bluuebunny/crossref_metadata_2025 huggingface dataset:
Estimating daily dose for pharmacoepidemiologic studies: Alprazolam as an example
Authors: Johnson Richard E. , McFarland Bentson H. , Corelle Charlotte A. , Woodson Gary T.
Published: October 2006

Pharmacoepidemiologic research utilizing large automated prescription databases requires measures of daily drug dose. The objectives of this report were to develop a measure of the average daily dose from such a database and to apply it to a specific drug (alprazolam) to determine if the average daily dose had changed over time.

An estimate of the average daily dose was developed by calculating total exposure (in mg) over time and dividing it by the total number of days of exposure over the same time period. The total number of days of exposure was calculated with an algorithm linking prescriptions into periods of use if certain conditions were met.

Applying the measure, the average daily dose of alprazolam increased after it was approved for use at higher doses, and we observed no seizure disorders among any users with highest average daily doses.

Since the data fields to develop the measure appeared to be valid and are common to most automated prescription systems, and given an assumption that the receipt of multiple dispensings in a consistent temporal sequence indicates that the drug is consumed, average daily doses can be estimated from large automated prescription databases.
Antibiotic prescribing patterns in a medical unit in Hong Kong
Authors: Chan Thomas Y. K. , Chan Juliana C. N. , Tomlinson Brian , Critchley Julian A. J. H.
Published: October 2006

Antibiotic prescribing patterns were retrospectively studied in one medical unit at the Prince of Wales Hospital in Hong Kong. Of the 563 patients admitted over a 5‐month period in 1991, 156 (27.7 per cent) received at least one oral or intravenous antibiotic. As a whole, the proportion of patients receiving antibiotics increased with age. An analysis of antibiotic prescribing patterns in 146 of these patients indicated that monotherapy with cefuroxime (32.9 per cent) or amoxycillin/ampicillin (21.9 per cent) was the most commonly used regimen during initial therapy of community, institutional or hospital‐acquired infections. Combination therapy (20.5 per cent) was mainly used for skin infections, septicaemia and biliary tract infections. Surprisingly, aminoglycosides (0.7 per cent) were rarely used. There is a need for larger studies on patients receiving antibiotic therapy in different specialities over longer periods particularly as antibiotics can account for 20 to 30 per cent of a hospital's total drug budget.
The single case format: Proposal for a structured message for the telematic transmission of information on individual case reports in pharmacovigilance
Authors: Moore N. , Montero D. , Coulson R. , De Abajo F. , Kreft‐Jais C. , Biron A. , Monteagudo J. L.
Published: October 2006

The development of telematic exchange of information in pharmacovigilance has as a consequence the necessary development of the messages used to transmit the information. The first of these messages is the one used to transmit information on individual case reports. Common formats exist on paper, but these have not been applied to electronic transmission. A structured message for the transmission of single case information has been developed within the ENS European research programme, by three National Pharmacovigilance administrations, and reviewed by the relevant European bodies. It has been submitted to the Western European Edifact Board MD9 for admission as an EDIFACT message, so that it will be possible to exchange information concerning these single cases, using standard EDI methodology.
Utilization dynamics and risk comparisons in studies that use prescription information
Authors: Van Staa Tjeerd‐Pieter , Abenhaim Lucien
Published: October 2006

This paper considers the effects of the time‐window design on risk comparisons in studies that use prescription information. A time‐window constitutes the number of exposure days assigned to each prescription. Prescription information was drawn from the Quebec Social Insurance System, which covers reimbursement claims for all people aged 65 years or older (random sample of about 5000 NSAID users in 1988).

Utilization dynamics as measured by refill dispensings were comparable between age or gender, but related to duration of prior NSAID use and drug type. We looked at the rates of starts of peptic ulcer therapy. The observed rates were lower with longer designs (4‐week window, 3.0; 12‐week window, 2.5; 24‐week window, 2.3). The strata based on age or gender showed a nondifferential rate attenuation with longer time‐windows. In contrast, strata which refill variability showed patterns of differential rate attenuation. A Monte‐Carlo simulation showed that uniform time‐windows in the presence of utilization variability can result in a bias away from the null.

We conclude that excessively long time‐windows underestimate the risk of exposure. Furthermore, lack of adjustment for utilization differences can lead to a biased rate ratio.
Measles passive immunity in infants from vaccinated and disease acquired mothers
Authors: Silva Juan J. , Fernández Maria Del Pilar , Suárez Mónica , Toledo Maria , Silva Cecilia A.
Published: October 2006

Background — Despite the decline in the incidence of measles in Chile, epidemics continue to occur. In Chile, measles vaccine is administered at one year of age, therefore, we hypothesized that control of epidemic measles may be improved with a better understanding of the immunologic status of infants.

Objective — To evaluate the immunologic status to measles of unvaccinated infants born to previously vaccinated and disease exposed mothers.

Method — Group A subjects were pregnant women with a documented history of measles infection, and group B subjects were pregnant women with a documented history of measles vaccination. Maternal blood samples and cord blood were obtained immediately following delivery. Blood samples were obtained from infants at 6 and 9 months of age. Samples were tested for anti‐measles antibodies using an ELISA technique.

Results — There were 41 subjects in group A and 35 in group B. Infant birth weight and the mothers age were comparable in the two groups. At delivery the titre of measles antibodies in cord blood was the same in the two groups. A higher mean antibody level pre‐delivery was observed in group A (disease exposed) mothers compared with group B (vaccinated) (p = 0.028). There was a significantly lower antibody titre at 6 months and 9 months compared with baseline in both groups (p = < 0.001), but no difference in titre between infants born to vaccinated versus disease exposed mothers. The levels of antibody titre were below protective levels at 6 and 9 months.

Conclusion — There is a rapid decline in measles antibody levels observed by 6 months in infants from mothers either previously exposed to measles or vaccinated. There is inadequate protection of infants from measles by 6 months based on immunological status, with no difference in infant immunologic status of infants from disease exposed and previously vaccinated mothers.
Use of heparin for the prevention of venous thromboembolism
Authors: Vallano Antoni , Vallés Joan‐Antoni , Gracia Rosa Maria , Arnau Josep‐Maria , Duran Salvador , Laporte Joan‐Ramon
Published: October 2006

The value of heparin in the prevention of venous thromboembolism has been shown effective and safe by controlled studies. However, how these studies have influenced physicians' decisions in thrombo‐prophylaxis is not known. With the aim of evaluating the frequency and the appropriateness of prophylaxis for venous thromboembolism in our centre, we performed a cross‐sectional study on a specific day. Among 667 patients who were admitted to hospital on this day, 134 (20 per cent) were receiving heparin. This had been prescribed for the prophylaxis of venous thromboembolism to 82 (12 per cent) patients. Immobilization was the risk factor most strongly associated with prophylaxis. Prophylaxis with heparin was only used in 79 out of 444 high‐risk patients (21.6 per cent). One hundred and eighty‐three patients had been subject to major surgery and heparin was being given only to 34 of them (18.6 per cent). A wide variability in the use of prophylaxis, depending on the hospital ward, was also recorded. We conclude that prophylaxis with heparin is underused in our milieu.
Intercommunity variations in antidiabetic drug utilization and in prevalence of diabetes mellitus
Authors: Olsson Jonny , Tollin Claes , Nilsson Sven , Melander Arne
Published: October 2006

In order to assess whether differences in the extent of antidiabetic drug utilization may be an indicator of variations in diabetes prevalence (Type 1 plus Type 2, including non‐pharmacologically treated diabetics), intercommunity variations of antidiabetic drug utilization (insulin plus oral agents) in Sweden were examined through sales expressed in defined daily doses per 1000 inhabitants per day and compared with intercommunity prevalence variations. There were large (two‐fold) and long‐lasting (>10 years) between‐county differences in antidiabetic drug sales. Low‐sales counties were found both in the doctor‐dense south and the doctor‐sparse north of Sweden, which argues against the assumption that the sales variation simply was due to different access to medical care. Recent diabetes prevalence figures have been obtained for eight municipalities in different parts of Sweden. In these, antidiabetic drug sales and diabetes prevalence (including non‐pharmacologically treated diabetics) showed a close correlation (r = 0.87; p < 0.01), supporting the assumption that variations in antidiabetic drug utilization may indicate variations in diabetes prevalence, at least in countries that, like Sweden, have uniform health care systems. The findings also suggest that, in Sweden, there is little intercommunity variation in the proportion of non‐pharmacologically treated diabetics. On the other hand, it is likely that there are many undetected diabetics in areas where no diabetes screening has been performed. Hence, although differences in antidiabetic drug sales may help to indicate where to look for differences in diabetes prevalence, drug sales data are no substitutes for prevalence studies.
Assessment of the risk associated with the use of individual non‐steroidal anti‐inflammatory drugs as causes of peptic ulcer bleeding
Authors: Langman M. J. S.
Published: October 2006

Use of non‐steroidal anti‐inflammatory drugs (NSAIDs) has repeatedly been shown to be associated with a raised risk of ulcer occurrence, hospitalization or complications. Available data suggest that risks may differ significantly between drugs, with diclofenac and ibuprofen appearing to have the lowest associated risks. Clinical treatment strategies should take account of such information.
Intent to treat: TheReductio ad absurdumthat became gospel
Authors: Salsburg David
Published: October 2006

The ‘Intent to Treat’ paradigm for the analysis of a controlled randomized clinical trial is the direct result of applying the Neyman‐Pearson formulation of hypothesis testing. If other formulations are used, the ‘Intent to Treat’ paradigm makes no sense. Criticisms of the Neyman‐Pearson formulation and whether it is applicable to scientific investigations have appeared in the statistical and philosophical literature since it was first proposed. This paper reviews the nature of that criticism and notes why the Neyman‐Pearson formulation, and with it the ‘Intent to Treat’ paradigm, is inappropriate for use in the analysis of clinical trials.
Chronic sinusitis: Temporal occurrence and relationship to medical claims for upper respiratory infections and allergic rhinitis
Authors: Gable C. B. , Jones J. K. , Lian J. F. , Rajan M. , Kennedy C.
Published: October 2006

Background — Preliminary data suggest that upper respiratory infection diagnoses, but not allergic rhinitis diagnoses, are temporally related to chronic sinusitis diagnoses.

Methods — We analysed monthly medical claims (ICD‐9CM codes) for allergic rhinitis, upper respiratory infection and chronic sinusitis for 1990–1991 from three databases: the National Disease and Therapeutic Index (NDTI), the COMPASS Ohio Medicaid and the Blue Cross/Blue Shield of Minnesota (BC/BS‐MN). We also assessed the timing and prevalence of upper respiratory infection, allergic rhinitis and chronic sinusitis in 200 cases from Ohio Medicaid.

Results — We found statistically significant positive correlations between upper respiratory infection and chronic sinusitis in NDTI (r = 0.96), Ohio Medicaid (r = 0.95), and BC/BS‐MN (r = 0.92), and statistically significant negative correlations between allergic rhinitis and chronic sinusitis in the NDTI (r = −0.55) and the BC/BS MN data (r = −0.57); the correlation between allergic rhinitis and chronic sinusitis in Ohio data was negative but not significant. Of the 200 sampled chronic sinusitis cases, 51.5% had upper respiratory infection with no allergic rhinitis‐related diagnoses in the previous year; 12.0% had both upper respiratory infection‐ and allergic rhinitis‐related diagnoses and 31% had neither. In the 90 days before chronic sinusitis, 74% of patients ages < 10 and 54% of ages > 10 had upper respiratory infection.

Conclusions — In these populations, upper respiratory infection diagnoses were closer temporally to chronic sinusitis diagnoses than were allergic rhinitis diagnoses. In the 200 cases, upper respiratory infection was diagnosed more frequently than allergic rhinitis prior to chronic sinusitis. Although not indicative of a cause‐effect relationship, these data suggest that upper respiratory infection may be a more common risk factor than allergic rhinitis for chronic sinusitis.
Frequency of adverse events among users of talwin Nx
Authors: Terris Barbara Z. , Jick Susan S. , Beeman Douglas W. , Jick Hershel
Published: October 2006

We used the automated data files at Group Health Cooperative to identify 1587 outpatient users of oral Talwin, Nx, a combination of pentazocine and naloxone. The clinical records of the Talwin users were reviewed to determine the occurrence of adverse events which were noted in the record in the four weeks after receipt of the drug. The overall rate of adverse events was 8.7 per cent with 6.7 per cent being directly attributed to the effect of Talwin Nx. Gastrointestinal effects were the most common adverse effect and were reported by 3.7 per cent of the patients. Hallucinations, the most serious effect, were experienced by 10 (0.6 per cent) recipients of the drug. None of the subjects in the study had any long‐term effect. Among those who received higher doses, the rate of adverse events was higher than it was for those who received lower doses. Compared to our previous study of oral pentazocine in hospitalized patients, Talwin Nx had a similar rate of hallucinations and a higher rate of gastrointestinal side‐effects.
Hyperlipidaemia in primary care — a randomized controlled trial on treatment information in Sweden: Design and methodology
Authors: Wahlström R. , Tomson G. , Diwan V. K. , Beermann B. , Sterky G.
Published: October 2006

This paper presents the design and methodology of a large scale information dissemination experiment in Swedish primary care, executed in collaboration with policy makers and information pharmacists, and focused on the effects of an information package presented verbally by community pharmacists, with regard to the doctors' knowledge, attitudes, perceptions and practice in the treatment of hyperlipidaemia.

The main study group comprised 570 doctors, belonging to 67 matched pairs of community health centres (CHCs), randomization being performed at group (i.e. CHC) level to minimize ethical and practical problems. The information derived from national expert guidelines, and was presented at four group sessions during six months at each of the intervention group CHCs, 79% of which fulfilled this requirement. Baseline and outcome data were collected from prescriptions, serum cholesterol test results, questionnaires on attitudes and case‐management evaluation. Moreover, interviews and field observations were conducted in a subsample of CHCs. We demonstrate ways of overcoming methodological problems such as minimizing the Hawthorne effect by introducing an extra, control group and the expectancy effect by not obtaining informed consent until the end of the study period.

There was a non‐respondence rate of 21% which is similar to results in trials on drug efficacy. The acceptance rate vis‐à‐vis the study evaluation was 86%, but might have been higher had the ethical and methodological aspects special to experiments with treatment information been better understood. The information model has afterwards been used in Sweden for information campaigns focused on therapeutic guidelines.
Elevation of serum triglyceride and cholesterol levels from isotretinoin therapy with concomitant oral contraceptives
Authors: Chen Yating , Xue Songlin , Dai Wanju , Labraico James
Published: October 2006

This is a matched case‐control study, using spontaneously reported data, to examine the effect of concomitant oral contraceptives on hypertriglyceridemia (HTG) and hypercholesterolemia (HCHL) among female patients who received isotretinoin therapy. Study subjects included all female isotretinoin users, aged 15 to 55, who experienced an adverse event following isotretinoin therapy and were reported to the manufacturer between January 1, 1982 and July 31, 1993. Cases were women who experienced HTG, HCHL, or both and were further classified into three groups ‘HTG only’, ‘HCHL only’, and ‘both HTG and HCHL’. Controls were women who experienced any adverse events other than HTG, HCHL, alopecia, diabetes mellitus, pancreatitis, and obesity. Two controls were randomly selected to match with each case by age (+/‐ 2 years) and by year of commencement of isotretinoin therapy. Statistically significant association was observed between concomitant OC use and HTG (OR = 3.36, 95 per cent CI = 1.30–8.65) as well as between concomitant OC use and HCHL (OR = 2.30, 95 per cent CI = 1.36–3.87) among female isotretinoin users. There was an unusual high frequency of concomitant OC use (OR = 12.0, 95 per cent CI = 3.12–45.36) among ‘both HTG and HCHL’ patients comparing to that of controls. These results suggest a possible interactive effect between oral contraceptives and isotretinoin on the elevation of serum triglyceride or cholesterol levels.
Adverse drug reactions in hospitalized patients: An operational procedure to improve reporting and investigate underreporting
Authors: Maistrello Italo , Morgutti Marina , Maltempi Maura , Dantes Marcello
Published: October 2006

Background — Adverse event (AE) underreporting is a serious obstacle to drug safety monitoring in hospitalized patients, and it is necessary to find new approaches for improving the situation. The aim of the present study was to try to improve reporting and to evaluate the difference between actual and expected reporting.

Methods — The drug surveillance programme was implemented in a 72‐bed internal medicine ward. A simple algorithm was printed on each page of the progress notes of the patients' medical record, which the physicians were asked to use in choosing the AEs to be reported to the drug surveillance system. The actual reporting was evaluated for a period of 12 months (1203 patients). Using the same algorithm, two reviewing doctors evaluated expected reporting by analysing all of the AEs deduced from the records of 120 randomly selected patients.

Results — Actual reporting: over a period of 12 months, the doctors reported 89 AEs (7.4 per 100 patients), whereas no event had been reported to the national drug surveillance system in the twelve months preceding the introduction of the project. Actual versus expected reporting: in 120 randomly selected patients, 22 AEs were considered by the reviewers as constituting the expected reporting; nine were actually reported.

Conclusions — The described drug surveillance programme led to a substantial improvement in adverse event reporting, although a considerable difference still remains between expected and actual reporting.
Spontaneous reporting of adverse drug reactions in an Italian region: Six years of analysis and observations
Authors: Conforti A. , Leone R. , Moretti U. , Guglielmo L. , Velo G. P.
Published: October 2006

Pharmacovigilance started in Italy in 1965, and from 1987 reporting of ADRs has been mandatory. Doctors have to send the filled forms on suspected ADRs to the Local Health Districts which transmit biannually all the reports to the Health Department.

In a Northern Italian Region (Veneto) spontaneous reporting of adverse drug reactions (ADRs) has been studied during the period 1988–1993. This Region contributes a substantial percentage of the total Italian reports. The total number of reports was 3700, most of these (54 per cent) coming from GPs. A great variability in the reporting rate among the 36 districts of Veneto Region (range: 0–8.8 per 10,000 inhabitants per year) and an important under‐reporting have been evident. Underreporting is also emphasized by the fact that in 1993 the Veneto doctors who sent at least one report were only 2.7 per cent. On the whole about 35 per cent of reports concerned minor reactions caused by drugs which have a well known toxicological profile. Comparison between reports coming from Veneto and the UK in some cases show a similar safety profile (omeprazole and simvastatin), whereas in other cases (e.g. terfenadine, glafenine, fluoxetine) no correspondence can be found. This article reveals the limits of the actual spontaneous reporting in Italy and suggests some possible measures for improving it.
Audit of care of acute inflammatory polyradiculoneuropathy in Italy
Authors: Beghi Ettore ,   The Italian Guillain‐Barré Study Group
Published: October 2006

A multicentre prospective investigation of the main treatment regimens for the Guillain‐Barré syndrome (GBS) was started in Italy to assess the quality of the care delivered for GBS in clinical practice. Between 14 April 1988 and 31 December 1993, 250 patients (157 males and 93 females aged 3 to 86 years) were recruited in 14 centres. The commonest treatments were plasma exchange (PE) (62 per cent), steroids (ST) (37 per cent) and immunoglobulins (IG) (19 per cent). Eighteen per cent of cases received ST and PE. These data contrast in part with reports on the treatment of GBS published between 1976 and 1993, which showed PE as an effective treatment, IG as a promising but still experimental drug, and ST as a failing therapeutic approach. The variables which seemed to affect the treatment choices most were centre, year of diagnosis, and disease severity. According to this survey, the treatment of GBS in Italy tends only partly to reflect the indications and recommendations in the main scientific reports. This not only indicates a suboptimal impact of the best available knowledge on the treatment of GBS, but also documents the need for more definite guidelines and further research through clinical trials.
Drug‐related problems as a cause of hospital admissions in Hong Kong
Authors: Chan Thomas Y. K. , Critchley Julian A. J. H.
Published: October 2006

The importance of drug‐related problems as a cause of hospital admissions in Hong Kong was studied in 925 patients admitted to two general medical wards at the Prince of Wales Hospital between November 1992 and February 1993. Drug‐related problems were judged to be the main reason for hospital admissions in 88 patients (9.5 per cent). These were adverse drug reactions (n = 57), drug poisoning (n = 22) and treatment failure consequent to noncompliance or inappropriate reduction in dosage (n = 9). The most important adverse drug reactions were gastrointestinal hemorrhage (36.8 per cent) and hypoglycemia (24.6 per cent), and the three drug classes that were most commonly involved were non‐steroidal anti‐inflammatory drugs (NSAIDs) (aspirin 12.3 per cent, non‐aspirin 28.1 per cent), sulphonylureas (19.3 per cent) and diuretics (12.3 per cent). Drug‐related problems are an important cause of hospital admissions, and much of the drug‐induced illnesses in Hong Kong could be preventable if particular attention was given to NSAID and sulphonylurea therapy. Patients should also be educated about the importance of good drug compliance.
Generic data
Authors: Walker Alexander M.
Published: October 2006

In an earlier issue of Pharmacoepidemiology and Drug Safety, I described an IMBRF/ISPE meeting on proposed European and British regulations on confidential medical data. ISPE members commonly deal in confidential medical data when they evaluate adverse drug reactions, when they make and respond to regulatory requests for population data on drug safety, and when they compare the health and economic consequences of treatment strategies! Here I would like to open a discussion of the first of the research areas that were raised by that meeting. This is the question of when data must be regarded as ‘personally identified’.
Infarct size estimated from peak creatine kinase is reduced in patients using beta‐blockers at the onset of chest pain
Authors: Landmark Knud , Abdelnoor Michael , Urdal Petter
Published: October 2006

In 418 patients (median 67 years) with acute myocardial infarction (AMI) we examined if ongoing β‐blocker treatment at the onset of AMI (n = 63) had beneficial effects on infarct size as judged from peak creatine kinase (CKmax) activity. The study had an observational exposed/non‐exposed design where we investigated the possible association between β‐blocker treatment and CKmax. Both crude and adjusted effects were looked for, in the latter adjusting for the effect of confounders such as thrombolytic treatment and age during AMI.

Crude effects: β‐blocker treatment significantly (p = 0.003) reduced CKmax, from 1171 U/1 to 790 U/1 (median values). In the 25% of patients with the largest infarcts, β‐blockers reduced the incidence of large infarcts by 61% (odds ratio = 0.39) (p = 0.015). Previous coronary heart disease reduced CKmax (p = 0.0001), whereas thrombolytic treatment significantly increase CKmax (p = 0.0001), probably due to reperfusion.

Adjusted effects: β‐blocker treatment significantly reduced CKmax (p = 0.03), and reduced the incidence of large infarcts by 54% (odds ratio = 0.46).

Thus, when adjusting for confounders, β‐blocker treatment at the onset of AMI reduced infarct size as well as the incidence of large infarcts. These observational results suggest real myocardial salvage.
Prescription drug screening for subsequent carcinogenicity
Authors: van den Eeden Stephen K. , Friedman Gary D.
Published: October 2006

Cancer occurrence was determined through 1988 among a cohort of 143,574 Kaiser Permanente Medical Care Program members whose prescription records were computer‐stored between 1969–1973. Age‐ and gender‐adjusted standardized morbidity ratios (SMRs) were determined by dividing the number of cancers observed among one category of drug users by the number expected based on the cancer experience of the cohort as a whole. This hypothesis‐generating screening programme examined 215 drugs and 56 cancer sites. Although a large number of drug‐cancer associations were nominally statistically significant, many of these have been previously reported and the primary focus of this report is on new findings. Among the new findings considered intriguing were associations of indomethacin with stomach cancer (SMR = 1.51, p < 0.05), prednisone with myeloid leukemia (SMR = 2.27, p < 0.05) and lymphosarcoma (SMR = 2.22, p < 0.002), sulfamethoxazole with lymphosarcoma (SMR = 2.90, p < 0.01), thiazides (SMR = 1.80, p < 0.05) and isoniazid (SMR = 8.46, p < 0.05) with gallbladder cancer.

Given the long follow‐up of this cohort, drug‐cancer relationships that are manifested only after latencies approaching two decades would have sufficient time to become apparent. However, since these data are based on pharmaceuticals dispensed over a short time period and because limited data on potential confounders were available, more definite investigations should follow‐up these results.
Pharmacovigilance education and certification report on a feasibility survey
Authors:   SIGAR
Published: October 2006

A survey conducted by the Special Interest Group on Adverse Reactions (SIGAR) identified an interest in developing a formal educational programme on pharmacovigilance. The majority of potential delegates had between 1 and 5 years of experience in pharmacovigilance and held higher qualifications. They were prepared to provide up to 6 hours of self‐study per week but only a minority would sponsor themselves.

Managers envisaged providing at least one candidate for up to three modules per annum. Preferred modules included regulatory requirements and guidelines, spontaneous reporting, methodologies and company systems. As a result of this favourable response an academic partner has been appointed in the United Kingdom and the course will commence in 1996.
Plasminogen activator inhibitor type‐1 (PAI‐1) polymorphism 4G/5G is associated with prostate cancer among men with a positive family history
Authors: Jorgenson Eric , Deitcher Steven R. , Cicek Mine , Liu Xin , Plummer Sarah , Casey Graham , Witte John S.
Published: October 2006

BACKGROUND

Variation in the expression of plasminogen activator inhibitor type‐1 (PAI‐1) is associated with many human diseases, including several types of cancer. In particular, tumor cell overexpression of PAI‐1 has been found to inhibit prostate cancer tumor growth, angiogenesis, and metastasis in mouse models. Normal host cell expression of PAI‐1 is influenced by the 4G/5G insertion/deletion polymorphism in the promoter region of the PAI‐1 gene. To evaluate the effect of PAI‐1 expression on cancer development, we examined the association of the 4G/5G polymorphism in a sibling‐based case‐control study of prostate cancer.

METHODS

One thousand one hundred thirty seven subjects, 655 cases, and 482 sibling controls from 526 families, were recruited from the major medical institutions in the greater Cleveland, OH area and from the Henry Ford Health System, Detroit, MI. A Cox age‐of‐onset model with robust variance estimation was used to evaluate the association between the PAI‐1 4G/5G polymorphism and prostate cancer.

RESULTS

No association was observed between the PAI‐1 4G/5G polymorphism and prostate cancer in the entire sample. We did, however, identify a statistically significant association between the PAI‐1 4G/5G polymorphism and prostate cancer in subjects with a family history of this disease (OR = 1.28, 95% CI 1.02–1.61, P‐value = 0.036). The PAI‐1 5G/5G genotype, associated with lower PAI‐1 expression, appears to drive this result as it was associated with an increased risk of prostate cancer and an earlier mean age of onset compared to those with the 4G/4G genotype (OR = 1.83, 95% CI 1.12–2.99) while the 4G/5G genotype group did not show a significant difference in prostate cancer risk compared to the 4G/4G genotype group (OR = 0.98, 95% CI 0.75–1.28).

CONCLUSIONS

These observations suggest that the 4G/5G polymorphism in PAI‐1 may explain some of the increased risk and earlier mean age of onset of prostate cancer due to a positive family history. Prostate © 2006 Wiley‐Liss, Inc.
A Comparison by QSAR, Crystallography, and Computer Graphics of the Inhibition of Various Dihydrofolate Reductases by 5‐(X‐Benzyl)‐2,4‐diamino‐pyrimidines
Authors: Li Ren‐Li , Hansch Corwin , Matthews David , Blaney Jeffrey M. , Langridge Robert , Delcamp Tavner J. , Susten Sandra S. , Freisheim James H.
Published: October 2006

The QSAR for forty 2,4‐diamino‐5‐(X‐benzyl)‐pyrimidines inhibiting human lymphoblastoid dihydrofolate reductase is reported and compared with the QSAR for inhibition of dihydrofolate reductase from E. coli, L. casei, chicken, and bovine liver sources by the same inhibitors. A preliminary attempt to integrate the experimental QSAR results with the three‐dimensional X‐ray structures of E. coli and chicken dihydrofolate reductase, using interactive computer three‐dimensional color graphics molecular modeling methods, is described.
Quantitative Comparative Studies on Peripheral and Central Bradycardia Induced by Imidazolidines
Authors: Timmermans Pieter B. M. W. M. , De Jonge Adriaan , van Zwieten Pieter A.
Published: October 2006

Central hypotensive activity of α‐adrenoceptor agonists generally parallels bradycardic potency. This has led to the conclusion that bradycardia, like the induction of hypotension, is also initiated within the central nervous system by stimulation of α2‐adrenoceptors. However, bradycardia has still been found for a very hydrophilic α‐adrenoceptor agonist not showing central hypotensive activity following systemic application. In view of this inconsistency quantitative comparisons were made between central hypotensive activity and overall bradycardic potency in anaesthetized normotensive rats after intravenous administration within a series of phenyliminoimidazolidines. The log dose‐bradycardic response curves of the more lipophilic derivatives were monophasic, whereas those of the hydrophilic compounds were characterized by a bisigmoidal shape. As a result of the dual nature of this effect, the potency of the drugs to decrease heart rate was quantified at 10%, pC10(HR), as well as at 20%, pC20(HR), effect level. Linear regression analysis showed a highly significant correlation between pC20(HR) and hypotensive activity. Lipophilicity, log P′, had to be added to verify this relationship for pC10(HR). For the latter variable, however, a linear relationship was derived with the potency of the compounds to inhibit cardiac frequency via stimulation of presynaptic α2‐adrenoceptors in the heart itself. These results strongly suggest that overall bradycardia of α‐adrenoceptor agonists may consist of a peripheral and a central component. Both mechanisms are governed by the stimulation of α2‐adrenoceptors. The peripheral mechanism (presynaptic cardiac α2‐adrenoceptors) is triggered by hydrophilic as well as lipophilic compounds following systemic application. The induction of central bradycardia (central α2‐adrenoceptors) and hypotension is but limited to the more lipophilic drugs.
Rationalisations among Heterocyclic Partition Coefficients Part 1: The π‐Value of Phenyl
Authors: Lewis Susan J. , Mirrlees Margaret S. , Taylor Peter J.
Published: October 2006

It is shown that πPh has a minimum theoretical value of ca. 1.7 in aromatic rings. This value is attained whenever phenyl is forced into a highly non‐planar conformation, as may happen through peri‐interactions or the heavy solvation of sterically hindering neighbouring groups. In the absence of such hindrance πPh will be greater, and can attain values as high as ca. 2.6 when there is no steric hindrance to coplanarity and two hetero‐atoms can be shielded. These and a number of intermediate situations are delineated; estimates of πPh are provided for each distinct case. The effect of phenyl substitution at sp3‐carbon is discussed in similar terms. It is shown that these variations make qualitative chemical sense and can be used for predictive purposes.
BC(DEF) Coordinates 4. Correlations with General Anesthesia, Nerve Blockade, and Erythrocyte Stabilization
Authors: Cramer Richard D.
Published: October 2006

The abilities of structurally diverse compounds to induce general anesthesia, block neutral conduction, or stabilize erythrocytes against osmotic shock are highly correlated (r > 0.96) by the compounds BC(DEF) coordinates alone. Assuming that a compound whose effects are produced by a receptor‐mediated, structurally specific, mechanism would have a potency greater than that predicted by its BC(DEF) co‐ordinates, a “positive outlier exclusion” procedure for extracting such selectively acting compounds from a set of data was developed. However, its application to these three data sets yielded little evidence of specificity. These results are consistent with the view that these processes are non‐specifically mediated and mechanistically similar, except that anesthetic potency is favored by partitioning from vapor into lipid, rather than from water into lipid. The equations obtained resemble the property equation for octanol/water partitioning more than property equations for other partitioning systems. Long chain hydrocarbons are unusual, both in having unexpectedly low nerve blockade activity and in having highly negative C coordinates.
Structural Information and a Flexibility Index from the Molecular Connectivity 3χp Index
Authors: Kier Lemont B. , Hall Lowell H.
Published: October 2006

The molecular connectivity 3χp index has been evaluated for its structure information content. This index has been found to relate closely to a quantitation of the number of gauche‐trans rearrangements possible in the molecule. The count of the number of three‐path fragments, 3Np carries similar information. Both indexes are shown to relate closely to density and to the Mann estimate of the average number of gauche arrangements in a molecule, Zg. The 3χp and 3NP indexes are superior to the Zg index in relating to alkane density. On the basis of the quantitation of gauche‐trans folding a flexibility index, F = n/1 ‐ 3NP has been empirically derived to rank alkanes according to a perception of their kinetic flexibility.
BC(DEF) Coordinates 5. Shape‐Specific vs. Orientation‐Averaged Interactions of Neuroleptics and Other Centrally Acting Drugs: Correlation of Effects in Five in vitro Test Systems
Authors: Yunger Libby M. , Cramer Richard D.
Published: October 2006

To evaluate further a methodology proposed for determining whether the pharmacological actions of compounds are due to shape‐specific or orientation‐averaged molecular interactions with biological systems, the activities of neuroleptics and other centrally acting drugs in five in vitro test systems were correlated with the compounds' BCDEF coordinates. It is hypothesized that shape‐specific interactions will tend to enhance the activity of a compound in the test system and, thus, these compounds would be the positive outliers in such an analysis. These compounds were floated and the correlation repeated until all of the specifically‐acting compounds were identified. Inhibition of [3H]haloperidol, [3H]flupenthixol, and [3H]dopamine binding by neuroleptics and catecholamines appeared to be primarily due to shape‐specific molecular interactions with the receptor. In contrast, neuroleptic‐induced inhibition of synaptosomal GABA accumulation and of calmodulin‐mediated phosphodiesterase activity appeared to be due to non‐specific interactions, that is, these effects could be explained exclusively by the same orientation‐averaged interactions that determine the overall physicochemical properties of the test molecules. Although lipophilic in character, non‐specific interactions with these biological test systems are less selective against bulky and polar molecules than are common models of lipophilicity such as partitioning between water and immiscible organic solvents.
Theoretical Investigations on Interactions Between Pharmacon Molecules and Receptor Models V: Construction of a Model for the Ribosomal Binding Site of Chloramphenicol
Authors: Höltje Hans‐Dieter , Tintelnot Marina
Published: October 2006

Interaction energies between the most stable conformations of chloramphenicol and Chloramphenicol derivatives and amino acids as binding site models were calculated using the multipol‐bond‐polarizability method. The resulting energies were correlated with the antibiotic activities of the drug molecules. A receptor model for the chloramphenicol molecule was constructed which consists of arginine and histidine as binding sites for the acyl sidechain and the substituted aromatic ring system, respectively.

The significance of the hypothetical receptor was challenged by determination of low energy conformations of a fragment from the ribosomal chloramphenicol binding protein L16 which comprises the single histidine residue of this protein. The results of these ECEPP calculations and of experimental histidine blockade prove the receptor model to be realistic.
Regularities of the Partition Coefficients of Bis, Tris, and Tetrakis(acetylacetonato)metal (II, III and IV) Complexes
Authors: Watarai Hitoshi , Oshima Hideo , Suzuki Nobuo
Published: October 2006

The partition coefficients of seven acetylacetonato complexes, Pt(acac)2, Pd(acac)2, Be(acac)2, VO(acac)2, Cr(acac)3, Al(acac)3 and Co(acac)3 and those of trifluoroacetylacetone (Htfa) and Be(tfa)2 were determined at 25°C employing dodecane, carbon tetrachloride, and/or benzene as an organic phase. The molar volumes of acetylacetonato complexes which include bis, tris and tetrakis complexes were also determined from precise density measurement at 25°C. Linear correlations between the partition coefficients of acetylacetone (enol form) and those of the bis, tris, and tetrakis complexes which include some available literature data were obtained, and interpreted in the frame of the modified regular solution equation which has a binary coefficient introduced to improve the simple geometric mean assumption. On the main factor governing the partition equilibrium, a general importance of cavity formation energy was concluded by comparison with the scaled particle calculation. Hydration in the bis complexes was suggested as an additional factor to govern partition coefficient.
Biological Receptor Maps. 1 Steric Maps. The SIBIS Method
Authors: Motoc Ioan
Published: October 2006

The SIBIS method for calculating the topographical steric map of biological receptor is described in detail. SIBIS is a self‐consistent type algorithm based upon a reference structure and which is well suited to delineate the main steric features of the receptor. Since the application of the method is not restricted to structurally congeneric molecules, the resultant steric map offers the linkage information to coanalyze structurally different compounds exhibiting common biological action. The molecular structure descriptor vector used in SIBIS permits the development of a simple method for quantitatively comparing the degree of relatedness of the shape of bio‐organic molecules exhibiting the same biological action but which may vary widely in their shape.
Structural Requirements for the Membrane Damaging Effect of Non Homologous Series of Nonionic Tenzides. Structural Requirements for the Biological Activity of Tenzides
Authors: Cserháti Tibor , Szőgyi Maria , Bordás Barna , Dobrovolszky András
Published: October 2006

The lipophilicity and the membrane damaging effect responsible for microbicidal activity of 26 nonionic tenzides belonging to various homologous series have been determined by reversed‐phase thin‐layer chromatography and by permeability measurements on dipalmitoyl‐phosphatidyl‐choline liposomes respectively. The lipophilicity correlated significantly to the membrane damaging effect, however it explained only about 35% of the total variance. Stepwise regression analysis showed that the requirements for the membrane disorganization are the presence of a bulky hydrophobic part to be built in to the hydrophobic alkyl chains of fatty acids and the optimum number (6–13) of ethylene‐oxide groups per molecule. Tenzides with too short ethylene‐oxide chains are buried in the lipid bilayer, the long ethylene‐oxide chains do not modify the membrane permeability.
Predictive Power of Robust Regression Applied to QSAR Studies
Authors: Moriguchi Ikuo , Komatsu Katsuichiro , Matsushita Yasuo
Published: October 2006

Robust regression methods were applied to 56 sets of structure‐activity data collected from the literature. The methods included the Huber estimator, the sine estimator, the biweight estimator, and least‐squares with a cut‐off option. On the basis of the kurtosis (Ku) for the error distribution of ordinary least‐squares (OLS) regression, the data sets were classified into two groups: 26 sets with Ku > 0, i.e., with thick‐tailed error distribution (Group A) and 30 sets with Ku < 0 (Group B). The predictive powers of the robust methods and OLS were compared by means of the leave‐one‐out technique. The robust methods generally produced greater correlation coefficients between observed and predicted activities than OLS for the sets of Group A, but the differences were not significant in the majority of cases, e.g., 17 of the 26 sets by use of the sine estimator. For Group B, the predictive results of the robust methods were comparable or rather inferior to those of OLS. It may be concluded that OLS does as well as robust techniques in most cases, and that the adoption of the complicated robust techniques is not warranted in QSAR studies except under extreme circumstances.
Chemometric Investigation of Antitumor Tests
Authors: Ebert Cynthia , Lassiani Lucia , Linda Paolo , Nisi Carlo , Alunni Sergio , Clementi Sergio
Published: October 2006

This study was aimed to investigate by principal components analysis, the information content of various routine antitumor tests collected on a series of p‐substituted aryldimethyltriazenes.

The results permit to detect that the effective doses, expressed as log T/C, are a measure better than the predetermined activity levels for stating the selective antimetastatic properties of these compounds.

In this respect, PCA appear to be more suitable then MRA in describing the data set.
The Application of the PHL Concept to QSAR: Detection of Data Deficiencies Cross Validation, Detection of Alien Effects
Authors: Mager Harry
Published: October 2006

Cross‐validation methods in which a portion of the data is used to estimate the model coefficients, and the remainder of the data is used to measure the prediction accuracy of the model are of outstanding significance in QSAR work.

The concept of data points with high leverage (PHL) based on leave‐one‐out estimates (LOO) is introduced to quantitative drug design. A new measure is derived allowing to judge the stability of the individual regression coefficients against sample structure variation. Furthermore, it seems to be possible to examine to which extent the coefficient for the physicochemical property xk(e.g. π) is influenced by special values of the physical property xj(e.g. Es), which allows to detect “alien effects”.

The procedure is applied to 7‐substituted 4‐hydroxyquino‐line‐carboxylic acids inhibiting respiration of Ehrlich ascites cells.
The Anesthetic Activity and Toxicity of Halogenated Ethyl Methyl Ethers, a Multivariate QSAR Modelled by PLS
Authors: Hellberg Sven , Wold Svante , Dunn William J. , Gasteiger Johann , Hatchings Michael G.
Published: October 2006

QSAR between anesthetic activity, toxicity, and a multi‐variate set of structural descriptors for a series of halogenated ethyl methyl ethers were analysed by the method of partial least squares in latent variables (PLS). A two dimensional model resulted describing 86% of the variance in anesthetic activity. A three dimensional model describes 87% of the variance in toxicity. A grouping of anesthetics according to their type of side effects was indicated by the data analysis.
Topological Pharmacophores New Methods and Their Application to a Set of Antimalarials Part 1: The Methods LOGANA and LOCON
Authors: Streich Wolf Jürgen , Franke Rainer
Published: October 2006

Topological pharmacophores are two‐dimensional substructural patterns characteristic of compounds possessing a desired biological property (e.g., high activity) while absent from compounds devoid of this property. Two new methods for the evaluation of such pharmacophores, LOGANA and LOCON, are presented which are both designed in such a way that full use can be made of the data handling capacity of computers while maintaining an optimal impact of the professional skill and experience of medicinal chemists with no special mathematical knowledge required. Both methods are based on the stepwise combination of substructural descriptors by means of the logical operations “and”, “or” and “not”. No assumptions about additivity of effects, linear models or the validity of certain statistical formalisms are necessary. While LOGANA deals with biological data in the form of classifications LOCON can be applied to activity data on a continuous scale. The advantages and limitations of the two methods are discussed.