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PubMed2002

Bioinformatics and rational drug design: tools for discovery and better understanding of biological targets and mode of action of drugs.

BACKGROUND: With the advent of modern high throughput technologies in both genomics and biological screening, and at the same time the enormous advances in computer technology, it is now feasible to use these tools in rational approaches in the search for new medicines. The role of bioinformatics in the search for new medicines is discussed. METHODS: Discussion of the author's own work on bioinformatics in drug research in future perspective. RESULTS: The emerging discipline of Bioinformatics plays a central role in the concert of technologies of the 'biological revolution' because it allows for handling of the enormous data load that comes with sequencing efforts and subsequent analyses of whole genomes, with mRNA profiling techniques and, last but not least, at a later stage of drug discovery the up-to-date application of rational drug design techniques to 3D structures of target proteins. This article covers and explains parts of the steps used in modern pharmaceutical research by means of a small number of examples. CONCLUSION: Bioinformatics is likely to play a pivotal role in the rational approaches for the search of new medicines.

Computational Biology↗

PubMed2003

What do graduates think about a two-week rational pharmacotherapy course in the fifth year of medical education?

The present study aims to assess the short- and mid-term post-graduation impact of a pharmacotherapy course in the fifth year at Marmara University School of Medicine by an objective (OSCE) and a subjective (questionnaires) evaluation. Statistical comparison of pretest, posttest-exposed case and posttest-unexposed case scores indicated both a retention and a transfer effect of training. The post-course questionnaire revealed that 95%of the students found the course useful and necessary; 97% reported that they will apply a rational pharmacotherapy approach using this model and communicate better with their patients. The post-graduation questionnaire also showed that the majority of them have learned general principles of rational pharmacotherapy(90%), gained good prescribing (90%) and communication skills (87.5%), and understood the importance of non-pharmacological treatment alternatives (100%). In general, they stated that they would apply the principles during their medical practice and they believed their colleagues would do too. In conclusion, the present study demonstrates the benefit of a clinical pharmacology programme focused on rational pharmacotherapy during the clinical years of medical education.

Analysis of Variance↗

PubMed2000

Lactational and metabolic effects in cows of lysine and methionine added to a ration deficient according to the I.N.R.A. method.

The effects of adding lysine and/or methionine to a ration of calculated deficiency in these amino acids of 10% and 20%, respectively, were studied in 24 Brown Swiss cows. The mixed rations (27% grass silage, 19% maize silage, 5% hay and 49% concentrate on DM basis) contained 14.5% CP on average. Lysine supply was selectively elevated by adding fish meal in exchange for other concentrate ingredients. Methionine was supplied in a rumen-protected form. Milk protein content was elevated whereas fat amount decreased by adding both amino acids. Lactose content increased without additional lysine from fish meal. Live weight, milk yield, milk fat content and protein amount remained unaffected by any variation of amino acids supply. Also nutrient digestibility and nitrogen balance were not changed by the treatments. Blood plasma concentrations confirmed the assumed variation in metabolic lysine and, less clear, methionine supply. Effects on plasma concentrations of other amino acids were relatively small. Most plasma hormones and enzymes, and metabolites in plasma, urine and milk did not respond to the variation in amino acid supply. Lysine addition via fish meal increased aspartate amino transferase and decreased urinary allantoin concentration. Additional methionine elevated plasma ornithine. Overall lysine and methionine appear to have been only marginally deficient in the unsupplemented ration fed for 3 weeks despite the deficiency of 10% to 20% as calculated by the I.N.R.A. method.

Amino Acids↗

PubMed1976

[Studies on the effect of nutritional factors on the rumen mucosa. 2. Report. Morphological conditions after feeding with fattening rations in various physical forms].

3 groups of fattening cattle (DSR breed) were fed rations of nearly identical composition for a period of 395-455 days. The rations consisted of either crushed (group I), finely ground (group II) or finely ground and pelleted material (group III). Samples of the ruminal mucosa from 26 animals were investigated macroscopically, microscopically and histologically. All samples from animals of group I were found to be normal whereas clumping of the villi, hyperkeratosis, atrophy and loss of villi over 40%-50% of the surface of the ruminal mucosa were observed in the animals from group II, and, to a larger extent in animals of group III. The main reason for the mentioned changes of that kind are the very fine foodstuff particles, less than 0.05 to 0.5 mm in length, which form extraneous deposits in the mucosa or act as cement substances between neighbouring villi. This leads to hyperkeratosis because these particles prevent desquamation of the corneal cells and at the same time produce conditions of compression; these, in turn, result in a hardening of the newly formed stratum corneum. Hypertrophy of the undamaged villi was observed in animals of group III receiving the pelleted ration (thickness of villi group III: 243 mum as compared with group I:196 mum). The unfavourable morphological state of the ruminal mucosa in animals of group III was associated with a reduced rate of daily weight gains and increased food consumption.

Animal Nutritional Physiological Phenomena↗

PubMed1983

[Ergotropic efficacy of 2,3-dimethylquinoxaline-1,4-dioxide and 2-methylquinoxaline-1,4-dioxide in growing broilers using hydrocolloid-rich rations as well as broiler fattening feed].

2,3-dimethyl-quinoxaline-1,4-dioxide and 2-methyl-quinoxaline-1,4-dioxide proved to be ergotropic in the feeding of a hydrocolloid ration as well as of a broiler fattening feed. They are at least equal to Nitrovin. The ergotropic effect of the hydrocolloid ration was higher than that of the conventional ration. For this reason methylated quinoxaline-1,4-dioxides are considered as belonging to the intestinal stabilisers. They increased nutrient and energy retention and decreased feed efficiency by approximately equal to 10%. Residues in the liver, the kidneys and the intestines could only be detected after 10 times the ergotropic amount.

Animal Feed↗

PubMed1984

Investigations of the influence of the content of plant crude protein in the ration on the utilisation of urea in dairy cattle. 5. 15N-fractions in the blood of lactating cows given 15N-urea intraruminantly.

The incorporation of urea-15N (given as an intraruminal drench or infusion) into plasma urea and protein of dairy cows fed isoenergetic rations with different levels of plant protein (9, 11, 12, 14, 15 and 17% in DM) was investigated. A nonlinear and asymptotic dependence between the plasma concentration of urea and protein level in the ration was stated. The availability of dietary urea-15N for plasma urea for 48 hours after administration was lowest in cows fed with low protein rations (9 and 11% of plant protein). On the contrary the highest incorporation of urea-15N into plasma protein of these animals was observed. The possible explanation of these results is presented.

Animals↗

PubMed1985

[Effect of type of starch and quantity in rations on apparent and true digestibility of nitrogen and nitrogen balance in sheep].

In a digestibility trial 5 semisynthetic rations were fed in 3 periods to 10 male sheep to examine the effects on N balance, components of faecal nitrogen and N digestibility. The rations contained constant amounts of nitrogen but different contents of cellulose and two different types of starch (untreated and steamflaked). Content and type of starch did not show any noticeable effect neither on excretion of undigested dietary nitrogen nor on true digestibility. There could not be noticed any effects on the apparent N digestibility by changing contents of cellulose or untreated starch. If the rations contained steamflaked corn starch, the animals excreted more faecal nitrogen and therefore showed a lower apparent N digestibility. Especially the water soluble N fraction of the faecal nitrogen was clearly higher. Compensation took place through a lower N excretion with the urine. The reason for increased faecal N excretion may be higher microbial protein synthesis in the rumen. This was accented by the allantoin excretion with the urine.

Animal Feed↗

PubMed1991

[Effect of graduated vitamin D3 doses and different ration composition on the 25OH-vitamin D3 plasma concentration and fattening and slaughter production of bulls].

In a individual feeding experiment (348 days) 24 fattening bulls were given either a ration high in roughage (2.8 kg concentrate mixture, wheat straw ad libitum: group I) or high in concentrate (5.6 kg concentrate mixture, wheat straw ad libitum group II) supplemented with various levels of vitamin D3 (0, 250, 500, 1,000, 2,000, 4,000 and 8,000 IU per 100 kg body weight (bw) and day) and minerals as required. After 58, 101, 134, 172, 205, 277 and 340 days 25-OH-D3 plasma concentration was estimated. Fattening and slaughtering parameters were measured. The 25OH-D3 plasma concentration was significantly influenced by vitamin D3 supply, kind of ration and day of taking samples. 25-OH-D3 plasma concentration decreased below 5 ng per ml when vitamin D3 supply was less than or equal to 250 IU per 100 kg bw and day. The initial plasma levels were maintained when 500 IU vitamin D3 per 100 kg bw and day was given (6.6 ng per ml). Administration of greater than or equal to 1,000 IU per 100 kg bw and day increased 25OH-D3 plasma level (greater than 10 ng/ml). Plasma 25OH-D3 concentration was significant higher when bulls consumed diets rich in concentrate (10.6 and 18.2 ng/ml for I and II after 340th day). Differences in content of cell walls and crude fat of rations may be responsible for results. Daily weight gain of bulls amounted to 712 and 945 g when fed diets I or II. Dry matter intake and live weight gain were not significantly influenced by different vitamin D3 supply. Clinical symptoms of rachitis did not appear.

Animal Feed↗

PubMed1993

[The effect of starch sources barley, maize and potatoes and their ration portions on the nutrient digestibility and energy utilization in ruminants. 4. Nitrogen metabolism in the rumen].

In 9 experimental periods on four adult bulls (LW 550 kg) fitted with re-entrant cannulae in the proximal duodenum isoenergetic rations were used on feeding level 1.7 with ground barley, ground maize or fresh potatoes as starch sources. The net energy parts of these concentrates in the ration amounted to 50, 25 and 10%. 50 to 80% of the ration DM consisted of dried grass and about 10% of sugar beet pulp. The dried grass supplied on an average 87, 79 and 62% of the feed crude protein. The intake of DM was 7.74 +/- 0.42 (mean +/- SD) kg/d. The energetic efficiency of microbial N synthesis in the rumen (g N/kg organic matter true fermented in the rumen, TFOM) was averaged 16.4 with a range of 10.6 to 21.4. The microbial efficiency achieved a maximum when the ratio of nitrogen-free extract to crude fibre in the diet was 1.7 and 2.1 with barley, 1.8 with potatoes and 2.1 and 3.3 with corn as starch source. Changes in the microbial efficiency were positively correlated with the rate of passage of non-microbial organic matter from the rumen (g/d) and with the duodenal flow rate (kg digesta/kg DM intake). The relation to the rate of carbohydrate fermentation in the rumen (in %) and to the amount of TFOM (g/d) was negative. The duodenal flow of microbial N and non-ammonia N (g/d) correlated negatively with the organic matter apparently fermented in the rumen (AFOM) and positively with the non AFOM. The amino acid (AA) profile of the duodenal protein was affected by the starch source. It was concluded that the metabolism of nitrogen in the forestomachs of cattle is affected by the source of starch and the ratio of forage to concentrate. There exists a relationship between both factors. The net synthesis of microbial protein in the rumen is not only the result of substrate fermentation. The passage of non-AFOM from the rumen significantly affects the energetic efficiency of microbial nitrogen synthesis and the duodenal supply of AA.

Amino Acids↗

PubMed1986

Rational diagnosis and treatment.

Clinical decisionmaking includes reasoning from prescientific or scientific theories, reasoning from uncontrolled or controlled experience, and reasoning based on empathic understanding and moral beliefs. The development of contemporary clinical thinking is discussed, and it is found that successive generations of medical practitioners have had different views of the rationality and relative importance of these modes of reasoning: that which is considered rational by one generation of doctors is sometimes denounced by the next. The author's book, Rational Diagnosis and Treatment, which is an example of clinical thinking in the 1960s and early 70s, is used to illustrate one particular view of clinical decisionmaking.

Clinical Trials as Topic↗

PubMed1980

Influence of ration physical form, ruminal degradable nitrogen and age on rumen epithelial propionate and acetate transport and some enzymatic activities.

Holstein bull calves were used to determine the influence of degradable nitrogen and ration physical form on rumen epithelial transport and enzymic activity. Rations contained 30, 45 and 60% ruminal degradable nitrogen (RDN), each with three forms (ground hay, GR; chopped hay, CH; and all concentrate, CONC). Rumen tissue samples were obtained by biopsy (8 weeks) and at slaughter (20 weeks). Acetate transport across rumen epithelium increased between 8 and 20 weeks in calves fed GR and CH, but not in calves fed CONC. Propionate transport was highest in calves fed GR and lowest in calves fed CONC at both 8 and 20 weeks. Transport of acetate and propionate was incresed with increasing RDN at 20 weeks. There were no differences in ruminal tissue lactate production. Rumen papillae of calves fed CONC were abnormal in morphology and at 20 weeks dry mucosal weights (mg/cm2) were highest. Lactate dehydrogenase and NADP-malic dehydrogenase activities were not different. Propionyl CoA synthetase activity was higher in 20-week calves fed CONC, compared to GR to CH. Glutamate dehydrogenase and aspartate aminotransferase activities were highest in 20-week calves fed 60% RDN rations, regardless of physical form.

Acetates↗

PubMed1997

Acute otitis media in pediatrics: are there rational issues for empiric therapy?

BACKGROUND: Acute otitis media in children is a significant clinical problem that requires a rational approach to treatment. The condition is extremely common and has important economic implications. At present there is considerable controversy over the most appropriate strategy and over the use and choice of antibiotics. OBJECTIVES: To analyze the various factors that influence therapeutic decisions and consider how these may assist in the formulation of a rational approach to therapy. DISCUSSION: Otitis media has a multifactorial etiology but it is extremely difficult to differentiate between bacterial and viral causes on clinical grounds. Culture of the middle ear fluid is rarely practicable; however, nasal swabs are relatively noninvasive and can provide useful microbiologic information, especially in excluding a bacterial cause. Published information provides little guidance on the most appropriate therapy; a rational approach to treatment is based on many considerations including the local epidemiology. The minimum criteria for the empiric choice of an antibiotic for acute otitis media are that it should be rapidly bactericidal and reach adequate concentrations in the middle ear fluid. In areas where beta-lactamase-producing strains are prevalent, a beta-lactamase-stable antibiotic should be chosen; good absorption from the gastrointestinal tract and high and consistent penetration into the middle ear are important characteristics. Compliance-enhancing factors such as fewer doses per day and good palatability are also important.

Adolescent↗

PubMedDate not supplied

Rational nursing: a concept analysis for practical application.

Rational nursing is a theoretical concept that serves as a practical, behavioral application of the nursing process. This article is a concept analysis that defines and clarifies rational nursing, examines relational and nonrelational propositions, and describes clinical and personal applications for the individual nurse. This relatively simple yet revolutionary tool can improve patient outcomes and prevent nursing burnout. Nurses involved with staff development, education, and retention will discover that teaching and reinforcing rational nursing provides nurses with minute-by-minute guidance to the treatment of the human response both in patient illness and their own practice of nursing.

Attitude of Health Personnel↗

PubMed2025

BOGO: A Proteome-Wide Gene Overexpression Platform for Discovering Rational Cancer Combination Therapies.

Cancer drug resistance remains a major barrier to durable treatment success, often leading to relapse despite advances in precision oncology. While combination therapies are being increasingly investigated, such as chemotherapy with small molecule inhibitors, predicting drug response and identifying rational drug combinations based on resistance mechanisms remain major challenges. Therefore, a proteome-wide, single-gene overexpression screening platform is essential for guiding rational therapy selection. Here, we present BOGO (Bxb1-landing pad human ORFeome-integrated system for a proteome-wide Gene Overexpression), a robust, scalable, and reproducible screening platform that enables single-copy, site-specific integration and overexpression of ~19,000 human open across cancer cell models. Using BOGO, we identified drug-specific response drivers for 16 chemotherapeutic agents and integrated clinical datasets to uncover proliferation and resistance-associated genes with prognostic potential. Drug response similarity networks revealed both shared and unique mechanisms, highlighting key pathways such as autophagy, apoptosis, and Wnt signaling, and notable resistance-associated genes including BCL2, POLD2, and TRADD. In particular, we proposed a synergistic combination of the BCL2 family inhibitor ABT-263 (Navitoclax®) and the DNA analog TAS-102 (Lonsurf®), which revealed that lysosomal modulation is a key mechanism driving DNA analog resistance. This combination therapy selectively enhanced cytotoxicity in colorectal and pancreatic cancer cells in vitro, and demonstrated therapeutic benefit in vivo in both cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) models. Together, these findings establish BOGO as a powerful gene overexpression perturbation platform for systematically identifying chemoresistance and chemosensitization drivers, and for discovering rational combination therapies. Its scalability and reproducibility position BOGO as a broadly applicable tool for functional genomics and therapeutic discovery beyond cancer resistance.

Journal Article↗

PubMed2003

Humanitarian Daily Rations: the need for evaluation and guidelines.

Over 13 million Humanitarian Daily Rations (HDRs) have been distributed by NGOs, international organisations and the US military since 1993. In that time, not a single technical end-user study of HDRs has been published. Nor have practical guidelines been established for HDR distribution or use. This paper seeks to establish a baseline of knowledge concerning HDRs, surveying their history, composition and distribution. Criticisms of the ration are reviewed. A comprehensive evaluation is required to understand and improve HDR distribution, end-use, perceptions, design and nutritional contents. HDRs must also be added to technical guidelines on planning nutritionally adequate rations.

Afghanistan↗

PubMed2004

Environmental risk, precaution, and scientific rationality in the context of WTO/NAFTA trade rules.

This article considers the role of scientific rationality in understanding statements of risk produced by a scientific community. An argument is advanced that, while scientific rationality does impose constraints on valid scientific justifications for restrictions on products and practices, it also provides flexibility in the judgments needed to both develop and apply characterizations of risk. The implications of this flexibility for the understanding of risk estimates in WTO and NAFTA deliberations are explored, with the goal of finding an intermediate ground between the view that science unambiguously justifies or rejects a policy, and the view that science is yet another cultural tool that can be manipulated in support of any decision. The result is a proposal for a dialogical view of scientific rationality in which risk estimates are depicted as confidence distributions that follow from a structured dialogue of scientific panels focused on judgments of evidence, evidential reasoning, and epistemic analysis.

Environmental Health↗

PubMed1989

Undergraduate medical school training in psychoactive drugs and rational prescribing in the United Kingdom.

The present study examines the extent and form of teaching on psychoactive drugs and the rational prescribing of them given to undergraduate medical students in the United Kingdom. All the 21 schools which replied taught on psychoactive drugs. The average was 15.4 hours of formal teaching (lectures, seminars, tutorials). The teaching on psychoactive drugs compares favourably with the average of 4.2 hours teaching given on alcohol related problems and 3.5 hours on drug dependence. It emerged that there was a great deal of variation in the amount of teaching on psychoactive drugs and many schools felt their teaching on rational prescribing was inadequate. There is a need to promote better co-ordination between medical school departments and to identify the key concepts which all medical schools teach. These steps would help to ensure improved teaching on psychoactive drugs and rational prescribing.

Curriculum↗

PubMed1995

Promoting rational prescribing: an international perspective.

Irrational prescribing is a global problem. Rational prescribing cannot be defined without a method of measurement and a reference standard. The former is now available but the latter needs further development. Proven effective interventions to promote rational prescribing in developed countries are treatment protocols based on wide consultation and consensus, properly introduced and with a possibility of feedback; face-to-face education focussed on a particular prescribing problem in selected individuals; structured order forms; and focussed educational campaigns. Essential drugs lists are probably effective when based on consensus and used within a comprehensive educational programme. Printed materials alone are not effective. In most cases the usefulness of such strategies in developing countries has not been proven and should be studied. Medical education in clinical pharmacology and pharmacotherapy should be based on the practical needs of future prescribes, should include the principles of rational therapeutics and problem solving, and should immunize the students against the influences they are likely to encounter in their professional life, such as patient pressure, drug promotion and irrational prescribing by peers. Within the scope of a national formulary, specialist departments in teaching hospitals should define prescribing policies as the basis for prescribing, teaching, examinations and medical audit.

Drug Prescriptions↗