[Classification and variability of drug assessment reports on the GENESIS group (SEFH) webpage]. / Caracterización y variabilidad de los informes de evaluación de medicamentos en la página web del grupo GENESIS de la SEFH.

OBJECTIVE: To analyse the assessment reports published on the GENESIS webpage (Group for Innovation, Assessment, Standardisation and Research in the Selection of Drugs) and assess the variability of the group's proposals to include drugs in the Formulary. METHOD: We analysed reports published by hospitals on the GENESIS webpage between 2004 and 2007. Data were collected on drugs and indications, ATC group, open or restricted access publications, hospital, and publication date. We drafted a questionnaire that would measure to what extent to what extent the 9-section model recommended by GENESIS was included in each report. For drugs with two or more reports, we analysed whether the recommendation coincided and the possible cause in the event of conflict. RESULTS: We analysed 416 reports corresponding to 185 different drug indications. 93% included 6 or more of the recommended sections, a number which increased over time. The most frequently included sections were: approved indications (92%), mechanism of action (95%), and references (86%) (percentages from 2007). Sections which had an increasing but lower percentage were: differential characteristics (60%), literature search method (40%) and conclusions with a summary of efficacy, safety and cost data (52%). 73% of which had definite recommendations, which coincided for 42 out of the 67 drugs with more than one recommendation report. CONCLUSIONS: The work carried out by the GENESIS group has enabled Spanish hospitals to share their drug assessment reports and making them more complete, although there are still some aspects that can be improved.

[Clinical and economic impact of the pharmacy resident incorporation into the healthcare team]. / Impacto clínico y económico de la incorporación del farmacéutico residente en el equipo asistencial.

OBJECTIVE: To quantify the impact of the incorporation of a hospital pharmacy resident into a healthcare team. To describe the work schedule followed. METHOD: The resident was integrated for 8 months in Medical Oncology, Intensive Care Unit, and Oncology Day Hospital. Interventions were recorded and evaluated using Atefarm software. Problem characteristics, type, and severity were recorded, as were acceptance, and costs avoided by interventions. RESULTS: In all, 2,415 drug-related problems were detected (10 per day, and 3.6 per patient), and 2,545 interventions for 672 patients were carried out. Most common problems were inadequate treatment duration, and conversion to oral route. Sixty-one percent of errors were prevented. Sixty-five percent of interventions influenced safety, 35% efficiency, and 25% effectiveness. Ninety-four percent of interventions were accepted. Costs avoided by the pharmacist amounted to 3,133 euro per month. CONCLUSIONS: The integration of a pharmacist in the healthcare teams optimizes therapy, reduces costs, prevents adverse events, and offers healthcare education.

Expresiones y criterios mejorables en la redacción de informes de evaluación y posicionamiento terapéutico / Expressions and criteria that could be improved in the writing of reports for drug evaluation and therapeutic positioning

En la revisión de borradores de informes para evaluación y posicionamiento de nuevos fármacos en un entorno multidisciplinar, se observan determinados errores de expresión o criterio que se repiten con frecuencia. Principalmente, están relacionados con la consideración de “diferencias” o tendencias no significativas, abuso de la reducción relativa del riesgo, errores en la valoración de resultados por subgrupos sin calcular la interacción estadística, confusiones en la interpretación de las comparaciones indirectas, sobrevaloración de la relevancia clínica con variables subclínicas y afirmaciones sesgadas en el apartado de seguridad, entre otros. También se observa a menudo ambigüedad o inhibición en el posicionamiento, especialmente en situaciones de precariedad en la evidencia disponible. El presente trabajo expone de forma sintética tales errores, aclara algunos términos comunes y propone expresiones o criterios alternativos que se consideran preferibles, con el fin de ofrecer una evaluación para la toma de decisiones en beneficio de los pacientes. (AU)

In the review of reports for evaluation and positioning of new drugs in a multidisciplinary setting, some usual errors of expression or criteria are observed. Most of them are related to the consideration of «differences» or non-significant trends, abuse of the relative risk reduction, errors in the assessment of results by subgroups without calculating the statistical interaction, misinterpretation of indirect comparisons, excess in the assessment of clinical relevance with subclinical variables and biased statements in the safety section, among others. Ambiguity or inhibition in positioning is also often observed, especially in situations of precariousness in the available evidence. This work summarizes such errors, clarifies some common terms and proposes alternative expressions or criteria that are considered preferable, in order to offer evaluations for decision-making focused on the benefit of patients. (AU)

Carotenoid biosynthesis in wild type and mutant strains of Mucor circinelloides.

Carotenoid biosynthesis in wild type Mucor circinelloides has been investigated and the biochemical characterisation of the MS1 and MS9 mutant strains, impaired in carotenoid formation, carried out. In liquid cultures, all strains produced carotenoids (mainly beta-carotene, but also xi-carotene, lycopene and gamma-carotene) at the onset of stationary phase of growth. Carotenogenesis was light dependent. In liquid cultures carotenoid formation in wild type was affected by diphenylamine, which prevented desaturation, nicotine, resulting in reduced carotenoid levels, but CPTA caused an increase in the total carotenoid content but a reduced beta-carotene level, with the accumulation of lycopene and gamma-carotene. The mutant strains MS1 and MS9 contained only 5.0 and 11.5% of wild type carotenoid levels, respectively. Cell extracts of light-grown mycelia, incubated with 3(R)-[2-14C] mevalonic acid, produced beta-carotene, but incorporations into carotenoids were substantially reduced in the cell extracts of MS1 and MS9. Analysis of prenyl diphosphate intermediates indicated that, compared to wild type, geranylgeranyl diphosphate accumulated in MS1. MS9 extracts produced a larger amount of prenyl phosphates and a more even distribution of radioactivity from mevalonic acid into farnesyl and geranylgeranyl diphosphates. Squalene and long chain prenyl phosphates were formed by the cell extracts of all strains. It is proposed that the MS1 strain possesses a mutation in a gene responsible for phytoene formation, whilst a regulatory mutation, affecting prenyl transferase activities has occurred in MS9.

Isogenic Strains of PHYCOMYCES BLAKESLEEANUS Suitable for Genetic Analysis.

The progeny of crosses between wild-type strains of Phycomyces usually do not exhibit all of the expected genotypes from meiosis. By backcrossing, we have isolated a new (+) mating-type strain, A56, which is nearly isogenic with the (-) wild-type NRRL1555 commonly used in Phycomyces research. Tetrad analysis of the backcrosses shows that meiosis becomes more regular as the parental (+) and (-) strains become more isogenic. In our two-factor crosses with unlinked markers, the regularity of meiosis is measured as the percent of reciprocal ditypes plus tetratypes in the progeny. We have shown that this percentage increases from about 15% for crosses between nonisogenic parents to 90% in the eighth backcross. The results indicate that routine, reliable recombination analyses are possible in P. blakesleeanus.

Genetic recombination in sexual crosses of phycomyces.

Sexual crosses between strains of Phycomyces blakesleeanus , involving three auxotrophic and one color marker and yielding a high proportion of zygospore germination, are described. Samples of 20-40 germ spores from 311 individual fertile germ sporangia originating from five two-factor and three three-factor crosses were characterized. The results show: (1) absence of any contribution of apogamic nuclei to the progeny, (2) confirmation of Burgeff's conjecture that the germ spores of any germ sporangium in most cases derive from one meiosis. In a cross involving two allelic markers the analysis of 175 pooled germ sporangia suggests an intragenic recombination frequency of 0.6%. All other factor combinations tested are unlinked. The bulk of the germ spores are homokaryotic. However, a small portion (4%) are heterokaryotic with respect to mating type.

Cloning and sequence analysis of the Mucor circinelloides pyrG gene encoding orotidine-5'-monophosphate decarboxylase: use of pyrG for homologous transformation.

A 3.2-kb BamHI genomic DNA fragment containing the pyrG gene of Mucor circinelloides was isolated by heterologous hybridization using a pyrG cDNA clone of Phycomyces blakesleeanus as the probe. The complete nucleotide sequence of the M. circinelloides pyrG gene encoding orotidine-5'-monophosphate decarboxylase (OMPD) was determined and the transcription start points (tsp) were mapped by primer extension analysis. The predicted amino acid sequence showed homology with the OMPD sequences reported from other filamentous fungi, with 96% similarity with the OMPD of P. blakesleeanus. Analysis of the sequence revealed the presence of two short introns whose length and location were confirmed by sequencing a cDNA clone and comparing this with its genomic counterpart. The intron splice sites and the 5'- and 3'-noncoding flanking regions show general features of fungal genes. Northern-blot hybridization revealed the pyrG transcript to be approx. 1.0 kb. The M. circinelloides pyrG cDNA clone was able to complement the pyrF::Mu-1 mutation of Escherichia coli when inserted between bacterial expression signals. Additionally, the genomic clone complemented the M. circinelloides pyrG4 mutation. When an M. circinelloides autonomous replication sequence was included in the transforming plasmid, the average transformation frequency obtained was 600 to 800 transformants per micrograms DNA and per 10(6) viable protoplasts.

ELISA--a possible alternative to establish a therapeutic drug monitoring system in severe and complicated falciparum malaria.

A modification of an enzyme-linked immunosorbent assay (ELISA) for the quantitative determination of plasma quinine levels is described. The test is rapid, sensitive and reproducible.

Blue-light receptor requirement for gravitropism, autochemotropism and ethylene response in Phycomyces.

Light, gravity and ethylene represent for plants and fungi important environment cues for spatial orientation and growth regulation. Coordination of the frequently conflicting stimuli requires signal-integration sites, which, however, remain largely unidentified. The genetic and physiological basis for signal integration was investigated with a set of phototropism mutants (genotype mad) of the UV- and blue-light-sensitive fungus Phycomyces blakesleeanus, which responds also to gravity, ethylene and nearby obstacles (autochemotropism or avoidance response). Both, class 1 and class 2 mutants display a reduced sensitivity to visible light. Class 1 mutants with defects in genes madA, B, C, I have preserved their sensitivity to gravity and ethylene, whereas class 2 mutants with defects in genes madD,E,F,G,J have lost it. We found that the phototropic sensitivity of class 1 mutants is affected roughly to the same extent in far UV and blue light. In contrast, the sensitivity loss of class 2 mutants is restricted mainly to the near-UV and the blue-light region, whereas the sensitivity to far UV is only mildly affected. This behavior of the class 2 mutants indicates that different photoreceptors mediate phototropism in far-UV and in near-UV/ blue light. The photogravitropic action spectra for two class 2 mutants with defects in genes madF and madJ display distortions between 342 and 530 nm and a bathochromic shift relative to the action spectrum of the wild type. These features indicate that the madF and madJ mutants are affected at the level of the blue-light photoreceptor system. As an implication we infer that an intact near-UV/blue-light photoreceptor system is required even in darkness for negative gravitropism, the ethylene response and autochemotropism. In Phycomyces, signal integration occurs, at least in part, at the level of the near-UV/blue-light photoreceptor system.

Benign familial hyperphosphatasemia: a report of two families and review of the literature.

Benign familial hyperphosphatasemia is a rare biochemical abnormality of hereditary nature, characterized by the presence of persistently elevated levels of serum alkaline phosphatase in several members of the same family, in the absence of disease or any known cause of hyperphosphatasemia. To date, there have been 29 pedigrees reported in the literature. Another two families affected with hyperphosphatasemia, originating in an increase in the bone isoenzyme, are described. The epidemiology, inheritance, isoenzymatic patterns, postulated mechanisms and clinical significance of this entity are discussed.

[Pathogenicity factors in Botrytis cinerea]. / Factores de patogenicidad de Botrytis cinerea.

Botrytis cinereais an important plant pathogenic fungi with a wide host range, which can make use of different infection mechanisms. Although genetic variation for resistance to B. cinereahas been observed within some species, no gene-for-gene relationship has been found. The development of resistant genotypes is, therefore, complicated. Any attempt to develop control strategies makes it necessary a detailed knowledge of both the fungal infection mechanisms and the plant defence mechanisms. The application of different experimental approaches allows the analysis of the infection process in different hosts, the description of the elements that participate in each stage of the process and the identification of those pathogenicity factors which are essential for the establishment of the interaction. The characterisation of the latter will provide information about key elements of the infection process as the basis for the development of effective, long term and environmentally friendly control strategis.

[Capillaroscopy in vasculitis]. / Capilaroscopia en las vasculitis.

A prospective study of the capillaroscopy changes in 15 patients afflicted with vasculitis is presented. 2 of them had classic polyarteritis nodos (PAN), 3 had Churg-Strauss allergic angiitis and granulomatosis, 2 had hypersensitivity vasculitis (HV), 6 had giant-cell arteritis (GCA) and 2 had polyangiitis overlap syndrome (POS). Periungual capillaroscopy (PC) showed isolated changes in 11 patients (73%). We observed more changes in those cases with active disease (83% vs. 67%); they were mainly microhemorrhage (without any statistical significance). There were no more findings in patients with a more generalised affliction (nervous system, kidneys and/or skin) than in the others. In conclusion, the capillaroscopy findings were few and non-specific. PC is a diagnostic method of negligible value in this type of disease.

[Drug information made available to the population via Internet from a Pharmacy Department]. / Información de medicamentos a la población desde el Servicio de Farmacia a través de Internet.

OBJECTIVES: To describe and discuss the work of a Pharmacy Department for the health-care portal www.viatusalud.com. METHODS: Using a web portal, a Pharmacy Department develops and updates a vademecum on drugs, and answers enquiries by end-users. RESULTS: On December 31, 2002 more than 750 records on drugs were available, and 3030 enquiries had been answered. CONCLUSIONS: With this drug information and online enquiry service, our Pharmacy Department helps meet the demand of health-care information posed by the community and by patients previously seen at Clínica Universitaria. In addition, it allows areas of improvement to be detected in the information to be offered to patients fron a Pharmacy Department, and represents a tertiary source of information for health-care professionals.

[Indirect comparisons in drug assessment reports on the GENESIS group (SEFH) webpage]. / Comparaciones indirectas en los informes de evaluación de medicamentos en la web del grupo GENESIS de la SEFH.

OBJECTIVE: Quantify use of indirect comparisons (IC) in drug evaluation reports published on the GENESIS Group web page for new drug assessment, standardisation, and drug selection research. METHOD: Retrospective study of drug reports written between 2008 and 2009. DATA COLLECTED: presence of an active comparator and details from any direct and indirect comparative studies included. RESULTS: An active comparator was present in 95% of the 337 analysed reports; 50% included a direct comparative study vs comparator. In 114 reports (34%), an IC was used; 69% of the ICs were made by the report author. Most ICs were narrative and none were adjusted. An IC could have been made in an additional 16% of the cases and possibly in 24% more. CONCLUSIONS: Most evaluated drugs have an active comparator but studies comparing them directly are not as common. ICs could be included in more reports along with quality control criteria.

Variability in activity and results from drug assessments by pharmacy and therapeutics committees in Spanish hospitals.

OBJECTIVE: To quantify the Spanish Pharmacy and Therapeutics Committees (P&TC) activity with regard to assessing and selecting drugs and describing variability in decisions made to include them. METHOD: Descriptive, cross-sectional study based on a questionnaire aimed to 513 hospitals with more than 75 beds. We included questions referring to the P&TC resolutions, the therapeutic positioning and assessment reports. Recruitment was carried out between November 2007 and January 2008. Variability among P&TC conclusions were presented in five categories or levels of coincidence. RESULTS: One hundred and seventy-five hospitals participated, with a response rate of 34% (54% of beds). The mean (SD) number of drug-indications assessed per hospital was 10.35 (7.45). The proportion of assessments that conclude with drug inclusion or rejection was 75.3 and 21.4%, respectively. 16.2% concluded with therapeutic equivalence. Conditions for use were established for 64% of them, and 33% were included in a clinical guide. With regard to variability, 81.0% of assessments coincided with the conclusion to include or reject the drug. A contradictory decision was made for 19.0%. CONCLUSIONS: Drug assessment and selection activity in hospitals involve an amount of work. The proportion of drugs approved is similar in different types of hospitals. There is extensive variability as regards deciding upon inclusion and is similar to studies conducted in other countries. They indicate that a standardising methodology would be recommendable.

Photoregulation of carotenogenesis in Phycomyces.

Mutants of Phycomyces defective in carotene regulation were studied in relation with the photo carotenogenic response. Quantitative complementation analyses revealed that carC, carA and carS mutations are recessive and complement for this photoresponse in carC * carA and carC * carS heterokaryons. A scheme of the regulation of carotenogenesis by light is proposed.