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At least 1,279 records · Page 71Linked to original sources
PubMed1999

Rational design of live-attenuated recombinant vaccine virus for human respiratory syncytial virus by reverse genetics.

RSV is a major cause of pediatric respiratory tract disease worldwide, but a vaccine is not yet available. It is now possible to prepare live infectious RSV completely from cDNA. This provides a method for introducing defined mutations into infectious virus, making possible the rational design of a live-attenuated vaccine virus for intranasal administration. This is particularly important for RSV, for which achieving the appropriate balance between attenuation and immunogenicity by conventional methods has proven elusive. We took advantage of the existence of a panel of biologically derived vaccine candidate viruses that were incompletely attenuated but well characterized biologically. The mutations in these viruses were identified by sequence analysis and characterized by insertion into recombinant virus, thereby providing a menu of known attenuating mutations. These included a series of amino acid point mutations, mostly in the L polymerase, and a nucleotide substitution in a transcription gene-start signal, a cis-acting RNA element. The second source of mutations was from experimental mutational analysis of recombinant virus and involves deletion of the NS1, NS2, or SH gene. We have reconstructed a previously tested, biologically derived attenuated virus, cpts248/404, in recombinant form and are now proceeding to introduce additional mutations from the menu to achieve stepwise increases in attenuation. The ability to modify the attenuation phenotype incrementally in a directed manner should result in an appropriate vaccine virus.

DNA, Complementary↗
PubMed2006

Rational design and applications of a Rac GTPase-specific small molecule inhibitor.

Rac GTPases are involved in the regulation of multiple cell functions and have been implicated in the pathology of certain human diseases. Dominant negative mutants of Rac have been the tool of choice in studying Rac function in cells. Given the difficulty of introducing high concentrations of the Rac mutants into primary cells and nonspecific effects of the mutants on Rho guanine nucleotide exchange factor (GEF) activities, it is desirable to develop small molecule inhibitors that could specifically inhibit Rac activities. Here we describe the rational design, characterization, and applications of a first-generation Rac-specific small molecule inhibitor. On the basis of the structure-function information of Rac interaction with GEFs, in a computer-based virtual screening we have identified NSC23766, a highly soluble and membrane permeable compound, as a specific inhibitor of a subset of GEF binding to Rac and, therefore, Rac activation by these GEFs. In fibroblast cells, NSC23766 inhibited Rac1 GTP-loading without affecting Cdc42 or RhoA activity and suppressed cell proliferation induced by a Rac GEF Tiam1. It has little effect on cell growth induced by a constitutively active Rac1 mutant. In addition, NSC23766 inhibited: (1) the anchorage-independent growth and invasion phenotypes of human prostate cancer PC-3 cells; (2) Rac activation and Rac-dependent aggregation of platelets stimulated by thrombin; and (3) Rac1 and Rac2 activities of hematopoietic stem/progenitor cells and induced their mobilization from mouse bone marrow to peripheral blood. Thus, NSC23766 is a lead small molecule inhibitor of Rac activity and could be useful for studying Rac-mediated cellular functions and for modulating pathological conditions in which Rac-deregulation may play a role.

Adenocarcinoma↗
PubMed2002

Receptor tyrosine kinases as rational targets for prostate cancer treatment: platelet-derived growth factor receptor and imatinib mesylate.

Over the past 15 years, numerous signal transduction pathways have been elucidated whose dysregulation may play an important role in the growth and survival of cancer cells. The success of imatinib mesylate (Gleevec; Novartis Pharmaceuticals, East Hanover, NJ), a small molecule that inhibits the activation of the BCR-Abl oncogene in the treatment of chronic myelogenous leukemia, has demonstrated how effective targeted strategies can be when properly applied. With the hope of selectively targeting other critical components of cancer growth and survival while minimizing toxicity to the host, numerous strategies have been developed to inhibit receptor tyrosine kinases for various growth factors commonly expressed by cancer cells. Success of targeted inhibitors is inherently dependent on the proper selection of patients whose tumors are dependent on these growth factor pathways. Unfortunately, in prostate cancer, such selection has been a difficult-to-impossible task to date. Because of the vast number of mutational events, it is difficult to demonstrate that any particular growth factor signaling pathway is critical. In addition, because of the type (mostly bone only) and nature (usually small foci) of metastases, limited access to tumor tissue in the advanced cancer population has hampered attempts to characterize patients by their molecular features or phenotype. This article will focus on defining alternative criteria for a rational drug target and novel study designs for testing these agents in prostate cancer. In particular, the neoadjuvant setting represents a unique opportunity for new drug development in prostate cancer. An example of a neoadjuvant study testing, imatinib mesylate, is presented to display the advantages and limitations of this study design.

Antineoplastic Agents↗
PubMed1990

Pharmacologic control of aberrant behavior in the mentally retarded: toward a more rational approach.

Drugs are frequently used to control aberrant behavior in the mentally retarded. However, despite decades of research, this approach to behavioral management has had very limited success. Slow progress in this area can be attributed, in part, to the lack of a theoretical framework to guide research. The main purpose of this review is to integrate clinical research in this area with evidence concerning the neurochemical mechanisms that mediate aberrant behaviors. It is concluded that a theoretical framework that takes into account the biological mechanisms that underlie disordered behavior and the actions of drugs provides the basis for a more rational approach to the development of pharmacological therapies in the mentally retarded.

Child↗
PubMed1998

Strategies to rationalize sepsis management--a review of 4 years' experience in Dundee.

Hospitals worldwide are facing an unprecedented crisis of rising cost of antibacterials due to the increasing rapid emergence and dissemination of antibiotic-resistant organisms, improper use of antibiotics and the use of broad spectrum parenteral agents. The last 25 years has seen the introduction of many measures to improve the quality of sepsis management, and specifically antimicrobial use. The present paper reviews the development, implementation and evaluation of some of the key strategies employed within the Dundee Teaching Hospitals NHS Trust (DTHT) to enhance recognition and assessment of sepsis and to rationalize the early and often empiric antibiotic treatment of patients in hospital with infection. Particular emphasis is given to optimizing the use of expensive parenteral agents in conjunction with promotion of oral switch therapy where appropriate.

Administration, Oral↗
PubMedDate not supplied

Toward the rational design of protein kinase casein kinase-2 inhibitors.

Casein kinase-2 (CK2) probably is the most pleiotropic member of the protein kinase family, with more than 200 substrates known to date. Unlike the great majority of protein kinases, which are tightly regulated enzymes, CK2 is endowed with high constitutive activity, a feature that is suspected to underlie its oncogenic potential and possible implication in viral infections. This makes CK2 an attractive target for anti-neoplastic and antiviral drugs. Here, we present an overview of our present knowledge about CK2 inhibitors, with special reference to the information drawn from two recently solved crystal structures of CK2alpha in complex with emodin and with 4,5,6,7-tetrabromo-2-azabenzimidazole (TBB), this latter being the most specific CK2 inhibitor known to date. A comparison with a series of anthraquinone and xanthenone derivatives highlights the crucial relevance of the hydroxyl group at position 3 for inhibition by emodin, and discloses the possibility of increasing the inhibitory potency by placing an electron withdrawing group at position 5. We also present mutational data corroborating the relevance of two hydrophobic residues unique to CK2, Val66 and Ile174, for the interactions with emodin and TBB, but not with the flavonoid inhibitors quercetin and fisetin. In particular, the CK2alpha mutant V66A displays 27- and 11-fold higher IC(50) values with emodin and TBB, respectively, as compared with the wild-type, while the IC(50) value with quercetin is unchanged. The data presented pave the road toward the rational design of more potent and selective inhibitors of CK2 and the generation of CK2 mutants refractory to inhibition, useful to probe the implication of CK2 in specific cellular functions.

Animals↗
PubMed2002

How much for a star? Elements for a rational choice of sample size in preclinical trials.

In the preclinical field, preliminary estimation of the number of experimental units to be included in a study is an important step in the setting up of the study. This estimation must be based on a dialogue between the experimenter and the statistician. This article, intended for both experimenters and statisticians, is designed to facilitate their dialogue by describing certain elements that are involved in the calculation of the optimal sample size in addition to the factors that influence their quantification. The proposed approach will result in better analysis of each experiment and, therefore, more globally, in rationalization of the use of experimental units.

Drug Evaluation, Preclinical↗
PubMed1999

Rationalizing a pharmacological intervention on the amyloid precursor protein metabolism.

The treatment of Alzheimer's disease remains a major challenge because of our incomplete understanding of the triggering events that lead to the selective neurodegeneration characteristic of Alzheimer's brains. The rational design of a pharmacological intervention is therefore a great theoretical challenge. One approach involves the study of the pharmacological modulation of the amyloid precursor protein metabolism, in which the goal is to reduce the formation of beta-amyloid in the hope of reducing the formation of a potentially neurotoxic peptide. Such an approach has led to the identification of a complex intracellular mechanism that can be regulated by neurotransmitters and other ligands.

Alzheimer Disease↗
PubMed2003

Single-tube nested quantitative PCR: a rational and sensitive technique for detection of retroviral DNA. Application to RERV-H/HRV-5 and confirmation of its rabbit origin.

It was reported earlier that a few patients suffering from non-Hodgkin's lymphoma had low amounts of DNA from the so-called fifth human exogenous retrovirus, HRV-5. A sensitive and rational method for large-scale screening for HRV-5 DNA was therefore developed. It is a single-tube nested quantitative PCR (stnQPCR), which uses two functionally isolated primer pairs and one probe target distinct from related endogenous retroviral sequences, yet encompassing known HRV-5 variation, allowing optimal use of sequence conservation. DNA from lymphoma, myeloma, and follicular dendritic cell lines was tested for HRV-5 positivity, as was DNA from whole blood of blood donors, non-Hodgkin's lymphoma and systemic lupus erythematosus patients, as well as DNA from lymph node biopsies of rheumatoid arthritis patients with lymphoma. One blood donor, one systemic lupus erythematosus patient, two previously known positive non-Hodgkin's lymphoma patients, and one rheumatoid arthritis lymphoma patient, came out positive. They had 24, 2, 148, 480 and 30 proviral copies per microg of DNA from PBMC or lymphoma tissue, respectively. During the completion of this work it was reported that HRV-5 is a rabbit endogenous retrovirus (RERV-H), and that HRV-5 positivity was due to presence of rabbit DNA. DNA from six RERV-H/HRV-5 positive samples was therefore retested. Three also contained rabbit mitochondrial DNA. A search for HRV-5 antibodies using synthetic peptides was negative in sera from three RERV-H/HRV-5 positive individuals, as well as in 144 other sera, according with a noninfectious origin of the RERV-H/HRV-5 DNA in human samples. A search for possible sources of rabbit DNA contamination was negative. Methods for prevention of PCR contamination were strictly adhered to. Three samples from RERV-H/HRV-5 positive individuals positive at the Uppsala laboratory were retested at one or two other laboratories, and all three were positive. Two other samples, which were positive in the Riga laboratory, were tested also in London and also found positive. One non-Hodgkin's lymphoma patient was RERV-H/HRV-5 positive in four consecutive samples, showing that positivity was a property of that patient. It is concluded that the stnQPCR developed to detect and quantify minute amounts of RERV-H/HRV-5 DNA is a principle which can be applied widely and HRV-5 is a RERV-H. Its presence in a few human blood samples could not be explained.

Animals↗
PubMed1997

Trans-synaptic stimulation of cortical acetylcholine and enhancement of attentional functions: a rational approach for the development of cognition enhancers.

Activation and restoration of cholinergic function remain major foci in the development of pharmacological approaches toward the treatment of cognitive dysfunctions associated with aging and dementia. Our research has been guided by the hypothesis that (re)activation of cortical cholinergic inputs is achieved as a result of trans-synaptic disinhibition of basal forebrain cholinergic neurons. This approach depends on the ability of benzodiazepine receptor (BZR) inverse agonists to reduce the potency of GABA to block neuronal excitation. BZR inverse agonists were found to augment cortical ACh efflux through interaction with cognition-associated activation of this system. Cortical cholinergic inputs have been implicated in the processing of behaviorally significant stimuli, i.e., attentional functions. Using a recently developed and validated task for the measurement of sustained attention, or vigilance, administration of BZR inverse agonists were found to selectively increase the number of false alarms in intact animals. However, in animals with a 50-70%, but not > 90%, loss of the cortical cholinergic inputs, treatment with BZR inverse agonists alleviated the lesion-induced impairment in sustained attention and enhanced activated cortical ACh efflux. A rational development of cognitive enhancers will benefit from experiments in which cognitive and neuropharmacological variables are assessed simultaneously, thus allowing the analysis of interactions between cognition-associated neuronal activity and the neuronal and cognitive effects of putative cognition enhancers.

Acetylcholine↗
PubMed2001

Rational selection and quantitative evaluation of antisense oligonucleotides.

Antisense oligonucleotides are an attractive therapeutic option to modulate specific gene expression. However, not all antisense oligonucleotides are effective in inhibiting gene expression, and currently very few methods exist for selecting the few effective ones from all candidate oligonucleotides. The lack of quantitative methods to rapidly assess the efficacy of antisense oligonucleotides also contributes to the difficulty of discovering potent and specific antisense oligonucleotides. We have previously reported the development of a prediction algorithm for identifying high affinity antisense oligonucleotides based on mRNA-oligonucleotide hybridization. In this study, we report the antisense activity of these rationally selected oligonucleotides against three model target mRNAs (human lactate dehydrogenase A and B and rat gp130) in cell culture. The effectiveness of oligonucleotides was evaluated by a kinetic PCR technique, which allows quantitative evaluation of mRNA levels and thus provides a measure of antisense-mediated decreases in target mRNA, as occurs through RNase H recruitment. Antisense oligonucleotides that were predicted to have high affinity for their target proved effective in almost all cases, including tests against three different targets in two cell types with phosphodiester and phosphorothioate oligonucleotide chemistries. This approach may aid the development of antisense oligonucleotides for a variety of applications.

Animals↗
PubMed1998

The demand for cocaine by young adults: a rational addiction approach.

This paper applies the rational addiction model to the demand for cocaine by young adults in the Monitoring the Future panel. The price of cocaine is added to this survey from the Drug Enforcement Administration's System to Retrieve Information from Drug Evidence. Results suggest that annual participation and frequency of use given participation are negatively related to the price of cocaine. In addition, current participation (frequency) is positively related to past and future participation (frequency). The long-run price elasticity of total consumption (participation multiplied by frequency given participation) of -1.35 is substantial.

Adolescent↗
PubMed2001

Enzyme engineering: rational redesign versus directed evolution.

Enzyme engineering is undergoing the most profound and exciting transformation in its history (1). It promises unprecedented expansion in the scope and applications of modified or improved enzymes with desired physical and catalytic properties. Two complementary strategies are currently available: rational redesign (2-5) and directed evolution (6,7). Although both approaches have met with great success, each has limitations. In this article, the perspectives for these enzyme-engineering strategies are discussed briefly.

Enzymes↗
PubMed1997

Regulating biotechnology: a rational-political model of policy development.

While technology assessment is seen as a mechanism for achieving effective and efficient use of health care resources, it has not as yet made the impact on policy decisions that its potential would suggest. Considerable barriers have been encountered in translating assessment results into policy concerning the adoption and use of technologies, with 'political' factors often being decisive. This paper places technology assessment in the content of the policy process to clarify both (a) how conflicting interests and organizational features can often hinder the selection of optimal policies, and (b) the potential roles technology assessment could nonetheless play. The resulting framework is termed the 'rational-political' model of policy development. The paper uses the example of policy making about the regulation of biotechnology, drawing on information from a survey of decision-makers (n = 561) involved in issues concerning the development, approval, and payment for pharmaceutical products.

Biotechnology↗
PubMed1985

Rationally designed combination chemotherapy for the treatment of patients with recalcitrant psoriasis.

In an effort to improve clinical response and reduce systemic toxicity, nine patients with recalcitrant psoriasis were treated with rational combinations of chemotherapeutic agents. Five patients received methotrexate by injection, 7.5 or 10 mg, followed 1 hour later by intravenous 5-fluorouracil, 170 to 562 mg/m2, on a weekly schedule. Four patients received oral triacetyl-azauridine, 2 to 4 gm daily, in combination with intravenous 5-fluorouracil, 225 to 600 mg/m2, administered every week. Three patients experienced greater than 75% clearing of disease, five patients experienced greater than 50% clearing, and only one patient failed to respond. Response rates did not differ between the two treatment groups. Adverse effects of these therapies were mild and infrequent. We conclude that 5-fluorouracil in combination with either methotrexate or triacetyl-azauridine is a relatively safe and effective alternative for the therapy of patients with severe psoriasis.

Adult↗
PubMed1986

Rational therapy for acne vulgaris: an update on topical treatment.

Acne vulgaris is a disorder of sebaceous follicles that usually begins at the time of the sharp increase in androgen production that occurs in adolescence. This disease is most prevalent among teenagers, but it does occur in patients in their twenties and thirties. Three major areas of pathophysiology have been identified in acne: hyperkeratinization and obstruction of sebaceous follicles, resulting from abnormal desquamation of follicular epithelium; an androgen-stimulated increase in the production of sebum; and proliferation of Propionibacterium acnes, which generates inflammation. Disruption of the preclinical precursor lesion known as the microcomedo produces inflammation, which leads to the pustules and papules of clinical disease and may eventually result in scarring. Rational therapy for acne should be directed at the three factors involved in the pathophysiology of the disease. Tretinoin (all-trans-retinoic acid) acts to normalize desquamation of follicular epithelium, promote drainage of comedones, and inhibit formation of new ones. Salicylic acid is also comedolytic, but to a much lesser degree. Benzoyl peroxide and topical or systemic antibiotics work by decreasing the follicular population of P. acnes, thus reducing inflammation. Direct injection of corticosteroids may be used to reduce large inflammatory lesions. Physical removal of comedones is also useful. Severe nodulocystic acne and other cases that fail to respond to these measures may be treated systemically with isotretinoin (13-cis-retinoic acid).

Acne Vulgaris↗
PubMed2000

Rational antibiotic therapy for respiratory disorders in dogs and cats.

Therapy of respiratory tract infections presents some unique challenges to the veterinary practitioner. These infections often involve underlying disease processes that have predisposed the patient to secondary bacterial infection and may complicate the response to therapy. Because of the diversity of microbial organisms that may colonize and invade the respiratory tract, treatment targeted at the infecting pathogens is best accomplished with bacterial culture and susceptibility testing. When these data are unavailable, rational antibiotic treatment should be based on familiarity with historical data and clinical experience. Optimal drug selection is based on predicted microbial susceptibility, drug distribution in the respiratory tract, and safety of the patient. Instituting the appropriate dosage regimen and duration of therapy maximizes the opportunity for a successful resolution of bacterial infections.

Animals↗
PubMed1988

Rational ordering of cervical spine radiographs following trauma.

A retrospective review of 312 hospitalized patients with cervical spine injuries was conducted to identify presenting signs, symptoms, and coexisting conditions, and to determine if any injuries were not diagnosed in the emergency department. Of the 257 (82%) patients who were alert on ED evaluation, 215 (84%) complained of neck pain or tenderness. Of the remaining 42 alert patients without neck pain, 34 had sensory or motor symptoms or signs suggestive of cervical spine injury, and eight had significantly painful other injuries. Of the 284 patients presenting within the first 48 hours after injury, 23 were not diagnosed initially, 21 because radiographs were initially read as negative and two because no radiographs were taken. A significant number of patients had more than one fracture of the spinal column. A stepwise approach to rational ordering of cervical spine radiographs in blunt trauma is proposed.

Adult↗