bluuebunny/crossref_metadata_2025 huggingface dataset:
Topical anesthetic‐induced methemoglobinemia and sulfhemoglobinemia in macaques: A comparison of benzocaine and lidocaine
Authors: Martin Dale G. , Watson Charles E. , Gold Mark B. , Woodard Claude L. , Baskin Steven I.
Published: October 2006

Benzocaine (BNZ) and lidocaine (LC) are commonly used topical (spray) anesthetics approved for use in humans. Benzocaine has structural similarities to methemoglobin (MHb)‐forming drugs that are current candidates for cyanide prophylaxis, while LC has been reported to increase MHb in man. In this study, we compared MHb and sulfhemoglobin (SHb) production in three groups of Macaques (Chinese rhesus and Indian rhesus (Macaca mulatta) and pig‐tailed macaques (Macaca nemestrina)) after exposure to BNZ and LC. Formation of SHb, unlike MHb, is not thought to be reversible and therefore is considered to be of greater toxic significance. Both MHb and SHb levels were measured periodically on a CO‐Oximeter. All rhesus macaques (n= 8) were administered an intratracheal/intranasal) dose of 56 mg (low dose) or 280 mg (high dose) of BNZ or 40 mg of LC in a randomized cross‐over design (all animals received all three treatments). Pig‐tailed macaques (n= 6) were given an intranasal dose of 56 mg of BNZ and 40 mg of LC. As no differences in the peak MHb or time to peak (mean ± SD) were observed among the three macaque subspecies, the data were pooled. Lidocaine did not cause MHb or SHb formation above baseline in any monkey. In contrast, all monkeys (n= 14) had a significant elevation in peak MHb formation after 56 mg of BNZ, which ranged from 4.0% to 19.4% with an average of 8.6 ± 4.0% (mean ± SD), with peak MHb levels reached at 30 min. The monkeys given the high dose of BNZ (n= 8) demonstrated higher peak MHb levels (P< 0.05) than the lower dose of BNZ: 14.7 ± 6.5% (mean ± SD) as the time to peak increased to 45 min. Slight increases in SHb levels (0.02–0.04 mm 1−1rise) measured (P< 0.05) after low and high BNZ doses were 54% and 75% higher than baseline SHb levels after LC. This study indicates that benzocaine applied topically in non‐human primates can readily increase MHb concentrations within 30 min to clinically relevant levels required for cyanide prophylaxis, but LC does not. The variability in the peak Hb levels after BNZ is likely to be due to the variability in absorption and/or metabolism of the drug. In addition, the slight increase in SHb seen in BNZ groups should prompt investigators to also evaluate this toxic Hb component when evaluating MHb‐forming drugs.
Factors affecting the bioavailability of benzo[a]pyrene from oils in mouse skin: Oil viscosity, grooming, activity and its prevention
Authors: Ingram A. J. , Lee R. , Phillips J. C.
Published: October 2006

In the main study, tritium‐labelled benzo[a]pyrene ([3H]BaP) was added to oils of a wide range of viscosity (from 13.5 to ca. 8000 cSt at 40°C) and these were applied once to mouse skin under conditions where grooming was either allowed or prevented. The binding of [3H]BaP to epidermal protein and DNA was assessed. In addition, some studies were conducted to investigate the effect of prior oil exposure on binding levels and to compare binding levels following single and multiple application.

It was found in the main study that the binding of [3H]BaP to both DNA and protein was increased as the viscosity of the oil vehicle decreased. Whereas only a twofold difference in DNA binding was found between the lowest and highest viscosity oil vehicle if grooming was allowed, a 14‐fold difference was seen if grooming was prevented. This was due to much higher binding levels with low viscosity oils when grooming was prevented. Protein binding showed similar results, although the difference between the grooming and non‐grooming situations was slightly less. Whether grooming was prevented or not, both DNA and protein binding of [3H]BaP were found to be inversely proportional to the logarithm of viscosity of the oil vehicle, but when grooming was prevented, the slope for DNA binding was 10 times steeper than when it was permitted.

Exposure of the skin to either high or low viscosity oils prior to the application of [3H]BaP in the same oil inhibited the binding to DNA but not to protein. In experiments where multiple applications of [3]BaP in oil were given, the difference in DNA binding between low and high viscosity oils was similar to that after a single application. This implied that the relative bioavailability of polycyclic aromatic hydrocarbons from oils of differing viscosity, as assessed following single application, is reasonably predictive of that following multiple applications.

In considering the relevance of the findings of the main study to long‐term animal studies and to human hazard, it is suggested that the situation where grooming was permitted is likely to be most relevant to animal studies, whereas that where grooming is prevented is more likely to represent human exposure. Hence, borderline positive findings in long‐term mouse skin painting studies with low‐viscosity oils should be regarded more seriously than similar findings with viscous oils. The findings should also be of assistance in making predictions of carcinogenicity from analytical data.
Dermal absorption of polycyclic aromatic hydrocarbons in the blood‐perfused pig ear
Authors: Vanrooij J. G. M. , Vinke E. , De Lange J. , Bruijnzeel P. L. B. , Bodelier‐Bade M. M. , Noordhoek J. , Jongeneelen F. J.
Published: October 2006

Urinary 1‐OH‐pyrene, a metabolite of pyrene, is a sensitive biological marker for dermal absorption of pyrene in man. In order to determine whether this metabolite is a reliable biomarker of cutaneous absorption of other polycyclic aromatic hydrocarbons (PAHs), the blood‐perfused pig ear model was used to compare the dermal absorption flux of pyrene with nine other PAHs after coal tar application. Cumulative absorption of PAHs into the perfusion blood, 200 min after application of an overdose of coal tar, ranged between 830 pmol cm−2 for phenanthrene to less than 4 pmol cm−2 for benzo[b]fluoranthene, benzo[k]fluoranthene, benzo[a]pyrene, dibenzo[ah]anthracene and indeno[123‐cd]pyrene. The results of this study show that when pyrene is used as a marker compound for PAH absorption through pig skin, the cumulative absorption of PAHs with a lower molecular weight will be underestimated: fluorene, tenfold; phenanthrene, 12‐fold; anthracene and fluoranthene, ca. twofold. The percutaneous absorption of PAHs with a higher molecular weight than pyrene will be overestimated: e.g. benzo[a]pyrene, sevenfold; indeno [123‐cd]pyrene, ca. 100‐fold. It is likely that this conclusion is also valid for dermal PAH absorption in man.
Effect of s‐triazine compounds on testosterone metabolism in the rat prostate
Authors: Kniewald J. , Osredečki V. , Gojmerac T. , Zechner V. , Kniewald Z.
Published: October 2006

The influence of s‐triazine compounds (atrazine, prometryne and deethylatrazine) on testosterone conversion and 5α‐dihydrotestosterone–receptor complex formation was studied in vitro and in vivo in the rat prostate. A marked in vitro influence of atrazine and prometryne (from 0.465 to 1.392 μmol) and their mixtures (in total concentration, 0.928 μmol) on 5α‐dihydrotestosterone formation was detected. 5α‐Dihydrotestosterone‐specific receptor complex formation was inhibited in vitro by ca. 0.5 μmol of atrazine or deethylatrazine and only in vivo by 6 mg of atrazine 100 g−1 body wt. daily during 7 days in the prostate cytosol. The inhibition of the enzymic activities responsible for testosterone conversion and steroid hormone–receptor complex formation was non‐competitive and reversible, and s‐triazine compounds act as antiandrogens.
Disturbances in rat smooth‐muscle induced by a substance with fungicide action
Authors: Milieva E. , Kristev A. , Stoichev N. , Nikolov A. , Nikolov N.
Published: October 2006

The fungicide substance QAS [N, N, N', N'‐tetramethyl‐N,‐N'‐di(8,15‐dichloropentadeca‐5,10‐dien)ethylenediamine methylsulphate] has a biphasic effect on the spontaneous electrical and mechanical activity of smooth‐muscle samples of rat corpus and guinea‐pig taenia coli.

During the first phase of QAS application membrane depolarization and increased spontaneous spike frequency were recorded. The tone of the preparations (resting tone) increased transiently. Calcium ion‐entry blockers did not affect the contractile effect of QAS, but K+‐channel blockers and some modulators of the second messenger system abolished or decreased it.

During the second phase depolarization increased progressively, spike frequency decreased and the increase in resting tone recorded during the first phase was eliminated.

The results reveal that the long‐lasting depolarizing effect of QAS (in concentrations used for plant protection) probably inactivates the entry of Ca2+ into the smooth‐muscle cells and disturbs Ca2+ homeostasis.
Toxicological evaluation of μ‐agonists. Part II: Assessment of toxicity following 30 days of repeated oral dosing of male and female rats with levo‐alpha‐noracetylmethadol hcl (norlaam)
Authors: Borzelleca Joseph F. , Egle John L. , Harris Louis S. , Belleville Jo Ann Nuite
Published: October 2006

This study evaluated levo‐alpha‐noracetylmethadol (NorLAAM), the first N‐demethylated metabolite of levo‐alpha‐acetylmethadol (LAAM), a long‐acting morphine‐like (μ) agonist, approved in 1993 to treat opiate dependence. After acute and 7‐day pilot studies to define dose levels appropriate for use in longer term evaluations, Sprague‐Dawley rats (20 of each sex per group) were gavaged with doses of 4.4–25.9 mg kg−1 day−1 for 30 days followed by a 14‐day recovery period. Treatment‐related effects included dose‐dependent CNS depression paralleled by changes in food consumption, body weight gain and fecal output, as well as reddish urine and abdominal staining. Tolerance developed by day 7. The spectrum of activity observed differed from the parent compound primarily in its time course. Cage‐biting and gnawing behavior were observed only with NorLAAM. Mortality was dose‐dependent, with deaths occurring predominantly during the first week. At day 30, all male‐treated groups exhibited statistically significant, dose‐dependent decreases in body weight gain and increases in serum cholesterol that returned to the control range following recovery. Increases in brain/body weight and testes/body weight ratios and decreases in kidney/brain, liver/brain, spleen/brain and heart/brain ratios, as well as decreases in kidney, liver, spleen and heart absolute weights, achieved statistical significance only for males. At terminal sacrifice, histological findings in the kidneys included increased incidences of tubular mineral deposition in mid‐ and high‐dose groups of both sexes and of corticomedullary mineral deposition in females. Hepatic centrilobular hypertrophy was evident in male and female mid‐ and high‐dose groups. Histopathological changes abated following the recovery period. In summary, acute and repeated administration of NorLAAM produced a pharmacodynamic profile commensurate with its role as the primary N‐demethylated metabolite of LAAM, which is more potent and less lipophilic than the parent compound; this was reflected in the toxicological outcomes observed. Like LAAM, NorLAAM's overall pattern of activity is consistent with its activity as a μ‐agonist, which stimulates hepatic microsomal enzymes in rodents.
Altered activation/detoxication enzymology following neonatal diethylstilbestrol treatment
Authors: Lamartiniere Coral A. , Pardo Guillermo A.
Published: October 2006

The effects of neonatal exposure to diethylstilbestrol (DES) on hepatic activation/detoxication enzyme levels in the adult rat were investigated. Neonatal exposure of male rats to DES (DES males) decreased the endogenous levels of UDP‐glucuronyltransferase as compared to control males. Female rats exposed neonatally to DES (DES females) had higher endogenous epoxide hydrolase and glutathione transferase activity levels than control females. Adult animals treated neonatally with DES also had altered metabolic potential following exposure to 3‐methylcholanthrene and phenobarbital. The DES males treated in adulthood with 3‐methylcholanthrene had higher benzo(a)pyrene hydroxylase activities and lower UDP‐glucuronyltransferase activity levels than did control males treated in adulthood with 3‐methylcholanthrene. The DES males exposed in adulthood to phenobarbital had reduced cytochrome P‐450 and glutathione transferase activity levels as compared with respective controls. The DES females treated in adulthood with 3‐methylcholanthrene had lower benzo(a)pyrene hydroxylase and epoxide hydrolase activity levels than control females receiving 3‐methylcholanthrene. The DES females challenged in adulthood with phenobarbital also had decreased benzo(a)pyrene hydroxylase, epoxide hydrolase, UDP‐ glucuronyltransferase, and glutathione transferase activity levels as compared with respective controls. Our results demonstrated that neonatal exposure to DES changed the endogenous levels of specific hepatic enzymes and altered the metabolic response of these adult animals to a carcinogen and a drug.
Germ cell depletion does not alter the morphogenesis of the fetal testis or ovary in the red‐eared slider turtle (Trachemys scripta)
Authors: Dinapoli Leo , Capel Blanche
Published: October 2006

In the red‐eared slider turtle, Trachemys scripta, both prospective male and female gonads contain primitive cord structures at the time when the gonad first forms. Primordial germ cells arrive in the gonad and accumulate on the coelomic surface. If testis development is initiated, these cords develop further at the same time that germ cells migrate from the coelomic surface and become sequestered in the interior of the cords. In contrast, in the developing ovary germ cells proliferate in a defined cortical domain, while the primitive cords regress and form flattened lacunae in the medulla. Because of their intimate association with these developmental processes, we investigated whether germ cells were required in turtles to establish the morphology of the fetal testis and ovary. We present evidence that normal morphological development of the fetal gonad occurs in both sexes in T. scripta after germ cell depletion, suggesting a conservation of developmental mechanisms across vertebrates. J. Exp. Zool. (Mol. Dev. Evol.) 308B:236–241, 2007. © 2006 Wiley‐Liss, Inc.
Managers on flexibility and innovation: are Porter's assumptions on leadership right? An empirical exploration
Authors: Kasper Helmut , Mühlbacher Jürgen
Published: October 2006

This paper is based on an empirical test of Porter's strategic model of role allocation between top and middle management. The empirical results show that in future both hierarchy levels favour flexibility instead of innovation. Although this tendency makes sense from a practitioner's point of view, it is completely inconsistent with the sustainable development of a company. Only a balance between flexibility and sufficient stability makes a company successful. Therefore managers have to find a fit between creativity, innovation and speed with clarity of focus, co‐ordination and control.

The authors recommend putting the anticipated change on a company's agenda as soon as possible. Only this will ensure the development of targeted qualification programmes and a future‐oriented distribution of competencies and responsibilities, within the framework of strategic HRM well before the first conflicts within companies occur.

Copyright © 2006 John Wiley & Sons, Ltd.
A rational elasto‐plastic spatially curved thin‐walled beam element
Authors: Pi Yong‐Lin , Bradford Mark Andrew , Uy Brian
Published: October 2006

Torsion is one of the primary actions in members curved in space, and so an accurate spatially curved‐beam element needs to be able to predict the elasto‐plastic torsional behaviour of such members correctly. However, there are two major difficulties in most existing finite thin‐walled beam elements, such as in ABAQUS and ANSYS, which may lead to incorrect predictions of the elasto‐plastic behaviour of members curved in space. Firstly, the integration sample point scheme cannot capture the shear strain and stress information resulting from uniform torsion. Secondly, the higher‐order twists are ignored which leads to loss of the significant effects of Wagner moments on the large twist torsional behaviour. In addition, the initial geometric imperfections and residual stresses are significant for the elasto‐plastic behaviour of members curved in space. Many existing finite thin‐walled beam element models do not provide facilities to deal with initial geometric imperfections. Although ABAQUS and ANSYS have facilities for the input of residual stresses as initial stresses, they cannot describe the complicated distribution patterns of residual stresses in thin‐walled members. Furthermore, external loads and elastic restraints may be applied remote from shear centres or centroids. The effects of the load (and restraint) positions are important, but are not considered in many beam elements. This paper presents an elasto‐plastic spatially curved element with arbitrary thin‐walled cross‐sections that can correctly capture the uniform shear strain and stress information for integration, and includes initial geometric imperfections, residual stresses and the effects of the load and restraint positions. The element also includes elastic restraints and supports, which have to be modelled separately as spring elements in some other finite thin‐walled beam elements. Comparisons with existing experimental and analytical results show that the elasto‐plastic spatially curved‐beam element is accurate and efficient. Copyright © 2006 John Wiley & Sons, Ltd.
A fast high‐resolution algorithm for linear convection problems: particle transport method
Authors: Smolianski A. , Shipilova O. , Haario H.
Published: October 2006

The paper is devoted to a novel explicit technique, the particle transport method (PTM), for solving linear convection problems. While being a Lagrangian (characteristic based) method, PTM has the advantage of Eulerian methods to represent the solution on a fixed mesh. The proposed approach belongs to the class of monotone high‐resolution numerical schemes, possesses the property of unconditional stability and works with structured and unstructured meshes. It is also demonstrated that the method has a linear computational complexity. The performance of the presented algorithm is tested on one‐ and two‐dimensional benchmark problems. The numerical results confirm that the method has the 2nd‐order spatial accuracy and can be significantly faster than the grid‐based methods of the same order. Copyright © 2006 John Wiley & Sons, Ltd.
Evaluation of early signals of drug‐induced stevens‐johnson syndrome in the WHO ADR database
Authors: Li Dakui , Lindquist Marie , Edwards I. Ralph
Published: October 2006

The WHO database of the Collaborating Programme for International Drug Monitoring, which currently contains data from 31 countries, was reviewed for all drug/Stevens‐Johnson syndrome associations. The total number of such reports was 1707, involving 106 medicines with three or more reports per drug. From this, 22 previously unreported signals were found. The average delay from the first report to a stronger signal involving three reports was 4.4 years, delay usually being due to confounding by other medicines excluding some reports from being included in the signal. Reports from, on average, 2.8 countries were required to make a signal, and it is concluded that the international database allows for an expedient way of finding strong adverse drug reaction signals of rare events.
Age and the spontaneous reporting of adverse reactions in the United Kingdom
Authors: Mann R. D. , Rawlins M. D. , Fletcher P. , Wood S. M.
Published: October 2006

A study designed to investigate the relationship between age, spontaneous ADR reporting rates, general practice prescription volumes and population sizes has shown that, in the UK, from age 15 years and above, greater numbers of prescriptions are issued for females than for males; the sex difference in prescribing rates is most marked in respect of women during their reproductive years. ADR reporting rates are also much affected by age and, in respect of all ADRs, are highest in the fifth and sixth decades but appear to decline thereafter. Reporting rates of serious ADRs show a similar, though less pronounced trend, and again appear to decline in the ninth decade.
Prescription of non‐steroidal anti‐inflammatory drugs for children: A survey of Quebec physicians
Authors: Blancquaert Ingeborg R. , Gray‐Donald Katherine , Spitzer Walter O. , Zvagulis Inta , Pless I. Barry
Published: October 2006

An essential step in the assessment of the relative benefits and risks of a drug's use is the monitoring of its actual utilization in specific populations. However, few studies have documented the extent to which non‐steroidal anti‐inflammatory drugs (NSAIDs) are prescribed for children. We surveyed a sample of 1448 Quebec physicians by mailed questionnaire to estimate approximately how often and for which indications NSAIDs, excluding ASA and acetaminophen, had been prescribed over the past year for children under 16 years of age. The sample included all pediatricians and rheumatologists in the province, and a stratified random sample of general practitioners. A response rate of 81.5 per cent was achieved. The proportion of physicians prescribing NSAIDs varied with speciality and clinical condition. The highest proportions were recorded for dysmenorrhea and juvenile rheumatoid arthritis, followed by tendinitis/bursitis, musculoskeletal trauma and recurrent headaches. Patterns of use were also explored for conditions such as osteochondroses, chronic or recurrent limb and back pain, tooth abscess, and patent ductus arteriosus. These data indicate that NSAIDs are prescribed for conditions for which they are not currently recommended in the pediatric population. Further research is thus required regarding the implications of their use for a wider range of conditions.
Pharmacoepidemiology using a UK database of primary care records
Authors: Hall Gillian
Published: October 2006

A number of large data resources in North America have been used successfully in pharmacoepidemiology for several years. The need for a similar resource in the UK has been identified for some time, but its development has only been possible as a result of large‐scale computerization of primary care record‐keeping. Currently, VAMP provides the only resource of this kind in Europe. This data resource has been proved capable of providing valuable research information and, consequent to recent upheaval, has a stable financial future.
Non‐steroidal anti‐inflammatory drugs and upper gastrointestinal bleeding, a post‐marketing surveillance case‐control study
Authors: Nobili A. , Mosconi P. , Franzosi Maria G. , Tognoni G.
Published: October 2006

A post‐marketing surveillance case‐control study was set up and applied in an Italian hospital network to quantify the risk of upper gastrointestinal bleeding (UGB) and exposure to non‐steroidal anti‐inflammatory drugs (NSAIDs). During the period of study 441 cases of UGB and 1323 controls were recruited. The odds ratios associated with NSAIDs use were estimated for intake occurring over two different periods of time prior to hospital admission (i.e. during the preceding week and month). A strong association emerged for aspirin intake, both in the week (ORMLR = 11.2; 95% CI 7.8–16.9) and in the month (ORMLR = 6.9; 95% CI 4.6–10.2) preceding hospital admission. A significant increase in the risk of UGB and use of diclofenac, naproxen and ibuprofen, and indomethacin was also found in the two exposure periods considered, while for piroxicam a significant association was only apparent in the analysis of 1‐month exposure. As expected, paracetamol and pyrazolone derivatives were not associated with UGB. This pilot experience has shown the feasibility of setting up a multicentre post‐marketing surveillance programme and of establishing a network for drug monitoring within the Italian National Health Service, capable of providing a thorough evaluation of the benefit/risk profile of drugs.
Safety of fluoxetine: Comparison with fluvoxamine
Authors: Price John , Waller Patrick , Wood Susan , MacKay Angus
Published: October 2006

This review examines data on the safety of two 5‐HT reuptake inhibitors, fluoxetine and fluvoxamine. A comparison of the spontaneous reports of suspected adverse reactions to each drug sent to the UK Committee on Safety of Medicines has been made. This does not reveal important differences in their safety profile.
Prescribing patterns for combinations of warfarin and potentially dangerous interacting drugs in a large general practice population
Authors: Johnson Z. , Dack P.
Published: October 2006

The objectives of this study were to find what proportion of patients in a large general practice population were prescribed warfarin during a 1‐month period and to determine what proportion were simultaneously prescribed potentially dangerous interacting drugs. Data from prescriptions issued by GPs for the month of January 1991 to the segment of the population of the Eastern Health Board area entitled to free medical care were linked with individual age and sex data. Age and sex‐specific prescription rates for warfarin were calculated and the frequency of prescribing interacting drugs was computed for warfarin‐treated patients. The subjects of the study were residents of the Eastern Health Board who are entitled to free health care‐333 621 persons in all. Results were as follows. The crude warfarin prescription rate was 3.9 per 1000 (95% Cl: 3.7–4.1) and the rate increased with age, especially for men aged 65–74 in whom it was 15.5 per 1000 (95% Cl: 13.4–17.5). Of 722 patients on warfarin for more than 1‐month, 31.6% (95% Cl: 28.2–35.0) were prescribed at least one interacting drug concurrently, and 5.7% (95% Cl: 4.1–7.6) were prescribed more than one interacting drug. Non‐steroidal anti‐inflammatory drugs, including aspirin, accounted for 35.9% of the interacting drugs. It is concluded that combinations of warfarin and potentially interacting drugs are relatively commonly prescribed in this large general practice population.
Rate of venereal disease goinfections in women with vaginal candidiasis: Michigan medicaid
Authors: Gable Carol Brignoli , Holzer Susan Sedory , Engelhart Luella , Sarma Syam , Smeltz Frank , Schroeder Donald A. , Friedman Rhonda B.
Published: October 2006

This study was designed to address a concern about the conversion of vaginal imidazoles from prescription only to over‐the‐counter OTC status. The Food and Drug Administration (FDA) was concerned that women may misdiagnose a venereal disease as candidiasis and delay effective medical therapy for the venereal disease by using the OTC product. We conducted an epidemiology study in Michigan Medicaid (1984) to determine the rate of venereal disease in women with vaginal candidiasis. The Medicaid population was selected because it was high‐risk markers for sexually transmitted diseases (STD) — low socioeconomic status and a high proportion of blacks. We used the medical and pharmaceutical claims of a 5% random sample of 98,020 women aged from 10 to 60 years with vaginal infections, who were continuously enroled in Medicaid and had no other known medical insurance. We defined a candidiasis episode as beginning with a diagnosis or prescription for candidiasis and followed by a 2 week study period. We excluded episodes with antibiotic therapy or venereal disease in the preceding 2 weeks. The study population included 2518 women with 3507 candidiasis episodes. We used a conservative approach in defining venereal disease to include Trichomonas, chancroid, gonorrhoea, herpes, syphilis, pelvic inflammatory disease (PID) and non‐specific or unidentified STD. These venereal diseases were identified by diagnosis, specific prescription medication or antibiotic therapy for the disease during the 2 week study period. The incidence rate of venereal coinfections was 15.3% and the prevalence rate was 17.0%, predominantly Trichomonas, non‐specific or unidentified STD and PID. The prevalence rate varied with age (10–19 years and 20–40 years) and race (white and black women) from 12.6 to 20.8%. These prevalence rates are probably an overestimate for the general United States population because of the high‐risk population in Michigan Medicaid and the conservative approach used to identify venereal disease. In 1990 after reviewing this study and clinical trial data, the FDA approved prescription vaginal candidiasis medications for OTC use.
Crisis management: The medical director's response
Authors: Fitzgerald J. D.
Published: October 2006

This paper discusses the incidence and type of adverse drug reactions in relationship to their impact on a pharmaceutical company. It emphasizes that managing such a crisis requires skills in organizational processes that are not normally needed in the daily operation of a commercial enterprise. The role of the medical director is defined as it relates to the management of such a crisis. The key processes of managing complex interdisciplinary groups, and the problem of re‐evaluating the risk/benefit profile of the drug in question, within a constrained time frame and with an inadequate database are described. The principles of crisis communication skills are outlined. A case is made for giving a higher priority to crisis prevention by adopting certain straightforward precautions.
Causality assessment of adverse drug reactions using decision support and informatics tools
Authors: Hoskins Richard E. , Mannino Salvatore
Published: October 2006

Informatics information organizing techniques have been applied to the causality assessment of adverse drug reactions since the 1970s. There has not appeared an easily applied and accurate method. The problem has to do with low quality and poorly organized input information or the attempted application of methods that are too rigid for some problems and inapplicable for others. Potentially the best current method, based on Bayesian probability, is difficult to use because of low quality or quantity of information. This handicap requires extrapolations which tend to result in a form of numerical global introspection. We suggest that the problem might be approached by using a generalized decision support algorithm which can be used with many different decision methods and proper informatics support for the immediate environment of the assessor in drug safety. The decision support algorithm we apply is based on an analytical hierarchical process algorithm implemented in the software CRITERIUM©. We give as an example the application of the algorithm to a suspected adverse drug reaction, cholestatic jaundice, as a result of treatment by chloropromazine. However, to support any decision‐making method, the information and informatics environment around the decision‐maker must be planned and developed. A set of requirements that best reflect adverse drug reaction causality assessment needs is discussed.
EURO‐ADR: Pharmacovigilance and research. A European perspective
Authors: Rawlins M. D. , Fracchia G. N. , Rodriguez‐Farré E.
Published: October 2006

This document presents the views of an Expert Group convened by the European Commission on pharmacovigilance in the European Community. The recommendations of the Expert Group for the development of pharmacovigilance are also presented.
Pharmacoepidemiology of warfarin use and deep venous thrombosis
Authors: Kurata John H. , Parker Charles , Kantor‐Fish Sandra , Deamer Robert , Ebert Emily , Nogawa Aki
Published: October 2006

Three Southern California hospitals from the Center for Studies in Family Medicine research network participated in a study of the characteristics of patients using warfarin and of patients hospitalized with deep venous thrombosis. Computerized hospital and pharmacy data bases were searched to identify warfarin users and patients with deep venous thrombosis who received care between July 1987 and July 1990. Information on patients was abstracted from medical records.

Of 337 warfarin users identified, 50% were male and the mean age was 51.6 years. The most common indications for warfarin therapy were cardiovascular conditions (45.8%) and deep venous thrombosis (31.8%). Warfarin therapy was initiated in the hospital for most patients (82%). Sensitivity to warfarin, as measured by the mean dose‐adjusted prothrombin time ratio, was 0.30. Female gender (p < 0.001) and increasing age (p = 0.03) were associated with increased sensitivity to warfarin (higher mean dose‐adjusted prothrombin time ratio). Regression analysis indicated that certain groups were significantly more sensitive to warfarin: females more than males (p < 0.0005); patients of other race/ethnicity more than blacks, hispanics, and whites (p < 0.05).

Among the 114 patients hospitalized for deep venous thrombosis, there were 134 hospitalizations and 98 patients had only one hospitalization. Fifty‐eight per cent of the patients were male; the mean age was 44.2 years. The mean dose‐adjusted prothrombin time ratio was 0.28 for hospitalized patients.
Auditing drug therapy by peer review — the German experience
Authors: von Ferber Liselotte
Published: October 2006

It is known that traditional lecturing hardly ever leads to improvement in either the quality or cost‐effectiveness of everyday prescribing.

In order, therefore, to improve their prescribing behaviour a group of physicians met to assess their prescribing routine for the second quarter of 1989. These discussions highlighted prescribing problems and allowed the development of pharmacotherapy guidelines tailored to the treatment situation which presents in primary health care practice. The prescription audit and review process was repeated so that the first comparison was between 1989 and 1990 and the second between 1989 and 1991.

The study group consisted of 11 primary health care physicians and two advisors — one with a background in pharmacotherapy and the other with experience of group dynamics. The group met six times a year for two years. In undertaking the evaluations and comparisons special attention was paid to those drug groups in which the prescribed quantities suggested the possibility of irrational prescribing.

Thus, the following problem areas were discussed and evaluated:

Prescribing of drugs of which the efficacy is not proven (e.g. drugs to enhance blood flow).

Prescribing psychotiopic drugs in combination.

Unnecessary prescribing of effective drugs (e.g. benzodiazepines, and H2 antagonists)

Excessively frequent prescribing in the elderly.

The cost‐effectiveness and usefulness of the review group process was also assessed.

It was found that in the course of a quarter of a year the 11 physicians treated 12,800 patients. In the first year of review (1989/1990) they saved 1,152,000 DM taking the four quarters together. In the second year the savings amounted to 1,381,000 DM. These savings were mainly the result of reduced prescription frequency and it was noted that the prescribing of less expensive drugs had only a minor effect.
Effect of federally mandated education policies on prescribing of isotretinoin to women of childbearing age
Authors: Heckbert Susan R. , Mtshali Glaudine , Platt Richard
Published: October 2006

We evaluated the effect of federally mandated educational interventions designed to reduce prenatal exposures to isotretinoin. We determined the number of isotretinoin courses prescribed at a health maintenance organization to women aged 15 through 44 between March 1987 and February 1990, and the number that had pre‐treatment pregnancy testing.

The number of courses initiated without pre‐treatment testing fell by 54%, from 3.6 to 1.7 courses per month after educational programs were in place (p < 0.01). This decrease was principally due to a decrease in prescribing from 1.1 to 0.6 courses per 1000 women‐years (p < 0.002), although testing also increased from 51% (54 of 105) to 58% (21 of 36) of courses. These overall changes resulted from two distinct patterns of responses by physicians. Physicians who initially tested in over 40% of, courses (aggregate testing, 71% of courses (50 of 70)) reduced their collective prescribing from 5.0 to 0.3 courses per month and maintained a stable testing rate. In contrast, physicians who initially tested in fewer than 10% of courses increased their collective prescribing from 2.3 to 3.0 courses per month, and also increased testing from 6% (two of 32) to 56% (15 of 27) of courses.
PEM report number 1. Nicardipine
Authors: Inman William , Kubota Kiyoshi , Wilton Lynda , Pearce Gillian
Published: October 2006

Patients (10,910) who had been treated with nicardipine by 5952 general practitioners between November 1986 and May 1988 have been studied by Prescription–Event Monitoring (PEM) for a period of one year. The events recorded on green forms were compared with three other calcium antagonists. The most frequent daily dose was 60 mg (59%). Nitrates had been co‐prescribed for 31% of the patients, diuretics for 28% and beta‐blockers for 23%.

The rates of events occurring during the first month of treatment with nicardipine were compared with the mean rates recorded during the second to sixth month of treatment with 32 other drugs, including amlodipine, isradipine and diltiazem. The comparison was restricted to those events which had been experienced by 10 or more patients during the first month of treatment (rates in excess of one per 1000). A ‘signal’ was noted when this rate exceeded the second to sixth month average rate by a factor of three or more. Strong signals were recorded for all the well known side‐effects of nicardipine which include flushing (the commonest side‐effect), palpitations, tachycardia, faintness, headache, dizziness and tremor.

Acute rashes, which were identified as an adverse reaction in the diltiazem study, were not seen in excess with nicardipine and heart block, which had been a rare but an important effect of diltiazem, was seen in only two patients.

Accepting the limitations of a study of roughly 10,000 patients, which would be virtually certain to detect any event with a true frequency greater than about one in 3000, we have found no serious problems during the course of this PEM study.
PEM report number 2. Terodiline
Authors: Inman William , Clarke Joan , Wilton Lynda , Pearce Gillian , Veldhuis Gerritt Jan
Published: October 2006

Patients (12,457) who had been treated by general practitioners between November 1986 and September 1987 have been studied by Prescription‐Event Monitoring (PEM) for a period of one year. The events recorded on green forms were compared with those recorded in 14 other PEM studies. Nearly 5000 of the patients were aged 70 or more. The most frequent indications for terodiline were incontinence (43%) and frequency (18%). The most frequent daily dose was 25 mg (62%). NSAIDs had been coprescribed for 11% of the patients, tranquillizers for 10% and diuretics and analgesics each for 7%.

The rates of events occurring during the first month of treatment with terodiline were compared with the mean rates recorded during the second to sixth month of treatment. This analysis was restricted to events experienced by more than one per 1000 patients during the first month of treatment. A ‘signal’ was noted when this rate exceeded the second to sixth month base‐rate by a factor of three or more or when the first‐month rate exceeded the pooled base‐rate for other drugs by a similar amount. All the well known side‐effects of terodiline were encountered. They included dizziness, blurring of vision, dry mouth, retention of urine and tremor. A number of other events were signalled, especially by the comparison with other unrelated drugs. Noteworthy were confusion, drowsiness and headache. Medical and surgical conditions such as urinary tract infection, bladder cancer or surgery to the genitourinary tract were also signalled in large numbers, but were clearly related to treatment with terodiline because they were part of the indications for its use.

We studied certain groups of events with special regard to the patient's age and the dose of terodiline. Confusion was obviously related to old age but not to dose. Drowsiness, in contrast, was linked to high dosage, but not to age. Blurring of vision was very obviously related to high dose and was more likely to be complained of by patients under the age of 60 years. Tremor was no obviously correlated either with age or dose of terodiline. We have also investigated a possible relation between the calcium‐antagonist effect of terodiline and a number of cardiovascular events, including syncope, cerebrovascular accident and transient ischaemic attacks. These might have been responsible for some of the unusually large numbers of falls, fractures or other injuries noted in the terodiline series.

The medical records of 1176 patients who had died were carefully studied and the cause of death was established in 94% of patients.

We were able to quantitate the side‐effects listed in the data sheet for terodiline. Dizziness, dry mouth, constipation, visual disturbances and retention all occurred during the first month with a frequency up to 10 per 1000 patients. Nausea, cited as a rare event, occurred in 8.5 per 1000. PEM detected a number of other unlisted events as likely to be causally related including drowsiness, confusion and headache.
PEM report number 5. Fluoxetine
Authors: Inman William , Kubota Kiyoshi , Pearce Gillian , Wilton Lynda
Published: October 2006

The selective serotonin reuptake inhibitor (SSRI) fluoxetine was first marketed in the United Kingdom in January 1989. It has been studied by Prescription‐Event Monitoring (PEM) in 12,692 patients who had received prescriptions from general practitioners in England between March 1989 and March 1990.

There were more than twice as many females in the series as males and the average ages were 49.4 and 50.1 years respectively. The majority of patients were taking 20 mg daily (89%), but doses ranged up to 120 mg daily. Where an opinion had been given, fluoxetine was said to have been effective in 57% of patients.

The events following treatment were compared with those reported after prescription of two other SSRIs, paroxetine and fluvoxamine, and with the ‘pooled’ results in 34 studies, in order to detect possible differences within the group of SSRIs and to obtain some impression of the background rates in a population of over 350,000 monitored by PEM.

Coincidental with the PEM study there was much publicity, initiated in the United States by a report of suicidal and aggressive behaviour. A subsidiary study of doctors' and patients' attitudes before and after a heavily biased television programme was initiated about one‐fifth of the patients in the PEM study. There was no evidence to suggest that the frequency of aggressive or suicidal behaviour following the use of fluoxetine was increased.

The overall incidence of side‐effects was low and no deaths were attributed to fluoxetine.
Generic prescribing in Ahmadu Bello University Teaching Hospital, Zaria, Kaduna State, Nigeria
Authors: Ogwuche E. A. , Olasehinde L. , Obiaga G. O.
Published: October 2006

A study was carried out to assess the generic prescribing pattern among medical doctors in Ahmadu Bello University (ABU) Teaching Hospital, Zaria, Nigeria.

The results indicate that 98 (49%) of the 200 drugs studied were prescribed using generic names while 64 (32%) were prescribed using both generic and proprietary names.

One hundred and ninety‐two (96%) of the 200 drugs studied are on the Essential Drugs List (EDL), Second Revision 1991 of the Federal Ministry of Health, Lagos, Nigeria.

The results further showed that out of the 77,889 prescriptions scrutinized, 48,451 (62.2%) were written using generic names only while 29,438 (37.8%) were prescribed using proprietary names.

Based on the above findings, more prescriptions were written using generic names than proprietary names during the period of this study, showing that the government's effort towards educating doctors to prescribe generically is achieving the desired results.
The quality of information recorded on a UK database of primary care records: A study of hospitalizations due to hypoglycemia and other conditions
Authors: Van Staa Tjeerd‐Pieter , Abenhaim Lucien
Published: October 2006

We assessed the utility of the clinical information on the VAMP Research data bank. This data bank contains information recorded by general practitioners in the United Kingdom. We compared information derived from photocopied hospital discharge summaries and GPs' questionnaires to the information recorded in the data bank. Data were obtained on 553 discharge summaries for 452 persons registered in 269 medical practices.

We found that the principal diagnosis of hospitalizations was present in the computerized records in 90.0 per cent of the time. Furthermore, 90.7 per cent of the discharge summaries for hypoglycemia were adequately recorded on the data bank, and 88.6 per cent of the data bank codes indicating hypoglycemia hospitalizations were correct. For most of the other reviewed medical conditions, we found that the sensitivity of computer notation and positive predictive value of computer codes was over 90 per cent. The agreement between computerized information on the severity of diabetes and GPs' questionnaire information was over 85 per cent.

We concluded that the data in the VAMP Research data bank have a high level of completeness and validity.
Antidepressant drug use in an ambulatory elderly population: A 14‐year overview
Authors: Stewart Ronald B. , Marks Ronald G. , Padgett Phillip D. , Hale William E.
Published: October 2006

The objective of the work was to identify changes in antidepressant drug use and determine if the prevalence of antidepressant use has changed over 14 years. A longitudinal analysis comparing antidepressant drug use at 14 yearly intervals from 1978–79 to 1991–92 was undertaken using the longitudinal health screening program of ambulatory elderly participants (Florida Geriatric Research Program). Participants included all subjects screened in the Florida Geriatric Research Program from 1 August 1978 to 31 July 1992. The outcome measures were self‐reported antidepressant drug use.

Approximately 3.0 per cent (range of 2.3 to 3.2 per cent over 14 yearly intervals) of participants in this program reported the use of an antidepressant drug. There was no statistically significant change in antidepressant use between 1978–79 and 1991–92 (p > 0.6630). Across all study intervals women reported more frequent use of antidepressant drugs than men. In 1991–92, amitriptyline and imipramine represented over 50 per cent of all antidepressant drug use in this elderly population. Less than 6 per cent of all antidepressant drug use was for fluoxetine, the newest selective serotonin uptake inhibitor.

The majority of elderly patients are receiving older tertiary amine tricyclic antidepressants such as amitriptyline, imipramine and doxepin that are not the preferred drugs for the elderly. Educational programs are needed to improve antidepressant prescribing for geriatric patients.