplines and protein binding.Internal and public available data were gathered and processed to allow flexible and interactive visualizations. The exposure was expressed as the unbound concentration of the compound and the treatment effect was normalized and scaled by including expert opinion on what a biologically meaningful treatment effect would be.The Knowledge Plot has been applied both retrospectively and prospectively in project teams in a number of different therapeutic areas, resulting in closer collaboration between multiple disciplines discussing both preclinical and clinical data. The Plot allows head to head comparisons of compounds and was used to support Candidate Drug selections and differentiation from comparators and competitors, back translation of clinical data, understanding the predictability of preclinical models and assays, reviewing drift in primary endpoints over the years, and evaluate or benchmark compounds in due diligence comparing multiple attributes.The Knowledge Plot concept allows flexible integration and visualization of relevant data for interpretation in order to enable scientific and informed decision-making in various stages of drug development. The concept can be used for communication, decision-making, knowledge management, and as a forward and back translational tool, that will result in an improved understanding of the competitive edge for a particular project or disease area portfolio. In addition, it also builds up a
Alam, Fahmida; Islam, Md Asiful; Kamal, M A; Gan, Siew Hua
Over the years, natural products have shown success as antidiabetics in vitro, in vivo and in clinical trials. Because natural product-derived drugs are more affordable and effective with fewer side-effects compared to conventional therapies, pharmaceutical research is increasingly leaning towards the discovery of new antidiabetic drugs from natural products targeting pathways or components associated with type 2 diabetes mellitus (T2DM) pathophysiology. However, the drug discovery process is very lengthy and costly with significant challenges. Therefore, various techniques are currently being developed for the preclinical research phase of drug discovery with the aim of drug development with less time and efforts from natural products. In this review, we have provided an update on natural products including fruits, vegetables, spices, nuts, beverages and mushrooms with potential antidiabetic activities from in vivo, in vitro and clinical studies. Synergistic interactions between natural products and antidiabetic drugs; and potential antidiabetic active compounds from natural products are also documented to pave the way for combination treatment and new drug discovery, respectively. Additionally, a brief idea of the drug discovery process along with the challenges that arise during drug development from natural products and the methods to conquer those challenges are discussed to create a more convenient future drug discovery process.
Nettleton, David O; Einolf, Heidi J
Evaluation of the potential of a drug candidate to inhibit or inactivate cytochrome P450 (CYP) enzymes remains an important part of pharmaceutical drug Discovery and Development programs. CYP enzymes are considered to be one of the most important enzyme families involved in the metabolic clearance of the vast majority of prescribed drugs. Clinical drug-drug interactions (DDI) involving inhibition or time-dependent inactivation of these enzymes can result in dangerous side effects resulting from reduced clearance/increased exposure of the drug being affected (the 'victim' drug). In this regard, pharmaceutical companies have become quite vigilant in mitigating CYP inhibition/inactivation liabilities of drug candidates early in Discovery including continued risk assessment throughout Development. In this review, common strategies and decision making processes for the assessment of DDI risk in the different stages of pharmaceutical development are discussed. In addition, in vitro study designs, analysis, and interpretation of CYP inhibition and inactivation data are described in stage appropriate context. The in vitro tools and knowledge available now enable the Discovery Chemist to place the potential CYP DDI liability of a drug candidate into perspective and to aid in the optimization of chemical drug design to further mitigate this risk.
Blake, Charles A; Barker, Kenneth L; Sobel, Burton E
This symposium addresses careers in drug development in industry; the performance of translational research by academia, industry, and both; and numerous factors pertinent to alliances essential to drug discovery and development. Drug development is a complex process that regularly involves effective collaborations between academic and physician scientists and industry. There are specific occupational factors affecting recruitment of scientists and physicians in drug development programs in industry; ideal backgrounds for successful applicants for positions in industry in drug development; ethical and regulatory considerations particularly germane to the performance of scientists and physicians in drug development programs in industry and at universities; and particular gratifications available to scientists in industry working on drug development. Both similarities and differences characterize the performance of translational research in industry compared with academia. In industry, logistic, operational, and scientific oversight is complex, especially because it often involves relationships with clinical enterprises outside of the corporation. The process is long and arduous from formulation of a good idea in discovery to acceptance of a novel drug in the marketplace. Collaborations and partnerships by industry often involving academia and confrontation of multiple issues are pivotal.
Neoadjuvant chemotherapy (NACT), neoadjuvant endocrine therapy (NAET), and neoadjuvant targeted therapy (NATT), more recently, have been adopted worldwide as standard of care in locally advanced and inoperable BC. These modalities, collectively called neoadjuvant systemic therapy (NAST), are also used for organ preservation and for mechanistic biological studies on drug response and resistance, drug development, and clinical trials. Furthermore, the response to NACT is a valuable indicator of long-term survival. In this work, the advantages and pitfalls of using NAST in BC for studying drug response and resistance for drug development and clinical trials are discussed as well as practical points on how to set up a NAST clinical trial in BC.
Qian, Feng; Huang, Jun; Hussain, Munir A
Drug-polymer solid dispersion has been demonstrated as a feasible approach to formulate poorly water-soluble drugs in the amorphous form, for the enhancement of dissolution rate and bioperformance. The solubility (for crystalline drug) and miscibility (for amorphous drug) in the polymer are directly related to the stabilization of amorphous drug against crystallization. Therefore, it is important for pharmaceutical scientists to rationally assess solubility and miscibility in order to select the optimal formulation (e.g., polymer type, drug loading, etc.) and recommend storage conditions, with respect to maximizing the physical stability. This commentary attempts to discuss the concepts and implications of the drug-polymer solubility and miscibility on the stabilization of solid dispersions, review recent literatures, and propose some practical strategies for the evaluation and development of such systems utilizing a working diagram.
Modhia, Ishan; Mehta, Anant; Patel, Rupal; Patel, Chhagan
Bioadhesive superporous hydrogel composite (SPHC) particles were developed for an intestinal delivery of metoprolol succinate and characterized for density, porosity, swelling, morphology, and bioadhesion studies. Chitosan and HPMC were used as bioadhesive and release retardant polymers, respectively. A 32 full factorial design was applied to optimize the concentration of chitosan and HPMC. The drug loaded bioadhesive SPHC particles were filled in capsule, and the capsule was coated with cellulose acetate phthalate and evaluated for drug content, in vitro drug release, and stability studies. To ascertain the drug release kinetics, the drug release profiles were fitted for mathematical models. The prepared system remains bioadhesive up to eight hours in intestine and showed Hixson-Crowell release with anomalous nonfickian type of drug transport. The application of SPHC polymer particles as a biomaterial carrier opens a new insight into bioadhesive drug delivery system and could be a future platform for other molecules for intestinal delivery. PMID:23984380
A novel functional‐genomics based concept of pharmacology that uses artificial intelligence techniques for mining and knowledge discovery in “big data” providing comprehensive information about the drugs’ targets and their functional genomics is proposed. In “process pharmacology”, drugs are associated with biological processes. This puts the disease, regarded as alterations in the activity in one or several cellular processes, in the focus of drug therapy. In this setting, the molecular drug targets are merely intermediates. The identification of drugs for therapeutic or repurposing is based on similarities in the high‐dimensional space of the biological processes that a drug influences. Applying this principle to data associated with lymphoblastic leukemia identified a short list of candidate drugs, including one that was recently proposed as novel rescue medication for lymphocytic leukemia. The pharmacological data science approach provides successful selections of drug candidates within development and repurposing tasks. PMID:27069773
clinical facililty. A microscope, UV light for phototoxicity studies * and both a table-top and a floor model refrigerated centrifuge are included. The...experience and expertise, he advised on all medical matters related to the qualification of subjects, including the need for obtaining specialized...reasons, none related to drug effect. Review of records at the end of the study when treatment codes were broken showed identical study days of
34floaters" could be related to the phototoxocity testing. Following an explanation of phototoxicity testing, the subject no longer noted an increase in the...the infusion, does not permit attribution of orthostatic intolerance to drug effect. No changes related to infusion of WR 149,024 . were observed in...considered related to the infusion of WR 149,024. Orthostatic Tolerance Testing: Orthostatic intolerance test results for all subjects are pre- sented
Virginia Polytechnic Inst. and State Univ., Blacksburg. Div. of Vocational-Technical Education.
This self-instructional module on developing ads that produce results is the sixth in a set of twelve modules designed for small business owner-managers. Competencies for this module are (1) identify three guidelines to be considered when you invest money in advertising, (2) identify the five basic elements of a printed advertisement, and (3)…
Bernkop-Schnürch, A; Scholler, S; Biebel, R G
The purpose of the present study was to generate mucoadhesive matrix-tablets based on thiolated polymers. Mediated by a carbodiimide, L-cysteine was thereby covalently linked to polycarbophil (PCP) and sodium carboxymethylcellulose (CMC). The resulting thiolated polymers displayed 100+/-8 and 1280+/-84 micromol thiol groups per gram, respectively (means+/-S.D.; n=6-8). In aqueous solutions these modified polymers were capable of forming inter- and/or intramolecular disulfide bonds. The velocity of this process augmented with increase of the polymer- and decrease of the proton-concentration. The oxidation proceeded more rapidly within thiolated PCP than within thiolated CMC. Due to the formation of disulfide bonds within thiol-containing polymers, the stability of matrix-tablets based on such polymers could be strongly improved. Whereas tablets based on the corresponding unmodified polymer disintegrated within 2 h, the swollen carrier matrix of thiolated CMC and PCP remained stable for 6.2 h (mean, n=4) and more than 48 h, respectively. Release studies of the model drug rifampicin demonstrated that a controlled release can be provided by thiolated polymer tablets. The combination of high stability, controlled drug release and mucoadhesive properties renders matrix-tablets based on thiolated polymers useful as novel drug delivery systems.
Pauwels, Ernest K J; Bergstrom, Kim; Mariani, Giuliano; Kairemo, Kalevi
The advances of nuclear medicine imaging instrumentation and radiopharmaceutical sciences allow their involvement in the developmental processes of therapeutic drugs. New chemical entities, meant as potential drugs, need to comply with the proof-of-principle. Tomographic imaging methods as PET, SPECT and CT have been used for small animal and human studies at an early stage of drug development. Using a drug candidate in a radiolabeled form in obtaining quantitative imaging data provides opportunity for a complete morphological and functional overview of targeting properties and overall pharmacokinetics. This can be helpful in go/no-go decision making. Microdosing, using e.g.1% of the proposed dose of the radiolabeled potential drug plays an important part in this early development and notably reduces the risk of serious adverse effects in human volunteers or patients. This paper primarily focuses on the way in which microdosing and SPECT imaging may contribute to the development of drugs. Furthermore, this paper illustrates how these techniques may help to eliminate weak drug candidates at early stage, making time and funds available for potential lead compounds. Eventually this approach facilitates and accelerates new drug approval. The present paper highlights how these techniques make drug development easier in the field of oncology and neurology.
Nakamoto, Masatoshi; Fukasawa, Motoaki; Tanaka, Satomi; Shimamori, Kazusuke; Suzuki, Aya; Matsuda, Masaru; Kobayashi, Tohru; Nagahama, Yoshitaka; Shibata, Naoki
In most vertebrates, sex steroids play a critical role in gonadal development, maturation of germ cells, and development of secondary sexual characteristics. Sex steroids are synthesized in steroid-producing cells (SPCs) in the testis known as Leydig cells, as well as in thecal and granulosa cells in the ovary. In SPCs, cholesterol is sequentially catalyzed by a set of steroidogenic factors and enzymes in order to produce sex steroids. Therefore, integrated expression of the genes involved in steroidogenesis is critical for the proper production of sex steroids. In the present study, regulatory mechanisms of steroidogenic factors and enzymes were examined. We focused on hsd3b, star and ad4bp/sf-1 as well as the description of temporal and spatial expression of these genes during gonadal development in medaka (Oryzias latipes). During testicular development, hsd3b, star and ad4bp/sf-1 were co-expressed in the interstitial somatic cells subsequent to the formation of the seminiferous tubule precursor, suggesting that ad4bp/sf-1 regulated the transcription of both hsd3b and star. During ovarian development, the expression pattern of hsd3b coincided with that of cyp11a1, but not with that of aromatase. Although ad4bp/sf-1 was mainly expressed in presumptive follicular cells, it was also detected in hsd3b positive interstitial cells in the developing ovary. Contrary to our expectations, the onset of star expression occurred during a later stage of ovarian development than the expression of other steroidogenic enzymes. Thus, the regulation mechanism of star transcription appears to differ from that of the other steroidogenic enzymes in the developing ovary, but not in the developing testis.
PSMA postivie LNCaP and C4-2 cells. 6 Task 3. Investigate the capability of m6 to drive adenovirus replication in a prostate cancer-specific manner...of PSES to direct adenovirus replication , and HSV-TK gene, a pro-drug enzyme gene, under the control of another copy of PSES enhancer to restrict
Background The Drugs for Neglected Diseases initiative (DNDi) is a not-for profit organization committed to providing affordable medicines and access to treatments in resource-poor settings. Traditionally drug development has happened “in house” within pharmaceutical companies, with research and development costs ultimately recuperated through drug sales. The development of drugs for the treatment of neglected tropical diseases requires a completely different model that goes beyond the scope of market-driven research and development. Artesunate and mefloquine are well-established drugs for the treatment of uncomplicated malaria, with a strong safety record based on many years of field-based studies and use. The administration of such artemisinin-based combination therapy in a fixed-dose combination is expected to improve patient compliance and to reduce the risk of emerging drug resistance. Case description DNDi developed an innovative approach to drug development, reliant on strong collaborations with a wide range of partners from the commercial world, academia, government institutions and NGOs, each of which had a specific role to play in the development of a fixed dose combination of artesunate and mefloquine. Discussion and evaluation DNDi undertook the development of a fixed-dose combination of artesunate with mefloquine. Partnerships were formed across five continents, addressing formulation, control and production through to clinical trials and product registration, resulting in a safe and efficacious fixed dose combination treatment which is now available to treat patients in resource-poor settings. The south-south technology transfer of production from Farmanguinhos/Fiocruz in Brazil to Cipla Ltd in India was the first of its kind. Of additional benefit was the increased capacity within the knowledge base and infrastructure in developing countries. Conclusions This collaborative approach to drug development involving international partnerships and
Smith, Judith A
Recently at the University of Houston College of Pharmacy, a new course was introduced to provide an overview of each phase of drug development research, from the initial chemistry assays and cell biologystudies to animal experiments and finally clinical trials for drug approval. The course, entitled "Clinical Research and Drug Development," is a three-credit elective introduced this past yearfor the entry-level Doctor of Pharmacy (PharmD) students and graduate students during the summer session at the college. Overall, the intent of this course is to develop students' interest in the topic of clinical research and drug development and provide a foundation of knowledge of basic research skills used in the drug development process. The approach for this course was to break the topics into three general modules: laboratory techniques, both analytical and cell biology/molecular, used in the drug development process; aspects of clinical research process; and writing grants and protocols. Throughout the course, students were strongly encouraged to consider pursuing independent research projects to help continue to develop their research skills in preparation for postgraduate training. As a result, on completion of the course, four students requested an opportunity to complete an independent research project. This course has introduced the various components of drug development and of conducting clinical research to students in the PharmD and graduate programs at the University of Houston College of Pharmacy.
Cobice, D F; Goodwin, R J A; Andren, P E; Nilsson, A; Mackay, C L; Andrew, R
In pharmaceutical research, understanding the biodistribution, accumulation and metabolism of drugs in tissue plays a key role during drug discovery and development. In particular, information regarding pharmacokinetics, pharmacodynamics and transport properties of compounds in tissues is crucial during early screening. Historically, the abundance and distribution of drugs have been assessed by well-established techniques such as quantitative whole-body autoradiography (WBA) or tissue homogenization with LC/MS analysis. However, WBA does not distinguish active drug from its metabolites and LC/MS, while highly sensitive, does not report spatial distribution. Mass spectrometry imaging (MSI) can discriminate drug and its metabolites and endogenous compounds, while simultaneously reporting their distribution. MSI data are influencing drug development and currently used in investigational studies in areas such as compound toxicity. In in vivo studies MSI results may soon be used to support new drug regulatory applications, although clinical trial MSI data will take longer to be validated for incorporation into submissions. We review the current and future applications of MSI, focussing on applications for drug discovery and development, with examples to highlight the impact of this promising technique in early drug screening. Recent sample preparation and analysis methods that enable effective MSI, including quantitative analysis of drugs from tissue sections will be summarized and key aspects of methodological protocols to increase the effectiveness of MSI analysis for previously undetectable targets addressed. These examples highlight how MSI has become a powerful tool in drug research and development and offers great potential in streamlining the drug discovery process. PMID:25766375
Award Number: W81XWH-11-1-0639 TITLE: Development of Pain Endpoint Models for Use in Prostate Cancer Clinical Trials and Drug Approval PRINCIPAL...Clinical Trials and Drug Approval 5b. GRANT NUMBER PC100563 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) Betty Diamond 5d. PROJECT NUMBER Ethan Basch...meet regulatory requirements for drug approval and labeling. The primary aim of this award is to conduct an observational longitudinal study in men
Miyamoto, Yukiko; Eckmann, Lars
Diarrheal diseases are among the leading causes of morbidity and mortality in the world, particularly among young children. A limited number of infectious agents account for most of these illnesses, raising the hope that advances in the treatment and prevention of these infections can have global health impact. The two most important parasitic causes of diarrheal disease are Cryptosporidium and Giardia. Both parasites infect predominantly the small intestine and colonize the lumen and epithelial surface, but do not invade deeper mucosal layers. This review discusses the therapeutic challenges, current treatment options, and drug development efforts against cryptosporidiosis and giardiasis. The goals of drug development against Cryptosporidium and Giardia are different. For Cryptosporidium, only one moderately effective drug (nitazoxanide) is available, so novel classes of more effective drugs are a high priority. Furthermore, new genetic technology to identify potential drug targets and better assays for functional evaluation of these targets throughout the parasite life cycle are needed for advancing anticryptosporidial drug design. By comparison, for Giardia, several classes of drugs with good efficacy exist, but dosing regimens are suboptimal and emerging resistance begins to threaten clinical utility. Consequently, improvements in potency and dosing, and the ability to overcome existing and prevent new forms of drug resistance are priorities in antigiardial drug development. Current work on new drugs against both infections has revealed promising strategies and new drug leads. However, the primary challenge for further drug development is the underlying economics, as both parasitic infections are considered Neglected Diseases with low funding priority and limited commercial interest. If a new urgency in medical progress against these infections can be raised at national funding agencies or philanthropic organizations, meaningful and timely progress is possible
Laughren, Thomas P
This article discusses changes in psychiatric drug development from a US Food and Drug Administration (FDA) standpoint. It first looks back at changes that have been influenced by regulatory process and then looks forward at FDA initiatives that are likely to affect psychiatric drug development in the future. FDA protects the public health by ensuring the safety and efficacy of drug products introduced into the US market. FDA works with drug sponsors during development, and, when applications are submitted, reviews the safety and efficacy data and the proposed labeling. Drug advertising and promotion and postmarketing surveillance also fall within FDA's responsibility. Among the many changes in psychiatric drug development over the past 50 years, several have been particularly influenced by FDA. Populations studied have expanded diagnostically and demographically, and approved psychiatric indications have become more focused on the clinical entities actually studied, including in some cases specific symptom domains of recognized syndromes. Trial designs have become increasingly complex and informative, and approaches to data analysis have evolved to better model the reality of clinical trials. This article addresses 2 general areas of innovation at FDA that will affect psychiatric drug development in years to come. Several programs falling under the general heading of the Critical Path Initiative, ie, biomarkers, adaptive design, end-of-phase 2A meetings, and data standards, are described. In addition, a number of important safety initiatives, including Safety First, the Sentinel Initiative, the Safe Use Initiative, and meta-analysis for safety, are discussed.
Szymański, Paweł; Frączek, Tomasz; Markowicz, Magdalena; Mikiciuk-Olasik, Elżbieta
Copper is one of the most interesting elements for various biomedical applications. Copper compounds show vast array of biological actions, including anti-inflammatory, anti-proliferative, biocidal and other. It also offers a selection of radioisotopes, suitable for nuclear imaging and radiotherapy. Quick progress in nanotechnology opened new possibilities for design of copper based drugs and medical materials. To date, copper has not found many uses in medicine, but number of ongoing research, as well as preclinical and clinical studies, will most likely lead to many novel applications of copper in the near future.
Cambodia, confronted by the spread of drug misuse among young people, requested support from international agencies to develop a drug treatment programme in 2000. The initial plan developed by the United Nations Office on Drugs and Crime was to set up a number of conventional drug treatment centres in urban areas. During the planning phase, however, the project was redesigned as a community based outreach programme. Ten Community Counselling Teams have been formed and trained in pilot areas, and within the first year of operation 462 drug and alcohol users contacted. Comprising former drug users, family members affected by drug use and health care staff, they have drug scene credibility, local knowledge and connectivity, and a rudimentary level of medical competence. Crucially, they enjoy the support of village elders, who are involved in the planning and reporting stages. While the Community Counselling Teams with their basic training in addiction counselling are in no position as yet to either provide or refer clients to treatment, they can provide brief interventions, organise self help groups, and most importantly provide an alternative to law enforcement. By taking a development centred approach, with emphasis on community, empowerment and inclusion, it provides a constructive and inclusive alternative to medical approaches and the compulsory drug treatment centres. The paper is based on an evaluation involving interviews with a range of stakeholders and a review of project documents. PMID:22410105
Maeda, Hideki; Kurokawa, Tatsuo
The cancer therapies currently available do not yet offer fully satisfactory treatments, even in 21st century, and efforts and progress are being made daily in the area of drug development. Anticancer drugs, which play the leading role in cancer therapy, are being developed dynamically around the world, and Japan is not an exception. Looking back on the history of developing anticancer drugs, cytotoxic drugs were the mainstream of drug development until the end of the 20th century. In the 21st century, they have been replaced by molecularly targeted drugs, and thus the development of cytotoxic drugs has been declining rapidly. There were various approaches to the development of anticancer drugs and clinical trial endpoints until the 1980s. In 1991, the "Guidelines for Clinical Evaluation Methods of Anti-Cancer Drugs in Japan" was issued. From 2000 onwards, there was vigorous discussion on the clinical trial endpoints of anticancer drugs in the United States. In conjunction with this discussion, the "Guidelines for Clinical Evaluation Methods of Anti-Cancer Drugs in Japan" was revised in 2005. The revised guidelines required survival data at the time of filing a new drug application (NDA) as a general rule. Around 2005, a bridging strategy was promoted as the "International Conference on Harmonization E5" was promulgated among Japan, the U.S. and EU, resulting in an outflow of clinical trials to overseas, with more non-Japanese survival data generated outside of Japan used for NDAs than Japanese data. Subsequently, the "Guideline for Basic Principles on Global Clinical Trials" was issued in 2007, which promoted the change in the mainstream approach from a bridging strategy to a pivotal, global study involving Japan. Thus, an era of full-fledged globalization in clinical trials began. We believe Japan will need systems to enhance the motivation for anticancer drug development, such as an expedited program or pediatric program, from now on. We hope that the
Zhang, Ming; Schmitt-Ulms, Gerold; Sato, Christine; Xi, Zhengrui; Zhang, Yalun; Zhou, Ye; St George-Hyslop, Peter; Rogaeva, Ekaterina
Traditional drug development for Alzheimer’s disease (AD) is costly, time consuming and burdened by a very low success rate. An alternative strategy is drug repositioning, redirecting existing drugs for another disease. The large amount of biological data accumulated to date warrants a comprehensive investigation to better understand AD pathogenesis and facilitate the process of anti-AD drug repositioning. Hence, we generated a list of anti-AD protein targets by analyzing the most recent publically available ‘omics’ data, including genomics, epigenomics, proteomics and metabolomics data. The information related to AD pathogenesis was obtained from the OMIM and PubMed databases. Drug-target data was extracted from the DrugBank and Therapeutic Target Database. We generated a list of 524 AD-related proteins, 18 of which are targets for 75 existing drugs—novel candidates for repurposing as anti-AD treatments. We developed a ranking algorithm to prioritize the anti-AD targets, which revealed CD33 and MIF as the strongest candidates with seven existing drugs. We also found 7 drugs inhibiting a known anti-AD target (acetylcholinesterase) that may be repurposed for treating the cognitive symptoms of AD. The CAD protein and 8 proteins implicated by two ‘omics’ approaches (ABCA7, APOE, BIN1, PICALM, CELF1, INPP5D, SPON1, and SOD3) might also be promising targets for anti-AD drug development. Our systematic ‘omics’ mining suggested drugs with novel anti-AD indications, including drugs modulating the immune system or reducing neuroinflammation that are particularly promising for AD intervention. Furthermore, the list of 524 AD-related proteins could be useful not only as potential anti-AD targets but also considered for AD biomarker development. PMID:28005991
Slikker, William; Young, John F.; Corley, Rick A.; Dorman, David C.; Conolly, Rory B.; Knudsen, Thomas; Erstad, Brian L.; Luecke, Richard H.; Faustman, Elaine M.; Timchalk, Chuck; Mattison, Donald R.
A workshop was conducted on November 18?19, 2004, to address the issue of improving predictive models for drug delivery to developing humans. Although considerable progress has been made for adult humans, large gaps remain for predicting pharmacokinetic/pharmacodynamic (PK/PD) outcome in children because most adult models have not been tested during development. The goals of the meeting included a description of when, during development, infants/children become adultlike in handling drugs. The issue of incorporating the most recent advances into the predictive models was also addressed: both the use of imaging approaches and genomic information were considered. Disease state, as exemplified by obesity, was addressed as a modifier of drug pharmacokinetics and pharmacodynamics during development. Issues addressed in this workshop should be considered in the development of new predictive and mechanistic models of drug kinetics and dynamics in the developing human.
Gaillard, Pieter J; Visser, Corine C; Appeldoorn, Chantal C M; Rip, Jaap
Drug delivery to the brain remains challenging due to the presence of the blood-brain barrier. In this review, 10 key development criteria are presented that are important for successful drug development to treat CNS diseases by targeted drug delivery systems. Although several routes of delivery are being investigated, such as intranasal delivery, direct injections into the brain or CSF, and transient opening of the blood-brain barrier, the focus of this review is on physiological strategies aiming to target endogenous transport mechanisms. Examples from literature, focusing on targeted drug delivery systems that are being commercially developed, will be discussed to illustrate the 10 key development criteria. The first four criteria apply to the targeting of the blood-brain barrier: (1) a proven inherently safe receptor biology, (2) a safe and human applicable ligand, (3) receptor specific binding, and (4) applicable for acute and chronic indications. Next to an efficient and safe targeting strategy, as captured in key criteria 1 to 4, a favorable pharmacokinetic profile is also important (key criterion 5). With regard to the drug carriers, two criteria are important: (6) no modification of active ingredient and (7) able to carry various classes of molecules. The final three criteria apply to the development of a drug from lab to clinic: (8) low costs and straightforward manufacturing, (9) activity in all animal models, and (10) strong intellectual property (IP) protection. Adhering to these 10 key development criteria will allow for a successful brain drug development.
Pellegrini, Federico; Budman, Daniel R
Anticancer agents that interfere with microtubulin function are in widespread use in man and have a broad spectrum of activity against both hematological malignancies and solid tumors. The mechanisms of actions of these agents have been better defined during the past decade, indicating that there are distinct binding sites for these agents and that they interfere with microtubulin dynamics (growth and shortening of tubules) at low concentrations and only evoke microtubulin aggregation or dissociation at high concentrations. Tubulin has been recently described in the nucleus of cells and in mitochondria. Downstream events from tubulin binding are believed to be critical events for the generation of apoptosis in the malignant cell. The effects of vinca alkaloids and taxanes are distinct, suggesting that the interference with the tubulin cap by high-affinity binding of effective agents is not the only mechanism of cytotoxic effect, and the low-affinity binding of drug, which distorts microtubulin function, may also be important. The epothilones share some of the binding characteristics of the taxanes and are in clinical trials because of cytoxic activity in taxane resistant cells. Tubulin has additional target sites for anticancer drugs including interference with the binding and function of microtubule associated proteins and interference with motor proteins which are essential for the transport of substances within the cell. Because many of these microtubule associated proteins have an ATP binding site, both computer-aided design and combinatorial chemistry techniques can be used to make agents to interfere with their function analogous to imatinib mesylate (Gleevec). Agents that interfere with the motor protein kinesin are entering clinical trials.
Kuroda, Junji; Plassmann, Stephanie; Hayashi, Makoto; Prentice, David E.
To illustrate the process of addressing adverse preclinical findings (APFs) as outlined in the first part of this review, a number of cases with unexpected APF in toxicity studies with drug candidates is discussed in this second part. The emphasis is on risk characterization, especially regarding the mode of action (MoA), and risk evaluation regarding relevance for man. While severe APFs such as retinal toxicity may turn out to be of little human relevance, minor findings particularly in early toxicity studies, such as vasculitis, may later pose a real problem. Rodents are imperfect models for endocrine APFs, non-rodents for human cardiac effects. Liver and kidney toxicities are frequent, but they can often be monitored in man and do not necessarily result in early termination of drug candidates. Novel findings such as the unusual lesions in the gastrointestinal tract and the bones presented in this review can be difficult to explain. It will be shown that well known issues such as phospholipidosis and carcinogenicity by agonists of peroxisome proliferator-activated receptors (PPAR) need to be evaluated on a case-by-case basis. The latter is of particular interest because the new PPAR α and dual α/γ agonists resulted in a change of the safety paradigm established with the older PPAR α agonists. General toxicologists and pathologists need some understanding of the principles of genotoxicity and reproductive toxicity testing. Both types of preclinical toxicities are major APF and clinical monitoring is difficult, generally leading to permanent use restrictions. PMID:22272032
Nichols, Alice I.; Preskorn, Sheldon H.
Objective: The avoidance of adverse drug-drug interactions (DDIs) is a high priority in terms of both the US Food and Drug Administration (FDA) and the individual prescriber. With this perspective in mind, this article illustrates the process for assessing the risk of a drug (example here being desvenlafaxine) causing or being the victim of DDIs, in accordance with FDA guidance. Data Sources/Study Selection: DDI studies for the serotonin-norepinephrine reuptake inhibitor desvenlafaxine conducted by the sponsor and published since 2009 are used as examples of the systematic way that the FDA requires drug developers to assess whether their new drug is either capable of causing clinically meaningful DDIs or being the victim of such DDIs. In total, 8 open-label studies tested the effects of steady-state treatment with desvenlafaxine (50–400 mg/d) on the pharmacokinetics of cytochrome (CYP) 2D6 and/or CYP 3A4 substrate drugs, or the effect of CYP 3A4 inhibition on desvenlafaxine pharmacokinetics. The potential for DDIs mediated by the P-glycoprotein (P-gp) transporter was assessed in in vitro studies using Caco-2 monolayers. Data Extraction: Changes in area under the plasma concentration-time curve (AUC; CYP studies) and efflux (P-gp studies) were reviewed for potential DDIs in accordance with FDA criteria. Results: Desvenlafaxine coadministration had minimal effect on CYP 2D6 and/or 3A4 substrates per FDA criteria. Changes in AUC indicated either no interaction (90% confidence intervals for the ratio of AUC geometric least-squares means [GM] within 80%–125%) or weak inhibition (AUC GM ratio 125% to < 200%). Coadministration with ketoconazole resulted in a weak interaction with desvenlafaxine (AUC GM ratio of 143%). Desvenlafaxine was not a substrate (efflux ratio < 2) or inhibitor (50% inhibitory drug concentration values > 250 μM) of P-gp. Conclusions: A 2-step process based on FDA guidance can be used first to determine whether a pharmacokinetically mediated
Arai, Hiroyuki; Furukawa, Katsutoshi; Tomita, Naoki; Ishiki, Aiko; Okamura, Nobuyuki; Kudo, Yukitsuka
Development of symptomatic treatment of Alzheimer s disease by cholinesterase inhibitors like donepezil was successful. However, it is a disappointment that development of disease-modifying drugs such as anti-amyloid drug based on amyloid-cascade theory has been interrupted or unsuccessful. Therefore, we have to be more cautious regarding inclusion criteria for clinical trials of new drugs. We agree that potentially curative drugs should be started before symptoms begin as a preemptive therapy or prevention trial. The concept of personalized medicine also is important when ApoE4-related amyloid reducing therapy is considered. Unfortunately, Japanese-ADNI has suffered a setback since 2014. However, Ministry of Health, Labour and Welfare gave a final remark that there was nothing wrong in the data managing process in the J-ADNI data center. We should pay more attention to worldwide challenges of speeding up new drug development.
Nicklas, Theresa A; O'Neil, Carol E
The diets of most US children and adults are poor, as reflected by low diet quality scores, when compared with the recommendations of the Dietary Guidelines for Americans (DGAs). Contributing to these low scores is that most Americans overconsume solid fats, which may contain saturated fatty acids and added sugars; although alcohol consumption was generally modest, it provided few nutrients. Thus, the 2005 DGAs generated a new recommendation: to reduce intakes of solid fats, alcohol, and added sugars (SoFAAS). What precipitated the emergence of the new SoFAAS terminology was the concept of discretionary calories (a "calorie" is defined as the amount of energy needed to increase the temperature of 1 kg of water by 1°C), which were defined as calories consumed after an individual had met his or her recommended nutrient intakes while consuming fewer calories than the daily recommendation. A limitation with this concept was that additional amounts of nutrient-dense foods consumed beyond the recommended amount were also considered discretionary calories. The rationale for this was that if nutrient-dense foods were consumed beyond recommended amounts, after total energy intake was met then this constituted excess energy intake. In the 2010 DGAs, the terminology was changed to solid fats and added sugars (SoFAS); thus, alcohol was excluded because it made a minor contribution to overall intake and did not apply to children. The SoFAS terminology also negated nutrient-dense foods that were consumed in amounts above the recommendations for the specific food groups in the food patterns. The ambiguous SoFAS terminology was later changed to "empty calories" to reflect only those calories from solid fats and added sugars (and alcohol if consumed beyond moderate amounts). The purpose of this review is to provide an historical perspective on how the dietary recommendations went from SoFAAS to SoFAS and how discretionary calories went to empty calories between the 2005 and 2010
Nicklas, Theresa A; O’Neil, Carol E
The diets of most US children and adults are poor, as reflected by low diet quality scores, when compared with the recommendations of the Dietary Guidelines for Americans (DGAs). Contributing to these low scores is that most Americans overconsume solid fats, which may contain saturated fatty acids and added sugars; although alcohol consumption was generally modest, it provided few nutrients. Thus, the 2005 DGAs generated a new recommendation: to reduce intakes of solid fats, alcohol, and added sugars (SoFAAS). What precipitated the emergence of the new SoFAAS terminology was the concept of discretionary calories (a “calorie” is defined as the amount of energy needed to increase the temperature of 1 kg of water by 1°C), which were defined as calories consumed after an individual had met his or her recommended nutrient intakes while consuming fewer calories than the daily recommendation. A limitation with this concept was that additional amounts of nutrient-dense foods consumed beyond the recommended amount were also considered discretionary calories. The rationale for this was that if nutrient-dense foods were consumed beyond recommended amounts, after total energy intake was met then this constituted excess energy intake. In the 2010 DGAs, the terminology was changed to solid fats and added sugars (SoFAS); thus, alcohol was excluded because it made a minor contribution to overall intake and did not apply to children. The SoFAS terminology also negated nutrient-dense foods that were consumed in amounts above the recommendations for the specific food groups in the food patterns. The ambiguous SoFAS terminology was later changed to “empty calories” to reflect only those calories from solid fats and added sugars (and alcohol if consumed beyond moderate amounts). The purpose of this review is to provide an historical perspective on how the dietary recommendations went from SoFAAS to SoFAS and how discretionary calories went to empty calories between the 2005
Prabhu, Vidya; Xu, Han
Site specific genome editing has been gradually employed in drug discovery and development process over the past few decades. Recent development of CRISPR technology has significantly accelerated the incorporation of genome editing in the bench side to bedside process. In this review, we summarize examples of applications of genome editing in the drug discovery and development process. We also discuss current hurdles and solutions of genome editing.
Cheng, Yu-Huei; Chuang, Li-Yeh; Chang, Hsueh-Wei; Yang, Cheng-Hong
Alzheimer's disease (AD) is the main cause of dementia for older people. Although several antidementia drugs such as donepezil, rivastigmine, galantamine, and memantine have been developed, the effectiveness of AD drug therapy is still far from satisfactory. Recently, the single nucleotide polymorphisms (SNPs) have been chosen as one of the personalized medicine markers. Many pharmacogenomics databases have been developed to provide comprehensive information by associating SNPs with drug responses, disease incidence, and genes that are critical in choosing personalized therapy. However, we found that some information from different sets of pharmacogenomics databases is not sufficient and this may limit the potential functions for pharmacogenomics. To address this problem, we used approximate string matching method and data mining approach to improve the searching of pharmacogenomics database. After computation, we can successfully identify more genes linked to AD and AD-related drugs than previous online searching. These improvements may help to improve the pharmacogenomics of AD for personalized medicine.
Chellan, Prinessa; Sadler, Peter J; Land, Kirkwood M
Apicomplexan parasites cause some of the most devastating human diseases, including malaria, toxoplasmosis, and cryptosporidiosis. New drug discovery is imperative in light of increased resistance. In this digest article, we briefly explore some of the recent and promising developments in new drug discovery against two apicomplexan parasites, Cryptosporidium and Toxoplasma.
... qualification process for drug development tools (DDTs) intended for potential use, over time, in multiple drug... Evaluation and Research (CDER) and DDT sponsors to support work towards qualification of an identified DDT and creates a mechanism for formal review of data by CDER to qualify the DDT and ensure that...
... HUMAN SERVICES Food and Drug Administration Development and Distribution of Patient Medication... patient medication information (PMI) to be provided to patients who are prescribed drug products. Under... determined that the current system is not adequate to ensure that patients receive the essential...
Scopetta, Mercedes A.
An approach to the treatment of Hispanic (particularly Cuban) American families with drug abusing members is presented in this paper. The approach, developed by the Spanish Family Guidance Center in Miami, Florida, views dysfunctionality and drug abuse as emerging from a family's internal disorganization and ecological imbalance. In order to treat…
Okamoto, Scott K.; Helm, Susana; McClain, Latoya L.; Dinson, Ay-Laina
The purpose of this study was to adapt and validate narrative scripts to be used for the video components of a culturally grounded drug prevention program for rural Native Hawaiian youth. Scripts to be used to film short video vignettes of drug-related problem situations were developed based on a foundation of pre-prevention research funded by the…
Bosworth, Kris; Yoast, Richard
Describes Drug Information, Assessment and Decisions for Schools (DIADS), computer-based information and decisions support system for development of school drug abuse prevention programs. Explains how DIADS provides access to cost-effective planning resource, helps schools assess program effectiveness, and guides selection of future activities.…
Loran, F.; Sheikh-Jabbari, M. M.
Continuing the analysis of [Loran F and Sheikh-Jabbari M M 2010 Phys. Lett. B 693 184-7], we classify all locally AdS3 stationary axi-symmetric unorientable solutions to AdS3 Einstein gravity and show that they are obtained by applying certain orientifold projection on AdS3, BTZ or AdS3 self-dual orbifold, respectively, O-AdS3, O-BTZ and O-SDO geometries. Depending on the orientifold fixed surface, the O-surface, which is either a space-like 2D plane or a cylinder, or a light-like 2D plane or a cylinder, one can distinguish four distinct cases. For the space-like orientifold plane or cylinder cases, these geometries solve AdS3 Einstein equations and are hence locally AdS3 everywhere except at the O-surface, where there is a delta-function source. For the light-like cases, the geometry is a solution to Einstein equations even at the O-surface. We discuss the causal structure for static, extremal and general rotating O-BTZ and O-SDO cases as well as the geodesic motion on these geometries. We also discuss orientifolding Poincaré patch AdS3 and AdS2 geometries as a way to geodesic completion of these spaces and comment on the 2D CFT dual to the O-geometries.
Khan, Masood U; Bowsher, Ronald R; Cameron, Mark; Devanarayan, Viswanath; Keller, Steve; King, Lindsay; Lee, Jean; Morimoto, Alyssa; Rhyne, Paul; Stephen, Laurie; Wu, Yuling; Wyant, Timothy; Lachno, D Richard
Increasingly, commercial immunoassay kits are used to support drug discovery and development. Longitudinally consistent kit performance is crucial, but the degree to which kits and reagents are characterized by manufacturers is not standardized, nor are the approaches by users to adapt them and evaluate their performance through validation prior to use. These factors can negatively impact data quality. This paper offers a systematic approach to assessment, method adaptation and validation of commercial immunoassay kits for quantification of biomarkers in drug development, expanding upon previous publications and guidance. These recommendations aim to standardize and harmonize user practices, contributing to reliable biomarker data from commercial immunoassays, thus, enabling properly informed decisions during drug development.