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PubMed1999

The procedure of new drug application and the philosophy of critical rationalism or the limits of quality assurance with good clinical practice.

K.R. Popper's philosophy of critical rationalism is concerned with the detection and removal of error. Fundamental contradictions exist between Popper's theory of knowledge and the present-day practice of the clinical investigation of new drugs. Currently, the public authorities concerned with the licensing of drugs pass judgment on trials, which are closely linked by the one-sponsor problem: the assertions made by the sponsor are not independently confirmed. This lack leads to excessive documentation and to costly monitoring and auditing, which are intended to ensure the credibility of results. In Popper's view, confirmatory trials, independent of the sponsor and supervised by the regulatory bodies, would be a better way to achieve reliable knowledge. The consequence would, among other things, be a reorganization of phase III of the clinical investigation of new drugs by dividing it into independent parts, one under the control of the sponsor and one under the control of the public authority. The implementation of this suggestion would lead to a more scientific manner of dealing with new drugs and to savings in terms of unproductive measures during the application process.

Clinical Trials, Phase III as Topic↗
PubMed2002

[A proposal for the rational use of the PET in oncology].

OBJECTIVE: This study aims to develop a Clinical Practice Guide for the rational use of the Positron Emission Tomography (PET) in Oncology, that makes it possible to approach the real existence of demand in the public health care service of Andalucía, by limiting the clinical indications, using criteria based on the existence of sufficient scientific evidence on the effectiveness and clinical impact of PET. METHOD: The consensus technique was used to elaborate the Guide, gathering a group of nuclear medicine experts. Prior to this a systematic research of the scientific literature was carried out, using strict criteria for the selection of the articles, such as the evaluation of the epidemiological data, work methodology, clinical and pathological diagnosis, gold standard references and statistical analysis. In each pathology group, the existence of alternative non-invasive diagnostic techniques was assessed, comparing its effectiveness and clinical impact with the PET, and the existence of useful treatments correlated with the results of the examination was also evaluated. When it was possible, we evaluated the cost-effectiveness of the PET. Finally, the cost-effectivity of the technique was assessed and the limitation of present and future resources and the economical costs arising from the PET costs and introduction were evaluated. RESULTS AND CONCLUSIONS: It was considered that the PET was indicated in the following clinical conditions: 1: Assessment of Colorectal Cancer recurrence in patients with increased levels of tumor markers and negative morphological imaging techniques. Suspicion of isolated resectable recurrence. 2: Restaging in patients with high risk melanoma. 3: Differential diagnosis of solitary pulmonary nodules. 4: Staging of non-small cell bronchial carcinoma. 5: Staging and detection of recurrences of lymphomas. 6: Restaging of head and neck cancer with possibilities of curative treatment. 7: Diagnosis of recurrences in differentiated thyroid cancer in patients with increased plasma levels of thyroglobulin and negative radioiodine scintiscan. 8: Staging and follow-up of medullary thyroid carcinoma. 9: Differential diagnosis between recurrent tumor and scar or radionecrosis in brain tumors.

Brain Neoplasms↗
PubMed2003

[About the rational use of intrathoracic transfers. Anatomical and surgical bases for the selection of twelve different muscular and omental flaps].

Because of their rich blood supply and of their original detersive and filling properties, the muscular pedicled flaps harvested from the trunk or the omental flap elevated from the abdomen may be very usefull to treat large defects or major septic problems in pleural, pericardic or mediastinal cavities. We here describe the main principles to be followed in such intrathoracic reconstructions performed in order to control severe mediastinites, aortic prosthetic infections, pleural empyemas and broncho-pleural, tracheo-esophageal or broncho-esophageal fistulas. In all these circumstances, the muscular or omental flaps which are transferred into the chest are selected according to the recipient field and to their respective access to the upper, middle and lower portions of the pleural space or mediastinum. Twelve different flaps so appear available to achieve the adequate reconstruction, filling or coverage of nine distinct topographic sites. Their rational use, based on various anatomical guidelines, allows to prevent or to cure efficiently 90% of the infectious or fistular complications frequently observed in the postoperative course of aggressive, functional or oncological, intrathoracic surgical procedures.

Abdomen↗
PubMed1997

Molecular modelling of CYP2E1 enzymes from rat, mouse and man: an explanation for species differences in butadiene metabolism and potential carcinogenicity, and rationalization of CYP2E substrate specificity.

Molecular modelling of substrates of cytochrome P4502E1 (CYP2E1) within the putative active site region of CYP2E1 constructed from the CYP102 crystal structure is reported. Structural characteristics of CYP2E1 substrates, such as molecular size, energy levels and polarity, calculated via molecular orbital procedures provide correlations with toxicity and carcinogenicity; and species differences in CYP2E1-mediated metabolism are rationalized in terms of interactions with putative active site amino acid residues, including Thr-437 and Phe-181. In particular, the activation of buta-1,3-diene can be explained by active site modelling with CYP2E1 enzymes sequenced from rat, mouse and man, where there is a non-conservative change T437H between rodent and human isozymes, together with a conservative change I438V between mouse and rat CYP2E1.

Amino Acid Sequence↗
PubMed2003

[Rational use of noninvasive cardiac stress testing in the diagnosis of coronary artery disease].

A variety of noninvasive tests are available to clinicians for the evaluation of patients in whom ischemic heart disease is suspected because of chest pain, clinical antecedents, or a combination of the two. Although all tests in general help to varying degrees to refine (by inclusion or exclusion) the diagnosis in a given patient, there are undoubtedly important differences between tests regarding their scope and diagnostic accuracy in general, and with respect to certain groups of patients in particular. Because of this, and in view of the obvious economic implications, the topic merits critical review before the information obtained from these tests is used in patient management. This review is not intended to cover all features that argue for or against all currently available noninvasive tests for ischemic heart disease, but to place into perspective the importance of the clinical assessment of the patient in the light of the results of testing, and to obtain a more rational idea of their usefulness. Despite the risk of excluding certain material of interest, excellent techniques such as magnetic resonance imaging will not be covered in the review, only because they have not yet been included in meta-analyses. Emphasis on the Bayesian rationale or paradigm, together with discussion of recent meta-analyses, offers a balanced perspective of the use and possible misuse of these diagnostic tests, and of their clinical and economic implications.

Bayes Theorem↗
PubMed1996

Rational approach to improving reductive catalysis by cytochrome P450cam.

Although halogenated hydrocarbons are noted for low chemical reactivity, small amounts are toxic to humans. Cytochromes P450 have been implicated in transforming these compounds to more reactive species, under anaerobic conditions, through reduction at the heme. A significant amount of effort has been directed toward turning this catalytic ability to our advantage by engineering P450 variants than can efficiently remediate these compounds in situ, before they come in contact with the human population. We have taken a 'rational' approach to this problem, in which a combination of theory and molecular modeling is applied to identify which properties of the enzyme have the greatest influence over reductive dehalogenation. Recent progress in this area is briefly reviewed. Two novel mutants, incorporating tryptophan (positions 87 and 396) and histidine (position 96, neutral and protonated) amino acid substitutions in the active site, are proposed and evaluated using molecular dynamics simulations. The upper bound on rate enhancement relative to wild-type is estimated in each mutant using electron transfer theory. The most significant rate enhancement is predicted for the His 96 mutant in the protonated state; while some His residues of certain proteins exhibit a pKa high enough to support a large protonated population, such information is not presently available for this proposed mutant.

Camphor 5-Monooxygenase↗
PubMed2003

Neuroblastoma directed therapy by a rational prodrug design of etoposide as a substrate for tyrosine hydroxylase.

Tumor directed cytotoxic therapy is one of the major challenges for the success of chemotherapy. In order to accomplish this goal in neuroblastoma, we rationally designed a prodrug of etoposide as substrate for tyrosine hydroxylase, a well established neuroblastoma associated enzyme. Here, we report synthesis and characterization of a 3,4 dihydroxy-phenyl carbamate derivative of etoposide. In order to demonstrate activation by tyrosine hydroxylase, the coding sequence of murine tyrosine hydroxylase was generated by reverse transcriptase-polymerase chain reaction from NXS2 neuroblastoma cells and cloned into the pRSET-A bacterial expression vector. The enzyme was expressed in Escherichia coli, characterized by Western blot and enzymatic activity was demonstrated by conversion of tyrosine into DOPA in the presence of cofactors using reversed phase high-performance liquid chromatography. Under these enzymatic conditions, we demonstrate conversion of 3,4 dihydroxy-phenyl carbamate prodrug into free etoposide. This effect was clearly mediated by the enzyme since bacteria transformed with the empty vector were ineffective of prodrug activation. Furthermore, tyrosine hydroxylase positive cells exposed to the etoposide prodrug were effectively killed in contrast to tyrosine hydroxylase negative controls. These findings demonstrate that etoposide can be designed as a prodrug substrate for tyrosine hydroxylase and thereby establish proof of concept for neuroblastoma directed enzyme prodrug therapy.

Animals↗
PubMed2003

Utility of physiologically based pharmacokinetic models to drug development and rational drug discovery candidate selection.

The present paper proposes a modeling and simulation strategy for the prediction of pharmacokinetics (PK) of drug candidates by using currently available in silico and in vitro based prediction tools for absorption, distribution, metabolism and excretion (ADME). These methods can be used to estimate specific ADME parameters (such as rate and extent of absorption into portal vein, volume of distribution, metabolic clearance in the liver). They can also be part of a physiologically based pharmacokinetic (PBPK) model to simulate concentration-time profiles in tissues and plasma resulting from the overall PK after intravenous or oral administration. Since the ADME prediction tools are built only on commonly generated in silico and in vitro data, they can be applied already in early drug discovery, prior to any in vivo study. With the suggested methodology, the following advantages of the mechanistic PBPK modeling framework can now be utilized to explore potential clinical candidates already in drug discovery: (i) prediction of plasma (blood) and tissue PK of drug candidates prior to in vivo experiments, (ii) supporting a better mechanistic understanding of PK properties, as well as helping the development of more rationale PK-PD relationships from tissue kinetic data predicted, and hence facilitating a more rational decision during clinical candidate selection, and (iii) the extrapolation across species, routes of administration and dose levels.

Animals↗
PubMed2006

[Elastic stockings and compression therapy, arguments favoring more rational use].

Elastic stockings and compression therapy are often considered as a major tool in the prevention and in the treatment of chronic venous insufficiency and of lymphedema. Nevertheless we must note that this therapeutic option is both underused and misused. We discuss the reasons for this paradox and the expected modes of action and pathophysiological benefits, and finally propose a prescription guide (indications, dosage, practice details) for a rational use of elastic stockings and compression therapy.

Humans↗
PubMed2006

[Evaluation of rational prescribing and dispensing of medicines in Mali].

Pharmaceutical policy in Mali is based on the concept of essential medicines and procurement of generic medicines. Unfortunately, increasing availability of generic medicines via different promotional programs can often be accompanied by their irrational use. This survey was thus designed to evaluate rational prescribing and dispensing of medicines in Mali. A cross-sectional survey was conducted from 1998 to 2005 in 30 primary health centers and 30 private dispensaries; in Bamako and in 6 of the 8 other regions of the country. In each of the visited facilities, 20 prescriptions dispensed at the time of the survey were collected. The average number of medicines per prescription was 3.2+/-1.3 and 2.8+/-1.2 respectively in the public and private sectors. Medicines were prescribed under generic name in 88.2% of the public sector prescriptions and in 30.9% of the private sector ones. Antibiotics were prescribed in 70.4% of the public sector prescriptions and in 50.0% of the private sector prescriptions. In the public sector 33.2% of the prescriptions had injections compared with 14.3% in the private sector (p<0.001). The median price per prescription was lower in the public sector (1575.0 CFA F, or 2.4 Euros, of which 91.3% were actually purchased by the patient) than in the private sector (5317.5 CFA F, or 8.1 Euros, of which 84.6% were purchased). Generic medicines are being used in the public sector but less frequently than in private practice. As therapeutic guidelines are already available, it would be useful to institute interactive information for practitioners through intensive visits by more experienced supervisors. The quality of the prescriptions could thus be optimized.

Cross-Sectional Studies↗
PubMed2001

Polypharmacy of heart failure. Creating a rational pharmacotherapeutic protocol.

In the management of chronic heart failure, polypharmacy is common, necessary, and often overlooked. The increasing costs of care, noncompliance, and frequent adverse drug interactions have led to diminishing benefits by simply adding additional drugs to the already complex regimen. This review outlines a rational pharmacotherapeutic protocol based on establishing overall therapeutic goals and confirming treatment targets, tailoring therapy to individual patients by balancing beneficial and adverse drug effects, and paying particular attention to patient education and other nonpharmacologic support.

Adrenergic beta-Antagonists↗
PubMed1996

Tissue effects and host response. The key to the rational triage of cervical neoplasia.

Genital HPV infections are associated with a spectrum of lesions ranging from benign condylomata to invasive cancer and its precursor lesions. The transformation zone of the cervix is the most frequent target of the high-risk HPV types. Depending on the nomenclature used, cancer precursors are subdivided on the basis of their morphologic presentation into dysplasias (mild, moderate, and severe); cervical intraepithelial neoplasias (CIN I, II, and III); or low-grade and high-grade squamous intraepithelial lesions (LGSILs and HGSILs). The HGSILs (i.e., moderate and severe dysplasias, CIN II and III lesions) are recognized universally as cancer precursors. The LGSILs (i.e., very mild dysplasia and mild dysplasias, condylomata and CIN I lesions), have shown that one of the most important denominators of their cancer potential is the presence of intermediate and particularly high-risk HPV types. HPV typing provides the most rational basis for selecting women with LGSILs to be colposcoped and treated or given follow-up treatment with Pap smears. Until the clinical significance of HPV typing is known, management decisions may be based on an individual's risk factors such as age, compliance, past history of abnormal Pap smears, sexual habits, and access to adequate cytologic diagnosis.

Colposcopy↗
PubMed2002

Targeting the molecular pathophysiology of gastrointestinal stromal tumors with imatinib. Mechanisms, successes, and challenges to rational drug development.

The development of imatinib as molecularly targeted therapy for GIST represents an important case study of rational drug development. It is a paradigm of how the molecular understanding of a cancer has resulted in a new effective therapy that targets the critical pathway upon which the GIST cells were dependent: the uncontrollably active KIT signaling pathway. Unresectable or metastatic GISTs have traditionally exhibited a rapid and fatal clinical course, with no evidence of benefit from any standard cytotoxic chemotherapy. The identification of KIT activation as a critical factor in the pathogenesis of GIST led to the search for a new type of therapeutic compound to serve as a KIT inhibitor and to interfere with the constitutive phosphorylation of the KIT kinase in GIST cells. Clarification of the molecular genetic pathophysiology of GIST and the role of KIT activation in this disease, therefore, has not only enabled improved diagnosis and differentiation of GIST from other mesenchymal neoplasms but has also been key in identifying new targeted strategies for therapeutic intervention. The improved understanding of the molecular pathophysiology of GIST, a disease that was previously untreatable with any available systemic therapy, has led to the development of imatinib, a well-tolerated agent that can inhibit the dysregulated KIT signaling pathways in GIST. Imatinib represents the first (and currently the only) effective systemic therapy for patients with unresectable GIST. Imatinib therapy can induce objective responses and stabilization of disease and can provide clinical benefit in the majority of GIST patients treated with the drug. Other strategies are beginning to be explored, such as the use of imatinib earlier the in course of GIST (e.g., as adjuvant therapy after definitive surgical resection of early-stage disease). Integration of signal transduction inhibitors into the armamentarium of cancer therapeutics will undoubtedly continue based on this important paradigm of GIST.

Antineoplastic Agents↗
PubMed1995

G. Paul Moore Lecture. Rational thought: the impact of voice science upon voice care.

Recent evolution in scientific knowledge and technology has led to monumental improvement in the standard of care for patients with voice disorders. New concepts in anatomy, physiology, measurement, and analysis have provided voice care professionals with not merely better understanding, but moreover an extensive vocabulary with which to think about voice function and dysfunction. Previously, we had to depend too much upon anecdote and "the art of medicine." Thanks to scientific advances, we now have the tools we need for rational thought about the human voice. This is the fundamental change responsible for recent great advances in voice care.

Humans↗
PubMed2001

Low-dose combination therapy: the rationalization for an ACE inhibitor and a calcium channel blocker in higher risk patients.

As more high-risk hypertensives are treated and the need for more intensive antihypertensive therapy is recognized, combination therapies are increasingly used. For initial therapy, particularly for relatively low-risk patients, low-dose combinations are often appropriate. For those who require additional therapy, higher doses of combinations may provide further efficacy while minimizing dose-dependent side effects of monotherapy, thereby improving adherence to therapy. Those combination agents should provide 24-h control with one daily dose, thereby ensuring protection in the early morning hours. Combining an angiotensin converting enzyme inhibitor and a calcium channel blocker is a rational approach to treating hypertension. Not only does it provide significantly better blood pressure control than individual components used as monotherapy, it also minimizes dose-dependent side effects. Also, combining agents from different classes results in complementary mechanisms of action that provide other cardiovascular protective benefits.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2003

Rational diuretic management in congestive heart failure: a case-based review.

The pharmacology and pharmacokinetics of diuretics are unique among therapeutic drugs. Knowledge of these principles can be used to great advantage in the management of heart failure, whereas ignoring them can lead to either minor or life-threatening adverse consequences. Two major categories of potential therapeutic problems are diuretic resistance and the development of disturbances in serum potassium and other electrolytes. Inhibition of sodium reabsorption in the loop of Henle or distal convoluted tubule leads to renal potassium wasting, whereas inhibition of sodium reabsorption in the collecting duct (either directly, as with triamterene or amiloride, or through aldosterone antagonism) causes potassium retention. Combining diuretics of different classes, a rational and frequently used strategy to counter diuretic resistance, can be anticipated to balance or magnify these effects, depending on the site of action of the individual drugs.

Aged↗
PubMed2002

Rational dosing of antimicrobial drugs: animals versus humans.

The rational dosing of antimicrobial drugs depends on knowledge of physiology, anatomy and pathology, including disease condition, and in major respects these differ between animals and humans and between species of animal. These differences lead to species variation in drug pharmacokinetics, which can be profound. This review highlights selected aspects of species differences in pharmacokinetics and considers underlying mechanisms by reference to ruminant and non-ruminant mammals, birds, fish and bees. For all species it is desirable and should be possible to design dosage schedules based on knowledge of drug pharmacokinetics and pharmacodynamics. There have been many attempts to integrate pharmacokinetic and pharmacodynamic data to provide dosage schedules which optimize efficacy and minimize opportunities for the development of antimicrobial resistance in both laboratory animal studies and human clinical trials. However, there have been relatively few studies in animal species of major veterinary interest. This review summarizes recent studies in four ruminant species (calf, sheep, goat and camel) which have used PK-PD integration to determine for the fluoroquinolone, danofloxacin, AUC/MIC ratios producing (a) bacteriostasis (b) bactericidal activity and (c) elimination of bacteria. Future possible developments in dosage schedule design are considered.

Animals↗
PubMed1999

Rational design of anti-dementia therapy.

Understanding the pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of new drugs is essential. The application of this information facilitates the design of a rational clinical trial programme and optimizes the chances for rapid and successful clinical development. Upon completion of each development phase, the information obtained must be evaluated critically to maximize the design of subsequent studies. Phase I trials represent the first time the drug is administered in humans and their primary objective is to evaluate the drug's safety and tolerability in man. Phase II trials represent the first time that the drug is administered to the target patient population. The objectives of Phase II trials are to verify the safety and tolerability of the drug in patients, and also to evaluate for the first time the clinical efficacy of the drug. During these phases of development, the use of PK and PD measures is helpful for establishing the therapeutic dose range as well as the suitability of the chosen efficacy measures for use in the pivotal Phase III trials. Here, using several examples of PK and PD data obtained from the clinical development studies of donepezil HCl, the application of these measures on the development of a drug for the treatment of Alzheimer's disease is discussed.

Alzheimer Disease↗