End group analysis of yeast fatty acid synthetase.

The purified yeast fatty acid synthetase complex has been subjected to amino and carboxyl terminal amino acid end group analysis. Amino end groups were studied by Edman degradation and by dansylation of the sodium dodecyl sulfate- or urea-denatured complex. No N-terminal amino acid could be identified by either method. C-terminal amino acids were investigated by tritium labeling and by digestion of the complex with carboxypeptidases A and B. By both methods, the two amino acids valine and lysine were consistently identified as the C-termini of two different polypeptide chains. After separation of the fatty acid synthetase subunits A and B by sodium dodecyl sulfate polyacrylamide gel electrophoresis lysine was identified as the C-terminus of subunit A and valine as that of subunit B. The results are interpreted as evidence that the yeast fatty acid synthetase complex is basically composed of two nonidentical and multifunctional polypeptide chains.

Interaction between quinolones and caffeine.

The effects of multiple doses of ofloxacin 200 mg, ciprofloxacin 250 mg or enoxacin 400 mg (all twice daily) on the pharmacokinetic properties of single doses of caffeine (220 to 230 mg) were investigated in 12 healthy volunteers. Intraindividual comparisons showed that ciprofloxacin and enoxacin significantly inhibited the elimination of caffeine. Ofloxacin, however, did not affect any of the measured pharmacokinetic properties of caffeine. Thus, caffeine should be avoided in patients with liver disorders, cardiac arrhythmias, latent epilepsy or in intensive care while undergoing treatment with enoxacin or ciprofloxacin.

A placebo-controlled comparative evaluation of diclofenac dispersible versus ibuprofen in postoperative pain after third molar surgery.

The analgesic efficacy of single oral doses of drinkable diclofenac dispersible 50 mg was compared with that of ibuprofen 400 mg and placebo in a randomized, double-blind, parallel-group trial in 257 adult patients (245 valid for efficacy) with severe postoperative pain after extraction of an impacted lower third molar. In this study, pain intensity (on a 100-mm visual analog scale) and pain relief from baseline (using a five-point verbal rating scale) were assessed serially during an observation period of 6 hours. Intake of rescue analgesic was permitted in case of insufficient therapeutic effect; however at least 1 hour should have elapsed after test drug consumption. On the main efficacy variable, namely, reduction in the pain intensity score, both diclofenac dispersible (n = 83) and ibuprofen (n = 80) were statistically significantly (P < .01) superior to placebo (n = 82) starting at 20 and 40 minutes, respectively, after drug intake. The active medications were also significantly (P < .01) better than placebo for the secondary efficacy parameters viz. summed pain relief scores over 6 hours (TOTPAR-6); frequency of remedication with a rescue analgesic in the three treatment groups (diclofenac, 24%; ibuprofen, 28%; placebo, 65%); mean time to remedication; and global evaluation. All the treatments were well tolerated. Thus assay sensitivity of this trial (ibuprofen significantly better than placebo) has been demonstrated; in addition, diclofenac as a dispersible formulation has been shown to be an effective analgesic for the treatment of post-surgical dental pain.

Compliance with prescription recommendations by physicians in practices.

OBJECTIVES: Few investigations are available on the primary supply of patients in Germany. But they play a key role due to their relevance in health politics and economics. An analysis has been carried out to determine the extent to which physicians in practices adhere to the recommendations in the package inserts and to determine the consequences of this behavior regarding the safety and efficacy of prescribed drugs. METHOD: The analysis was carried out with the IMS HEALTH mediplus patient database, which is a database providing anonymous access to a representative panel of physicians and patients in Germany. More than 1,000 medical practices including more than 5 million patients and over 75 million prescriptions can be analyzed in a cross and/or longitudinal section. The evaluation time period per patient currently exceeds 10 years with monthly updates. RESULTS: Kava-Kava drug prescriptions indicate that the recommended daily dose was significantly overstepped in 78% of the cases. The recommended daily dose complied in only 41% of the cases whereas in 3 9% of the cases, the drug was underdosed. DISCUSSION: These results may give an explanation why Kava-Kava prescriptions are associated with a high incidence of adverse drug reactions. On the other hand, lack of efficacy in many patients was mainly due to the fact that the drug was underdosed.

Lipid-lowering therapy: do hospitals influence the prescribing behavior of general practitioners?

OBJECTIVE: This investigation addresses the question whether physicians in hospitals influence the prescribing behavior of general practitioners regarding patients who are discharged following hospitalization. Case studies for patients on lipid-lowering therapy were used as an example. METHODS: All analyses described were carried out with mediplus, a longitudinal patient database with anonymous access to a representative and valid panel of physicians and patients in Germany. A total of more than 1,000 medical practices with over 6 million patients and over 100 million prescriptions can be analyzed using a cross- and/or longitudinal section of the database. The longest time period per patient exceeds 12 years commencing in 1989 and there are monthly updates. This allows not only cross-tabulation analysis but also time-dependent longitudinal analysis. RESULTS: The results of the study demonstrated that hospitals significantly influence the prescribing behavior of general practitioners. The sum of lipids lowering drugs prescribed in hospitals after admission increased by approximately 45% compared to the initial situation in practices. Physicians in hospitals play a significant role in causing a shift in treatment patterns of practice-based physicians with a reduction in use traditional fibrates in favor of cholesterin synthesizing enzyme inhibitors. CONCLUSION: The results of this investigation showed a significant increase in lipid-lowering therapy with a shift from fibrates to the more innovative CSE-inhibitors in the treatment pattern of patients following hospitalization. This study also demonstrates that the patient database used provides a useful insight into the extent of hospital physician influence on prescribing behavior of general practitioners and that this behavior can be quantified.

Use of the mediplus patient database in healthcare research.

OBJECTIVE: Public health systems require fast and precise analyses of physicians' day-to-day diagnoses and therapy behavior regarding qualitative, safety or economical aspects. A partnership between physicians in practices and a database organization (IMS Health, Frankfurt, Germany) which has been in existence for more than 10 years has developed a procedure for documenting various types of studies with regard to diagnosis and therapy behavior. This endeavor has facilitated scientific progress by providing precise analytical information and guidelines. METHODS: The database used has the name mediplus. It is a longitudinal patient database with anonymous access to a representative and valid panel of physicians and patients in Germany. A total of more than 1,000 medical practices and over 75 million prescriptions have been documented in a cross and/or longitudinal section. The longest time period per patient is more than 10 years starting in 1989, with monthly updates. RESULTS: Analyses have been obtained detailing prescription behavior of doctors regarding diabetes therapy and enable recommendations to be made regarding the therapy of migraine and the eradication of Helicobacter pylori infections. Information is also retrievable on drug safety studies in general and the extent to which hospitals influence the prescription behavior of doctors treating patients after discharge. DISCUSSION: The mediplus patient database combines all decision relevant information on physicians, patients, diagnoses and course of therapies and thus makes possible the investigation of the courses of diseases and therapy patterns. The monthly update enables trends to be identified at an early stage. The mediplus database is an ideal instrument for the enforcement of quantitative and qualitative analyses of patient histories because it directly links the individual diagnoses with the corresponding therapies. The database is currently undergoing extension with additional specialist groups such as pediatricians, neurologists, orthopedists, urologists, ENT specialists, surgeons and pulmonologists.

Off-label use of proton pump inhibitors and P-blockers in general practices: an analysis using the Disease Analyzer--mediplus patient database.

OBJECTIVE: The off-label use of medicines is a widespread phenomenon in medical practice but discussion on the legality of using drugs outside their licensed indications is still ongoing. Prescription recommendations and prescribing habits can differ greatly. We have used a database tool to analyze replies to a batch of questions which included the question "Is the off-label use of medications common?". The analysis was carried out using the Disease Analyzer--mediplus patient database, which is a database tool registered in Germany. It enabled the anonymous access to a representative panel of physicians and patients. More than 1,500 medical practices representing approximately 2.5 million patients were analyzed in a cross-sectional or longitudinal manner. The Disease Analyzer--mediplus database is unique in that it has direct links to individual diagnoses and the corresponding therapy. RESULTS: The findings demonstrated that proton pump inhibitors (PPI), which are licensed for the treatment of gastric ulcer and gastric reflux, are also used off-label in gastritis. The off-label use varies from 30 - 40% of prescriptions. The data indicate that the prescribing behavior has been influenced by the ending of the patent protection on omeprazole. A second instance which has been identified involves the beta-blocker carvedilol, which is licensed for the treatment of heart failure (24% of the total number of patients receiving the drug) but it was found that other beta-blockers are used off-label in this indication at a rate of more than 10% of prescriptions. CONCLUSION: The off-label use of drugs is high, especially in gastritis and heart failure. The investigation has also confirmed that the Disease Analyzer--mediplus database provides quantitative and qualitative analyses combining all relevant information concerning physicians, patients, diagnoses and therapy and that this information can be used to evaluate prescribing habits and trends with regard to the off-label use of drugs.

Treatment behavior of doctors regarding Helicobacter pylori infections.

OBJECTIVE: Since the detection of the gastric acid resistant bacterium Helicobacter pylori in the year 1982 there has been a fundamental change regarding the therapy of ulcers. According to expert opinion these infections should be treated and eradicated, whereby the so-called triple-therapies are considered to be the most effective ones. Whether such recommendations to eradicate Helicobacter pylori can be put to use in daily practice is an important question that is frequently asked. METHODS: All analyses described in the study here were done using mediplus, a longitudinal patient database with anonymous access to a representative and valid panel of physicians and patients within Germany. A total of more than 1,000 medical practices and over 75 million prescriptions can be analyzed in a cross- and/or longitudinal section. The longest time period per patient is more than 10 years starting in 1989 with monthly updates. RESULTS: With regard to existing recommendations, doctors overestimate their own compliance with the recommendations because only a fraction of traceable Helicobacter pylori infections are actually eradicated. Within the period of observation the therapy behavior has changed significantly in favor of the triple-therapies, but there are relevant differences between practitioners and internal specialists. DISCUSSION: Only a fraction of traceable Helicobacter pylori infections are adequately treated by doctors. The results show a very alarming situation due to the gap between "state of the art" and what is being achieved and carried out in daily practice. The potential for possible cost reductions and saving on resources is probably high. CONCLUSION: The results lead to the conclusion that in the treatment of Helicobacter pylori infections there is a potential for cost saving which is unused from the pharmacoeconomical point of view.

Urinary pathogens and bacterial sensitivity in hospitalized urological patients based upon clinical aspects.

For a total of 396 hospitalized urological patients with complicated and/or hospital-acquired urinary tract infections (UTI) urinary pathogens with colony counts of 10(5)/ml or more were determined, several species were then subclassified by epidemiological markers. The minimal inhibitory concentrations (MIC) were measured using the agar dilution method for seven penicillins and for four penicillin combinations, for six oral and 14 parenteral cefalosporins, for three older and five newer quinolones, for two aminoglycosides, for two monobactams, for trimethoprim alone and in combination with sulfamethoxazole, for fosfomycin and for imipenem. Sensitivity and resistance of the strains were defined using breakpoints according to DIN 58.940 or analogous concentrations. The bacterial spectrum and the rate of resistant strains were correlated to clinical aspects pertaining to sexual status, age and underlying abnormalities within the urinary tract. There was a statistical difference in the frequency of E. coli and enterococci between patients with (complicated UTI) and without (uncomplicated UTI) abnormalities. Within the group of complicated UTI Proteus spp. were found significantly more often in patients with urolithiasis, Klebsiella spp. and staphylococci in patients with prostatic tumours (benign and malignant), enterococci in patients with prostatic and other tumours and E. coli in patients with abnormalities other than urolithiasis or tumours. Almost all antibiotics tested could be used in patients with uncomplicated UTI for empiric or calculated therapy if a rate of resistance of up to 10% is acceptable. In patients with urolithiasis only the newer acylaminopenicillins, the newer (fluoro-)quinolones, trimethoprim in combination with sulfamethoxazole, fosfomycin and imipenem fulfill this criterion. In order to treat complicated UTI with underlying tumours within the urinary tract empirically only piperacillin, apalcillin, imipenem and some of the newer quinolones (ofloxacin, ciprofloxacin and pefloxacin) could be recommended. The same was true for patients with indwelling catheters still present or recently removed.

Control of fatty-acid synthetase biosynthesis in Saccharomyces cerevisiae.

143 out of 308 fas1 mutants (47%) and 139 out of 443 fas2-mutants (32%) genetically studied in this laboratory fail to complement with any other fas-mutant (deficient in fatty acid synthetase) of the same gene locus. From these noncomplementing fas-mutants no mutant fatty acid synthetase can be isolated using the wild-type enzyme purification procedure. Furthermore the noncomplementing fas-mutants generally contain no material immunologically crossreacting with a specific fatty acid synthetase antiserum. However, subunits obtained after dissociation of the complex with sodium dodecylsulfate still cross react with this antiserum. Therefore, it is concluded that noncomplementing fas-mutants contain no fatty acid synthetase component proteins, though one of the two fas-loci is mutationally unaffected. This conclusion was further confirmed by 14C-labeled amino acid incorporation studies which indicated that in noncomplementing fas-mutants, other than in wild type and complementing fas-mutant cells, no label was incorporated into fatty acid synthetase subunits or precursor proteins. At nonpermissive temperature, the same biochemical and immunological characteristics were observed with temperature-sensitive non-complementing fas-mutants. These results suggest that noncomplementing fas-mutants either represent regulatory mutants unable to induce the mutationally unaffected other fas-gene locus or that they are association-defective mutants. In both cases the resulting individual subunits of the complex may be rapidly degraded by intracellular proteases.

[Graphic presentation of visual analog scales for pain evaluation in rheumatology]. / Grafische Darstellung visueller Analogskalen zur Schmerzbeurteilung in der Rheumatologie.

The scores of visual analog scales, used for rating of rheumatological pains, are scarcely normal distributed. The presentation of these findings by mean and standard deviation can be evidently distorted. Furthermore range and extreme values are missing. The new grafical method-box and whisker plot-is more adequate to those data. Comparing both methods in a clinical trial the possible gain of information is illustrated.

Doctors' prescription behaviour regarding dosage recommendations for preparations of kava extracts.

BACKGROUND: There are many publications on the use of kava extracts as a treatment alternative to tricyclic antidepressants and benzodiazepines, but little has been done to investigate the potential adverse effects that may be associated with prolonged or high-dose usage. OBJECTIVES: To investigate the extent to which physicians comply with the recommended daily dose (RDD) of an antidepressant such as kava and the consequences of this behaviour with regard to the safety and efficacy of frequently prescribed kava extracts (Trade names: Antares, Laitan and Kavasporal forte). METHOD: The analysis was carried out using the patient database MediPlus, which provides anonymous access to a representative and valid panel of physicians and patients in Germany. RESULTS: Prescriptions for Antares showed that the RDD of 1 tablet per day was exceeded in 58.2% of the cases, while those for Laitan showed that the RDD of 1 capsule per day was significantly exceeded in 75.6% of the cases; a one-off prescription was issued in 66% of the cases. As a result, the required effect diminished very quickly. Prescriptions for Kavasporal forte showed that the daily dosage of 2 capsules per day complied with the recommendations in only 49.1% of the cases; in 38.8% of the cases, the dosage dropped below the respective recommendation. As a consequence, the lower-dosed Kavasporal forte was prescribed for longer periods than the higher-dosed Antares and Laitan. CONCLUSIONS: In the case of a low-dosage recommendation, we saw a trend to over-dose in prescribing behaviour, which increases the risk of undesirable adverse reactions. On the other hand, we saw a trend to under-dose in the case of a higher dosage recommendation. This fact may explain the unexpected inefficacy of the therapy. These trends affected the duration of therapy, whereby a dosage lower than the RDD was prescribed for a longer period than a dosage higher than the RDD.

[Comparative in-flight study of a scopolamine-containing membrane plaster versus dimenhydrinate under defined acceleration conditions]. / Vergleichende Inflight-Untersuchung eines Scopolamin-haltigen Membranpflasters versus Dimenhydrinat unter definierten Beschleunigungsreizen.

The efficacy and tolerability of Scopoderm TTS (SCOTTS), a transdermal system containing scopolamine, were compared with those of the oral antiemetic dimenhydrinate (double-dummy technique) in a controlled, double-blind, within-patient study including 20 test persons with proven motion sickness. During a 1-h test flight, SCOTTS proved to be as effective as dimenhydrinate. The efficacy and tolerability of both SCOTTS and dimenhydrinate were assessed as to be equally good. Due to its galenic properties, SCOTTS is effective over a 72-h period and therefore is useful in the prevention of motion sickness during long-distance flights, where it is superior to dimenhydrinate.

Hemodynamic and neurohumoral response to hydralazine versus captopril: a controlled study in idiopathic dilated cardiomyopathy.

To study the hemodynamic and neurohumoral effects of hydralazine versus captopril after the first dose, 15 patients with idiopathic dilated cardiomyopathy (NYHA Class II and III) were included in a crossover trial with a washout period of three days. Hemodynamic parameters were measured by using a Swan-Ganz thermodilution catheter, and venous blood was sampled during supine rest and standardized upright exercise before (control) and 60 min after drug administration. Compared to the control phase, hydralazine induced an increase in heart rate and cardiac index (p less than 0.01), and a decrease in mean arterial pressure and pulmonary wedge pressure (p less than 0.01, p less than 0.05, respectively). The hemodynamic effects were associated with increased norepinephrine plasma concentration during upright exercise (p less than 0.05) and increased plasma renin activity (p less than 0.01). After administration of captopril, heart rate at rest (p less than 0.05), mean arterial pressure, and pulmonary wedge pressure decreased significantly (p less than 0.01). Cardiac index remained unchanged. Norepinephrine plasma concentrations were not significantly influenced despite a tendency to lower levels during upright exercise. Plasma renin activity increased (p less than 0.01) and aldosterone at rest decreased significantly (p less than 0.05). These differences in neurohumoral response between both drugs may be important for their long-term effects.