Undertreatment of hypercholesterolaemia: a population-based study.

AIMS: To assess the level of undertreatment of hypercholesterolaemia in the general population, taking intra-person variability in serum cholesterol concentrations into account, and to identify determinants of undertreatment of hypercholesterolaemia. METHODS: In this cross-sectional study, data from two population-based surveys on cardiovascular disease risk factors conducted between 1987 and 1997 in the Netherlands were used. For all 64 757 respondents aged 20-59 years, treatment eligibility for lipid-lowering drug use was established according to the Dutch Cholesterol Consensus. Multivariate logistic models were used to identify determinants of undertreatment. RESULTS: During the study period, 56.8% of the study population had undesirable cholesterol concentrations (serum total cholesterol> 5 mmol l(-1)) and 5.5% of those were eligible for pharmacological treatment based on their absolute risk of coronary heart disease. Of those eligible for pharmacological treatment, 16.3% were treated, and 19.6% of those treated had their serum total cholesterol concentration controlled. Only 3.2% of those eligible for pharmacological treatment were both treated and controlled. We identified several determinants for undertreatment, e.g. male gender and younger age for primary prevention and female gender and older age for secondary prevention. Treatment has improved slightly in more recent years. CONCLUSIONS: Over 95% of the population eligible for the pharmacological treatment of hypercholesterolaemia was either untreated or was uncontrolled. To decrease undertreatment, identification of high-risk patients should be increased. Those who are treated with lipid-lowering medication could further benefit from more aggressive treatment, especially with statins.

Evaluation of patient outcomes in an area where prescribing of anticholinergic antidepressants was influenced by academic detailing.

OBJECTIVE: To evaluate, on a patient level, the effect of a "physician-level intervention" that successfully reduced the incidence of anticholinergic antidepressant prescribing. DESIGN: Cross-sectional surveys with questionnaires sent before and after intervention. SETTING: Additional study in an RCT to reduce the prescribing of highly anticholinergic antidepressants in the elderly in the South Holland Islands. PARTICIPANTS: Elderly patients (age 60-95 years) who used antidepressants in 1995 and 1996 in our research area according to a health insurance prescription database. MAIN OUTCOME MEASURES: Prevalence of adverse events related to antidepressant use, severity of depression and quality of life were compared in users living in the intervention and control areas. RESULTS: Prior to our intervention we sent 2,359 questionnaires of which we could use 827 (35%) for analysis. At baseline, there were no statistically significant differences between the intervention and control areas. After the intervention 3,375 questionnaires were sent, of which 939 (28%) could be used. The occurrence of "dry mouth" and "coughing" and the "amount of pain" were lower in the intervention area compared to the control area (p < 0.05). CONCLUSION: We found no indications that adverse events, severity of depression or quality of life were changed in an unfavourable direction, when comparing patients inside and outside the intervention area.

Start of a selective serotonin reuptake inhibitor (SSRI) and increase of antiparkinsonian drug treatment in patients on levodopa.

AIMS: We determined whether the start of selective serotonin reuptake inhibitors (SSRI) in levodopa users was followed by a faster increase of antiparkinsonian drug treatment. METHODS: Selected were all levodopa users of 55 years and older from the PHARMO prescription database. The rate of increase of antiparkinsonian drug treatment was compared using Cox's proportional hazard model for starters of SSRI (n = 15) with starters of tricyclic antidepressants (TCA) (n = 31) and with patients not using antidepressants (n = 304), and was adjusted for age, gender, and duration of levodopa use. RESULTS: The hazard ratio for the SSRI group compared with the TCA group was 4.2 (95% confidence interval 1.4, 12.6) and compared with the second control group was 2.7 (1.2, 5.2). CONCLUSIONS: The start of SSRI therapy in levodopa users is followed by a faster increase of antiparkinsonian drug treatment.

Antipsychotics and Parkinson's disease: association with disease and drug choice during the first 5 years of antiparkinsonian drug treatment.

OBJECTIVE: Psychosis is a common complication of the drug treatment of Parkinson's disease (PD). Treatment of this complication is difficult as most antipsychotic drugs worsen motor symptoms of PD. Only the atypical antipsychotic clozapine improves psychosis without worsening of parkinsonism. The aim of the present study was to assess the rate of initiation of antipsychotic treatment in patients with PD compared with controls. The quality of pharmacotherapy was determined by assessing which antipsychotic drugs were initiated. METHODS: Data came from the PHARMO database, which includes drug-dispensing information for all residents of six Dutch cities. Selected were all persons aged 55 years and older who used levodopa for at least 180 days and who started antiparkinsonian drugs at least 180 days after entry into PHARMO. These patients were matched to at most three controls for age, gender, pharmacy and time of use. The association between rate of initiation of antipsychotic drug treatment and PD was determined using the Cox proportional hazards model. RESULTS: The study included 271 patients with PD and 748 controls. During follow-up, 38 patients and 25 controls started taking an antipsychotic drug; relative risk was 3.9 (95% confidence interval 2.3, 6.4). Six patients with PD received an atypical agent (16%). Clozapine was given to five patients with PD. No control used clozapine. Haloperidol was most frequently prescribed to the patients (29%) and the controls (36%). CONCLUSION: Patients with PD began taking antipsychotic drugs almost four times more frequently than controls. The quality of pharmacotherapy can be improved by prescribing atypical antipsychotic drugs to patients with PD.

Influence of benzodiazepines on antiparkinsonian drug treatment in levodopa users.

OBJECTIVES: Animal studies showed that benzodiazepines decrease the concentration of dopamine in the striatum. Benzodiazepines may therefore affect the treatment of Parkinson's disease. This study determined whether start of a benzodiazepine in patients on levodopa was followed by a faster increase of antiparkinsonian drug treatment. METHODS: Data came from the PHARMO database, which includes information on drug dispensing for all residents of six Dutch cities. Selected were all patients aged 55 years and older who used levodopa for at least 360 days. The rate of increase of antiparkinsonian drug treatment was compared between starters of a benzodiazepine and controls who did not start a benzodiazepine with the use of Cox's proportional hazard model. RESULTS: Identified were 45 benzodiazepine starters (27 women, mean age 76.4 years) and 169 controls (83 women, 74.3 years). Antiparkinsonian drug treatment increased faster in the benzodiazepine group; relative risk was 1.44 (95% confidence interval 0.80-2.59). CONCLUSION: This study has not found any statistically significant increase in antiparkinsonian drug treatment when a benzodiazepine was started in a small population of chronic levodopa users.

Evaluation of antiparkinsonian drugs in pharmacy records as a marker for Parkinson's disease.

AIM: The aim of this study was to determine whether use of antiparkinsonian drugs in pharmacy records can be used as a marker for patients with Parkinson's disease (PD). METHOD: Data were obtained from the Rotterdam Study, a community-based prospective cohort study among people aged 55 years or older who were all screened for PD. For 5510 persons, of whom 74 had PD, pharmacy records were available. Stepwise logistic regression analysis was used to evaluate whether age, sex and use of the antiparkinsonian drugs amantadine, anticholinergics, dopamine agonists, levodopa and selegiline, were predictive variables for PD. For each individual a probability for having PD was calculated. Sensitivity, specificity and positive predictive value (PPV) were calculated at different cut-off values based on calculated probabilities. RESULTS: More than 90% of the users of levodopa, bromocriptine, selegiline, and users of at least two different antiparkinsonian drugs had PD. Age, use of amantadine, anticholinergics, bromocriptine, levodopa, and selegiline were predictive variables for PD. After application of different cut-off values, sensitivity was at most 66.2%, and specificity was at least 99.8%. A PPV of higher than 90% was obtained at higher probabilities. CONCLUSION: Based on the high PPV of our predictive model, antiparkinsonian drugs can be used as a reliable marker for PD in pharmacy records. Because sensitivity is low, pharmacy records cannot be used to estimate prevalence of PD.

Drug-Induced lipid changes: a review of the unintended effects of some commonly used drugs on serum lipid levels.

Many drugs besides lipid-lowering drugs affect serum lipid levels in either a potentially harmful or beneficial way, and may therefore increase or decrease the risk of cardiovascular disease. Diuretics, beta-blocking agents, progestogens, combined oral contraceptives containing 'second generation' progestogens, danazol, immunosuppressive agents, protease inhibitors and enzyme-inducing anticonvulsants adversely affect the lipid profile. They increase total cholesterol, low density lipoprotein cholesterol and triglycerides by up to 40, 50 and 300%, respectively, and decrease high density lipoprotein cholesterol by a maximum of 50%. Conversely, alpha-blocking agents, estrogens, hormone replacement therapy, combined oral contraceptives containing 'third generation' progestogens, selective estrogen receptor modulators, growth hormone and valproic acid show mostly beneficial effects on the lipd profile. Some drugs, for example, isotretinoin, acitretin and antipsychotics, mainly elevate triglyceride levels. Adverse or beneficial effects on serum cholesterol levels do not always translate into a higher or lower, respectively, incidence of cardiovascular disease. because these drugs may influence cardiovascular risk through multiple pathways. In some cases, excessive cholesterol levels occur, for example, with protease inhibitor therapy, and several cases of pancreatitis attributable to drug-induced hypertriglyceridaemia have been reported. Some general guidelines on the management of drug-induced dyslipidaemia can be given. Replacement of the dyslipidaemia-inducing drug by an equivalent alternative therapy is preferred. However, such alternatives are often difficult to find. If there is no equivalent alternative and treatment with the dyslipidaemia-inducing drug must be initiated, monitoring of serum lipid levels is important. If drug use is expected to be long term, the existing guidelines for the management of dyslipidaemia in the general population can be applied to drug-induced dyslipidaemia. In cases of extreme hyperlipidaemia, medication use should be reassessed.

Reducing prescribing of highly anticholinergic antidepressants for elderly people: randomised trial of group versus individual academic detailing.

OBJECTIVE: To compare the effect of individual educational visits versus group visits using academic detailing to discuss prescribing of highly anticholinergic antidepressants in elderly people. DESIGN: Randomised controlled trial with three arms (individual visits, group visits, and a control arm). SETTING: Southwest Netherlands. PARTICIPANTS: 190 general practitioners and 37 pharmacists organised in 21 peer review groups were studied using a database covering all prescriptions to people covered by national health insurance in the area (about 240 000). INTERVENTION: All general practitioners and pharmacists in both intervention arms were offered two educational visits. For physicians in groups randomised to the individual visit arm, 43 of 70 general practitioners participated; in the group visit intervention arm, five of seven groups (41 of 52 general practitioners) participated. MAIN OUTCOME MEASURES: Numbers of elderly people (>/=60 years) with new prescriptions of highly anticholinergic antidepressants and less anticholinergic antidepressants. RESULTS: An intention to treat analysis found a 26% reduction in the rate of starting highly anticholinergic antidepressants in elderly people (95% confidence interval -4% to 48%) in the individual intervention arm and 45% (8% to 67%) in the group intervention arm. The use of less anticholinergic antidepressants increased by 40% (6% to 83%) in the individual intervention arm and 29% (-7% to 79%) in the group intervention arm. CONCLUSIONS: Both the individual and the group visits decreased the use of highly anticholinergic antidepressants and increased the use of less anticholinergic antidepressant in elderly people. These approaches are practical means to improve prescribing by continuing medical education.

Estimation of incidence and prevalence of Parkinson's disease in the elderly using pharmacy records.

PURPOSE: We determined the prevalence and incidence of Parkinson's disease among persons aged 55 years and older in pharmacy records. METHODS: Data came from the PHARMO database which includes information on drug dispensing for all residents of six Dutch cities. We selected all persons aged 55 years and older who had used antiparkinsonian drugs, and calculated a chance for having Parkinson's disease with use of a previously validated logistic regression model. We used a cut-off of 0.5 (sensitivity 62%, positive predictive value 92%). Prevalence was estimated on the first Wednesday of October 1997, incidence on the first Wednesday of October 1993 until 1997. A patient was incident, if the first prescription for an anti-parkinsonian drug was dispensed at least 180 days after entry into PHARMO. Prevalence and incidence were standardized to the Netherlands population of 1 January 1998. The prevalence was adjusted for the sensitivity and positive predictive value of the model. RESULTS: The unadjusted prevalence (per 100,000) for those aged 55-64 years was 111, 65-74 years 598, 75-84 years 1551 and for persons aged 85 years and older 1847. The adjusted and standardized prevalence was 970 per 100,000 (95% confidence interval 869 to 1071). The incidence (per 100,000 person years) for persons aged 55-64 years was 12, 65-74 years 108, 75-84 years 257 and for persons aged 85 years and older 247. The standardized incidence was 109 per 100,000 person years (96 to 121). CONCLUSIONS: Prevalence and incidence were in range with the literature. Pharmacy records therefore seem to be a useful tool for continuous monitoring of incidence and prevalence of Parkinson's disease.

The completeness of medication histories in hospital medical records of patients admitted to general internal medicine wards.

AIMS: Accurate recording of medication histories in hospital medical records (HMR) is important when patients are admitted to the hospital. Lack of registration of drugs can lead to unintended discontinuation of drugs and failure to detect drug related problems. We investigated the comprehensiveness of medication histories in HMR with regard to prescription drugs by comparing the registration of drugs in HMR with computerized pharmacy records obtained from the community pharmacy. METHODS: Patients admitted to the general ward of two acute care hospitals were included in the study after obtaining informed consent. We conducted an interview on drugs used just prior to hospitalization and extracted the medication history from the HMR. Pharmacy records were collected from the community pharmacists over a 1 year period before the admission. Drugs in the pharmacy records were defined as possibly used (PU-drugs) when they were dispensed before the admission date and had a theoretical enddate of 7 days before the admission date or later. If any PU-drug was not recorded in the HMR, we asked the patient whether they were using that drug or not. RESULTS: Data were obtained from 304 patients who had an average age of 71 (range 40-92) years. The total number of drugs according to the HMR was 1239, 43 of which were not used. When compared with the pharmacy records we found an extra 518 drugs that were not recorded in the HMR but were possibly in use. After verification with the patients, 410 of these were indeed in use bringing the total number of drugs in use to 1606. The type of drugs in use but not recorded in the HMR covered a broad spectrum and included many drugs considered to be important such as cardiovascular drugs (n = 67) and NSAIDs (n = 31). The percentages of patients with 0, 1, 2, 3, 4, 5-11 drugs not recorded in the HMR were 39, 28, 16, 8, 3.6 and 5.5, respectively. Of the 1606 drugs in use according to information from all sources, only 38 (2.4%) were not retrievable in the pharmacy records when the complete year prior to hospitalization was evaluated. CONCLUSIONS: The medication history in the hospital medical record is often incomplete, as 25% of the prescription drugs in use is not recorded and 61% of all patients has one of more drugs not registered. Pharmacy records from the community pharmacist can be used to obtain more complete information on the medication history of patients admitted to the hospital.

A nation-wide study on the practice of euthanasia and physician-assisted suicide in community and hospital pharmacies in The Netherlands.

PURPOSE: In recent years the attitudes and practices of euthanasia (E) and physician-assisted suicide (PAS) among health care workers have been evaluated in different countries. There is, however, still an information gap on the role of pharmacists in these matters. The aim of our study was to study the attitudes and practices of E and PAS among pharmacists. METHODOLOGY: We conducted a nation-wide survey into the practice, including adherence to guidelines, of E and PAS in community and hospital pharmacies (CP and HP) in the Netherlands. Furthermore, the attitude of community pharmacists concerning this subject was evaluated. Anonymous questionnaires were sent to a random sample of 50% (n = 755) of all CP and to all (n = 101) HP. RESULTS: The response rates were 52% and 51% for CP and HP, respectively. Most of the CP-respondents (95%) agreed with the concept of E and PAS and would dispense drugs for these purposes. When the data were extrapolated to all pharmacies, there were 1351 and 340 dispensing of drugs for E and PAS per year in CP and HP (94% of all requests), respectively. In most cases the pharmacist had been notified of the condition of the patient (CP: 93%, HP 87%) and a written request was obtained (CP: 74%, HP: 79%). The drugs were often handed personally to the physician (CP: 98%, HP: 86%). Involvement of pharmacy technicians was more common in HP than in CP (31% versus 6%). The most frequently dispensed drugs were muscle relaxants with barbiturates (CP: 47%, HP 71%), barbiturates only (CP: 19%, HP: 6.1%), and muscle relaxants with benzodiazepines (CP: 14%, HP: 7.6%). CONCLUSION: Most pharmacists are supportive of E and PAS and are prepared to fill prescriptions written for these purposes.

Effects of hypercholesterolemia on the contractions to angiotensin II in the isolated aorta and iliac artery of the rabbit: role of arachidonic acid metabolites.

The aim of this study was to investigate the effect of hypercholesterolemia on the angiotensin II-induced contractions in the isolated aorta and iliac artery of the rabbit, with respect to the role of arachidonate metabolites. Furthermore, the effect of the angiotensin-converting enzyme inhibitor ramipril was studied on the responses to angiotensin II in the cholesterol-fed rabbit. After 12 weeks of cholesterol diet (0.3%), endothelium-dependent relaxations to acetylcholine were significantly fewer compared with control (30.2 +/- 5.9% vs. 73.0 +/- 1.7%) in the aorta but not in the iliac artery of the rabbit. The angiotensin II- and methoxamine-induced contractions were also significantly lower compared with control in the aorta (101.4 +/- 6.7% vs. 60.9 +/- 4.2% and 160.2 +/- 5.7% vs. 135.8 +/- 8.0%, respectively) but not in the iliac artery. The lipoxygenase inhibitor nordihydroguaiaretic acid (NDGA) selectively attenuated the angiotensin II-induced contractions in rabbit aortic rings from the control group only in the presence of the endothelium, whereas it had no effect on the responses to angiotensin II in the cholesterol group (with or without endothelium). In the iliac artery, NDGA inhibited the responses to angiotensin II in both the control and cholesterol groups. Treatment with ramipril (0.33 mg/kg/day) significantly improved the maximal angiotensin II-induced contraction in the aorta of rabbits fed a cholesterol diet for 16 weeks to 61.0 +/- 7.3% (vs. 32.7 +/- 9.0% in the cholesterol group). We conclude that hypercholesterolemia leads to a reduction of angiotensin II-induced contractions in the aorta and not in the iliac artery of the rabbit. This reduction might be related to loss of endothelium-dependent lipoxygenase products and is partially reversed by ramipril.

A nested case-control study on mortality in users of ibopamine.

BACKGROUND: A recent interim analysis of the PRIME II placebo-controlled study showed a significantly higher mortality in the group treated with ibopamine than in the control group. The objective was to study mortality in patients on ibopamine, and to assess risk factors for death. METHODS: All 2147 drug-dispensing outlets (DDO) in the Netherlands were asked to provide a printout of the complete medication history of users of ibopamine. A reaction was received from 92% of the DDO. From the 14,024 identified former or current users of ibopamine, a sample of 3148 patients (22%) was enrolled in the follow-up study. All general practitioners (GP) of these patients received an enquiry pertaining to the vital status of their patient, cause of death, primary cause and NYHA classification of heart failure, echo- and electrocardiographic data, serum creatinine, admissions and the effects of ibopamine. Cases were defined as patients who died during the follow-up period which ended on the day of return of the questionnaire or the day of decease (index date). Two random controls were obtained for each case from the non-deceased patients at the index date. The design was a follow-up study with risk factor assessment in a nested case-control design. RESULTS: Questionnaires were returned regarding almost 70% of the sample. Mortality in this group was 25%. A case-control analysis was performed with the first 104 cases and 208 random controls. Patients with NYHA class IV had a 3-times increased risk of dying. In patients with a serum-creatinine level in the highest quartile the risk of dying was increased threefold. Higher doses of ibopamine seemed to have a protective effect. Significantly more cases than controls used amiodarone. Also, opioids were used more often, which may be related to their use in terminal cardiac failure. CONCLUSION: NYHA classification and serum-creatinine levels were independent risk factors for death in patients with heart failure on ibopamine. Although there were increased risk estimates for current use of ibopamine and amiodarone, these did not reach statistical significance. This may be related, however, to the fact that this analysis was restricted to the first 20% of cases.

[Privacy and drug surveillance: a study of the viewpoints of medication users]. / Privacy en geneesmiddelenbewaking: een onderzoek naar de opvattingen van gebruikers van geneesmidelen.

OBJECTIVE: To study the views of patients regarding privacy in relation to the procedures of postmarketing surveillance studies. DESIGN: A population-based cross-sectional study (survey). SETTING: Dutch community pharmacies. METHODS: From a source population of 1030 pharmacists 30 (2.9%) were selected at random; 28 (93.3%) of them co-operated with the investigation. Pharmacists were visited for one day each in their pharmacies during which visit their patients were asked to fill in a questionnaire. On the day of the visit, a random number of patients were asked whether the prescriptions were for themselves. Out of a total of 1277 patients in the 28 pharmacies, 849 (66.5%) used the filled prescriptions themselves. Of these 849, 669 patients (78.8%) co-operated and completed a questionnaire pertaining to their perceptions of privacy in relation to reporting of adverse drug reactions (ADR) and postmarketing surveillance studies. RESULTS: Of the 669 respondents 628 (94%) had no objection against the reporting of ADR to the Inspectorate for Health Care by their medical practitioner or pharmacist. 505 (77%) respondents did not object to the use of their medical data, even if these were not anonymous, as long as the data were kept strictly confidential. Most patients were of the opinion that such data could be used without asking permission. Males would more readily give their permission than females. CONCLUSIONS: Most respondents had no objections to use of their medical data for postmarketing surveillance studies. The large majority of patients did not object to the reporting of ADR to the Inspectorate for Health Care.

The use of confidential medical data and postmarketing surveillance: a survey of the opinion of patients.

OBJECTIVES: To study the perceptions of patients regarding privacy in relation to the performance of postmarketing surveillance studies. DESIGN: A population-based cross-sectional study (survey). SETTING: Out of a source population of 1030 pharmacists a random sample of 30 (2.9%) was taken. Twenty-eight (93.3%) of them co-operated with the investigation. Pharmacists were visited for 1 day each in their pharmacy during which visit their patients were questioned with a closed questionnaire. SUBJECTS: On the day of the visit a random sample of patients was taken and asked whether they had filled prescriptions for their own use. Out of a total of 1277 patients in the 28 pharmacies, 849 (66.5%) used the filled prescriptions themselves. Of these 849, 669 patients (78.8%) co-operated and completed a questionnaire pertaining to their perceptions and viewpoints of privacy in relation to the reporting of adverse drug reactions (ADR) and postmarketing surveillance studies. RESULTS: Of the respondents 94% had no objection to the reporting of ADR to the Inspectorate for Health Care by their medical practitioner or pharmacist. Among the respondents 77% did not object to the use of their medical data, even if these data were not anonymous, as long as the data were kept strictly confidential. Most patients were of the opinion that such data could be used without asking permission. Males would more readily give their permission than females. CONCLUSIONS: Most respondents did not have objections to the use of their medical data for postmarketing surveillance studies. The large majority of patients did not object to the reporting of ADR to the Inspectorate for Health Care.

Non-compliance in elderly people: evaluation of risk factors by longitudinal data analysis.

Studies on risk factors for drug non-compliance have not taken into account the possibility of correlated outcomes. We therefore conducted a study into risk factors for non-compliance by using analysis techniques that adjust for these correlations (longitudinal data analysis). Data were obtained from interviews and pharmacy records in a cross-sectional survey in Amsterdam. The subjects were 157 elderly people aged 70 years or older. Of these subjects, 37 were residents of a home for the elderly, 40 were community-dwelling elderly who needed to be visited regularly by a district nurse, and 80 were community-dwelling elderly who did not need to be visited by a district nurse. Most drugs (78%) were used according to the directions; the remainder (22%) were not used as intended. Odds ratios (95% confidence intervals) for non-compliance for moderate and poor/wrong knowledge of the purpose of a drug as compared with good/correct knowledge were 2.8 (1.2-6.7) and 4.2 (1.5-12), respectively. Drug regimens of two times daily and more than two times daily were associated with odds ratios for non-compliance of 4.5 (1.6-12) and 4.2 (1.7-11), respectively, compared to a regimen of once daily. Compliance increased if a drug was prescribed by a specialist instead of a general practitioner odds ratio 0.1 (0.04-0.4)]. There was no significant relation between compliance and the number of drugs prescribed to a patient, sex, age, living situation, patient group, or perceived effect. This study, which was based on longitudinal data analysis, demonstrates that in elderly people non-compliance with drug therapy is related to the knowledge of purpose of a drug, the complexity of a drug regimen, and the type of prescriber. The positive association between compliance and the number of drugs prescribed found in former studies was not confirmed.

[Discoloration of teeth by drugs]. / Meldingen van tandverkleuring door geneesmiddelen.

Since 1979 the Dutch Centre for Monitoring of Adverse Reactions to Drugs received 37 reports of tooth discoloration, attributed to the use of drugs. It concerned sixteen males and 21 females with an average age of respectively twelve and 26 years. Most cases were attributed to the use of amoxicillin (n = 16) and doxycycline or minocycline (n = 7). Pseudo-discolorations are chiefly caused by antimicrobial agents, possibly by chromogenic precipitates in the pellicle or by overgrowth with chromogenic micro-organisms.

Role of lipoxygenase products in the effects of angiotensin II in the isolated aorta and perfused heart of the rat.

The objective of this study was to determine whether arachidonate metabolites are involved in the vasoconstrictive effects of angiotensin II in rats. In the isolated perfused heart, dexamethasone (4 mg/kg) significantly suppressed the maximal decreases in coronary flow induced by angiotensin II and vasopressin (reference drug). In the heart, the nonselective lipoxygenase inhibitor nordihydroguaiaretic acid (NDGA, 1 muM) markedly suppressed the angiotensin II-induced decreases in coronary flow. NDGA (10 muM) inhibited both angiotensin II- and methoxamine- (reference drug) induced contractions in aortic rings with (in the presence of L-NAME) and without endothelium. In the heart, the leukotriene synthesis inhibitor MK-886 (0.3 muM) significantly reduced the maximal effects to angiotensin II, but the leukotriene antagonist FPL 55712 (0.1 and 0.3 muM) had no effect. We conclude that in the isolated perfused rat heart angiotensin II-induced decreases in coronary flow are in part mediated by Hpoxygenase products, which might be derived from the 5-Hpoxygenase pathway, but are probably not leukotrienes. Furthermore, endothelium independent Hpoxygenase products mediate part of the contractile responses to angiotensin II in the isolated rat aorta.

Comparison of the antiatherogenic effects of isradipine and ramipril in cholesterol-fed rabbits: I. Effect on progression of atherosclerosis and endothelial dysfunction.

This study was designed to compare the effects of a calcium antagonist (isradipine) and a converting enzyme inhibitor (ramipril) on progression and regression of atherosclerosis in hypercholesterolemic rabbits. Sixty rabbits in three groups were fed a 0.3% cholesterol diet for 4 weeks. After this induction period, group II received the 0.3% cholesterol diet, group III received cholesterol diet with isradipine (0.33 mg/kg/day), and group IV received cholesterol with ramipril (0.33 mg/kg/day) for 12 more weeks. A group of 20 rabbits received a standard diet throughout the study (group I). After 16 weeks, 10 rabbits were randomly chosen from each group and used in the progression study. The other rabbits were placed on a standard diet and remained on their respective drug regimen for 12 more weeks. In the progression phase of the study, ramipril significantly attenuated the percentage of aortic lesions in group IV (35 +/- 6%) as compared with group II (56 +/- 6%, p < 0.05), whereas isradipine had no effect. Acetylcholine (ACh)-induced maximum endothelium-dependent relaxations (EDR) of aortic rings were significantly reduced by the atherogenic diet to 37 +/- 4 versus 77 +/- 2% in group I (p < 0.05). Treatment with ramipril significantly improved maximum EDR to 53 +/- 3% (p < 0.05 vs. group II). Isradipine had no significant effect on impaired EDR. Aortic rings with endothelium from group II developed supersensitivity to sodium nitroprusside (SNP) and had significantly reduced basal cyclic GMP levels as compared with those of group I. Both drugs prevented development of supersensitivity to SNP and blunted the cholesterol-induced reduction in basal cyclic GMP levels.(ABSTRACT TRUNCATED AT 250 WORDS)