A survey on the implementation of clinical medication reviews in community pharmacies within a multidisciplinary setting.

BACKGROUND: Polypharmacy is common in chronic medication users, which increases the risk of drug related problems. A suitable intervention is the clinical medication review (CMR) that was introduced in the Netherlands in 2012, but the effectiveness might be hindered by limited implementation in community pharmacies. Therefore our aim was to describe the current implementation of CMRs in Dutch community pharmacies and to identify barriers to the implementation. METHODS: An online questionnaire was developed based on the Consolidated Framework for Implementation Research (CFIR) and consisted of 58 questions with open ended, multiple choice or Likert-scale answering options. It was sent out to all Dutch community pharmacies (n = 1,953) in January 2021. Descriptive statistics were used. RESULTS: A total of 289 (14.8%) community pharmacies filled out the questionnaire. Most of the pharmacists agreed that a CMR has a positive effect on the quality of pharmacotherapy (91.3%) and on medication adherence (64.3%). Pharmacists structured CMRs according to available selection criteria or guidelines (92%). Pharmacists (90%) believed that jointly conducting a CMR with a general practitioner (GP) improved their mutual relationship, whereas 21% believed it improved the relationship with a medical specialist. Lack of time was reported by 43% of pharmacists and 80% (fully) agreed conducting CMRs with a medical specialist was complicated. Most pharmacists indicated that pharmacy technicians can assist in performing CMRs, but they rarely do in practice. CONCLUSIONS: Lack of time and suboptimal collaboration with medical specialists are the most important barriers to the implementation of CMRs.

Implementation fidelity of a clinical medication review intervention: process evaluation.

Background Implementation of clinical medication reviews in daily practice is scarcely evaluated. The Opti-Med intervention applied a structured approach with external expert teams (pharmacist and physician) to conduct medication reviews. The intervention was effective with respect to resolving drug related problems, but did not improve quality of life. Objective The objective of this process evaluation was to gain more insight into the implementation fidelity of the intervention. Setting Process evaluation alongside a cluster randomized trial in 22 general practices and 518 patients of 65 years and over. Method A mixed methods design using quantitative and qualitative data and the conceptual framework for implementation fidelity was used. Implementation fidelity is defined as the degree to which the various components of an intervention are delivered as intended. Main outcome measure Implementation fidelity for key components of the Opti-Med intervention. Results Patient selection and preparation of the medication analyses were carried out as planned, although mostly by the Opti-Med researchers instead of practice nurses. Medication analyses by expert teams were performed as planned, as well as patient consultations and patient involvement. 48% of the proposed changes in the medication regime were implemented. Cooperation between expert teams members and the use of an online decision-support medication evaluation facilitated implementation. Barriers for implementation were time constraints in daily practice, software difficulties with patient selection and incompleteness of medical files. The degree of embedding of the intervention was found to influence implementation fidelity. The total time investment for healthcare professionals was 94 min per patient. Conclusion Overall, the implementation fidelity was moderate to high for all key components of the Opti-Med intervention. The absence of its effectiveness with respect to quality of life could not be explained by insufficient implementation fidelity.

Factors associated with antihypertensive medication non-adherence: a systematic review.

Non-adherence to antihypertensive medication is the most important cause of uncontrolled blood pressure and is influenced by multiple interrelating factors. Understanding the complexity of medication non-adherence and its associated factors is important to determine intervention strategies. Therefore, a systematic review was performed aimed to identify factors associated with antihypertensive medication non-adherence. Different databases were searched for observational studies reporting on factors associated with non-adherence to antihypertensive medication. Titles, abstracts and full texts were reviewed by three researchers. Subsequently, the methodological quality of each study was assessed. Factors that were extracted from the included studies were categorised as factors with consistent or inconsistent evidence to put their potential importance into perspective. Forty-four studies were included. Higher co-payment, side effects and a poor patient-provider relationship were identified as factors with consistent evidence since consistent significant relationships were found for these factors whenever studied. The relationships between non-adherence and multiple other factors were inconsistent among the reviewed studies. However, some of these factors deserve some consideration. Since multiple potentially relevant factors were identified, patient-tailored interventions focussing on identifying and addressing patients' specific barriers to adherence are needed. Further research should clarify the influence of inconsistent factors on adherence and their potential to be addressed in interventions.

The Use of Antidepressants, Anxiolytics, and Hypnotics in People with Type 2 Diabetes and Patterns Associated with Use: The Hoorn Diabetes Care System Cohort.

Objective. With depression being present in approximately 20% of people with type 2 diabetes mellitus (T2DM), we expect equally frequent prescription of antidepressants, anxiolytics, and hypnotics. Nevertheless, prescription data in people with T2DM is missing and the effect of depression on glycaemic control is contradictory. The aim of this study was to assess the prevalence of antidepressants, anxiolytics, and/or hypnotics use in a large, managed, primary care system cohort of people with T2DM and to determine the sociodemographic characteristics, comorbidities, T2DM medication, and metabolic control associated with its use. Method. The prevalence of antidepressants, anxiolytics, and/or hypnotics use in the years 2007-2012 was assessed in the Hoorn Diabetes Care System Cohort from the Netherlands. Results. From the 7016 people with T2DM, 500 people (7.1%) used antidepressants only, 456 people (6.5%) used anxiolytics and/or hypnotics only, and 254 people (3.6%) used a combination. Conclusion. We conclude that in our managed, primary care system 17% of all people with T2DM used antidepressants, anxiolytics, and/or hypnotics. Users of antidepressants, anxiolytics, and/or hypnotics were more often female, non-Caucasian, lower educated, and more often treated with insulin.

[Clinical medication reviews in elderly patients with polypharmacy: a cross-sectional study in Dutch community pharmacies]. / Medicatiebeoordelingen bij ouderen met polyfarmacie.

OBJECTIVE: To investigate the nature and prevalence of drug related problems (DRPs) in older patients with polypharmacy identified by community pharmacists in daily practice through means of a clinical medication review (CMR) and assess the implementation rate of proposed interventions to solve DRPs. DESIGN: A cross-sectional study METHOD: We analysed the CMR data of 3,807 older patients (≥ 65 years) with polypharmacy (≥ 5 drugs) completed in January-August 2012. Using the "Service Apotheek Medicatie Review Tool" (SAMRT, Service Pharmacy Medication Review Tool), pharmacists in 258 community pharmacies registered the patients' year of birth, gender, dispensing data, DRPs, and proposed and implemented interventions. RESULTS: Pharmacists identified a median of two DRPs (interquartile range 1-4; mean 3.0) per patient. The DRP categories overtreatment (25.5 %) and undertreatment (15.9 %) were found to occur most frequently. On average, 46.2 % of the proposed interventions to address DRPs were implemented as proposed. In 22.4 % of cases the intervention differed from the proposal, whereas in 31.3 % of cases no intervention was implemented. CONCLUSION: In daily practice, community pharmacists identified a mean of three DRPs in older patients with polypharmacy, a number comparable to that found in controlled studies. Over- or undertreatment caused nearly half of the identified DRPs. The majority (69.9%) of the proposed interventions led to an intervention for the patient.

Effectiveness of insulin therapy in people with Type 2 diabetes in the Hoorn Diabetes Care System.

AIMS: To identify HbA1c trajectories after the start of insulin treatment and to identify clinically applicable predictors of the response to insulin therapy. METHODS: The study population comprised 1203 people with Type 2 diabetes included in the Hoorn Diabetes Care System (n = 9849). Inclusion criteria were: age ≥ 40 years; initiation of insulin during follow-up after failure to reach HbA1c levels ≤ 53 mmol/mol (7%) with oral glucose-lowering agents; and a follow up ≥ 2 years after initiating insulin. Latent class growth modelling was used to identify trajectories of HbA1c . Subjects considered to be 'off target' had HbA1c levels ≥ 53 mmol/mol (7.0%) during one-third or more of the follow-up time, and those considered to be 'on target' had HbA1c levels ≥ 53 mmol/mol (7.0%) during less than one-third of the follow-up time. RESULTS: Four HbA1c trajectories were identified. Most people (88.7%) were classified as having a stable HbA1c trajectory of ~57 mmol/mol (7.4%). Only 24.4% of the people were on target in response to insulin; this was associated with lower HbA1c levels and a higher age at the start of insulin treatment. CONCLUSIONS: Using latent class growth modelling, four HbA1c trajectories were identified. A quarter of the people starting insulin were on target. Low HbA1c levels and advanced age at the start of insulin therapy were associated with better response to insulin therapy. Initiating insulin earlier improves the likelihood of achieving and sustaining glycaemic control.

A common polymorphism in the ABCB1 gene is associated with side effects of PGP-dependent antidepressants in a large naturalistic Dutch cohort.

The drug efflux transporter permeability glycoprotein (PGP) and cytochrome P450 (CYP) 2C19 are important for eliminating antidepressants from the brain and body. The ABCB1 gene, encoding for PGP, and CYP2C19 gene have several variants that could influence enzyme function and thereby the effect of PGP- and 2C19-dependent antidepressants. We investigated the association of antidepressant side effect and common genetic variation in 789 antidepressant users. In PGP-dependent antidepressant users, the A-allele of the rs2032588 single-nucleotide polymorphism (SNP) was associated with a lower number of side effects after adjusting for gender, age, dosage and duration of use, (B=-0.44, q=4.6 × 10(-3)). This association was different from and absent in non-PGP-dependent antidepressant users. Other SNP associations as well as an interaction analysis between the rs2032588 SNP and the CYP2C19 SNPs were not statistically significant after adjusting for covariates and multiple comparisons. The association of rs2032588 with antidepressant side effects suggests the involvement of the ABCB1 genotype in the clinical pharmacology of PGP-dependent antidepressants.

Discontinuation of statins among patients with type 2 diabetes.

BACKGROUND: Statins play an important role in the prevention of cardiovascular disease in type 2 diabetes. Several studies have reported low adherence with statins among patients with type 2 diabetes. Studies comparing discontinuation of statins compared with discontinuation of oral anti-diabetics within the same individuals before and after initiation of oral anti-diabetic drugs are not available. The aim of this study was to describe discontinuation among patients with type 2 diabetes prescribed statins prior to and after initiation of oral anti-diabetics and to compare statin discontinuation with discontinuation of oral anti-diabetics. METHODS: We report an observational cohort study among patients initiating treatment with statins prior to or after initiation of oral anti-diabetics between 1999 and 2007. Patients were classified as starting statins prior to initiation (Prior users) or after initiation (After users) of anti-diabetics. Discontinuation was defined as an interval of 180 days or more between the theoretical end date of a statin/anti-diabetic prescription and the dispensing date of the next statin/anti-diabetic prescription. RESULTS AND CONCLUSIONS: We included 3323 starters with oral anti-diabetic drugs in our study; 2072 patients initiated statins in the period of observation. Discontinuation rates for statins were higher compared with oral anti-diabetics (52.1 vs 15.0%). After users discontinued statin therapy more frequently compared to prior users (62.8 vs 48.2%). Discontinuation of statins is higher compared with anti-diabetic discontinuation. Patients starting statins after the initiation of oral anti-diabetic treatment are more likely to discontinue treatment than patients who initiate statins before the start of oral anti-diabetics.

Potential drug interactions in cancer therapy: a prevalence study using an advanced screening method.

BACKGROUND: In cancer patients, drug interactions may intensify adverse events or reduce antitumour effects. We assessed the prevalence of potential drug interactions (PDIs) among ambulatory cancer patients on i.v. treatment using an advanced screening method. PATIENTS AND METHODS: Data on drugs used for comorbidities, anticancer agents, over-the-counter (OTC) drugs, and comorbidities were collected by means of a structured interview among the patients and review of medical charts. PDIs were identified using electronic (Drug Interaction Facts software, version 4.0) and manual screening methods (peer-reviewed reports). RESULTS: In this study, 278 patients were enrolled. We identified 348 PDIs. Of all patients, 161 (58%) had at least one PDI. Of all PDIs, 34% was classified as major and 60% as moderate. Coumarins, quinolones, antiepileptics, and hydrochlorothiazide were frequently part of a PDI. Interactions that potentially cause QT interval prolongation, gastrointestinal toxicity, and central nervous system depression were also common. In multivariate analysis, an increasing number of drugs [odds ratio (OR) = 1.4, confidence interval (CI) 1.23-1.52; P < 0.001] and the use of an OTC drug (OR = 0.56, CI 0.32-0.97; P = 0.045) were risk factors. CONCLUSIONS: PDIs are common in patients treated for an (haemato-) oncological disease. Screening for potential interactions should take place routinely before administering chemotherapy.

Medication review and patient counselling at discharge from the hospital by community pharmacists.

AIMS: In 2001, the Association of Amsterdam Community Pharmacists adopted a programme to improve the pharmaceutical care of patients who were discharged from hospital with five or more drug prescriptions. A comprehensive protocol for pharmaceutical care at discharge (IBOM-1) was developed. The aim of the study was to evaluate the initial IBOM protocol and to study the effects of the protocol on drug therapy and patient satisfaction as well as on drug use compliance and mortality. METHOD: A controlled intervention study involving 37 community pharmacies and 715 of their registered patients who were discharged from a hospital and using at least five prescribed drugs in the years 2001-2003. The intervention included an extensive medication review and drug counselling at the patient's home. MAIN OUTCOME MEASURE: Pharmacy intervention activities, changes in medication, discontinuation of drugs prescribed at discharge, mortality, time spent on the intervention activities, and medication cost savings were all evaluated. Patient satisfaction was measured by means of a questionnaire. RESULTS: 379 and 336 patients were enrolled in the intervention and control groups, respectively. The mean number of drugs per patient not dispensed, concomitantly dispensed, or of which the quantity was changed was higher in the intervention group than in the control group (0.70 +/- 1.74 vs. 0.40 +/- 1.43, 0.11 +/- 0.40 vs. 0.038 +/- 0.26, and 0.29 +/- 1.05 vs. 0.097 +/- 0.52, respectively). The mean number of drugs for which the dose or dosage form was changed was similar in both groups. Substitution of brand for generic or vice versa was greater in the intervention group. Changes resulting from a PAIS signal were similar in both groups. The mean number of drugs per patient for which contact was required with the physician or the Pharmacy Hospital Service Desk was higher in the intervention group (0.35 +/- 0.51 vs. 0.16 +/- 0.38). About 40% of home visits resulted in the clearing of redundant drug supplies. The IBOM-1 intervention did not influence discontinuation of drugs prescribed at discharge, nor did it influence mortality. Medication costs were slightly reduced. More patients of intervention pharmacies than of control pharmacies indicated that they were (very) satisfied with the drug counselling by their community pharmacist upon delivery of their discharge medication (87% vs. 50%; chi(2) < 0.001). CONCLUSIONS: Structured pharmaceutical care according to the IBOM-1 protocol led to more changes in drug therapy. Home visits resulted in the clearing of redundant home drug supplies. In addition, patients were highly satisfied with the counselling at discharge from hospital by their community pharmacist. Patient counselling at discharge from hospital by pharmacists, therefore, appears to be a meaningful pharmaceutical care activity.

Evaluation of a pharmacotherapy context-learning programme for preclinical medical students.

AIM: To evaluate a context-learning pharmacotherapy programme for approximately 750 2nd, 3rd and 4th year preclinical medical students with respect to mastering cognitive pharmacotherapeutic skills, i.e. choosing a (drug) treatment and determining patient information. METHODS: The context-learning pharmacotherapy programme consists of weekly organized role play sessions in the form of consulting hours. Fourth year students sit for a therapeutic Objective Structured Clinical Examination (OSCE) in the form of consulting hours at the outpatient clinic. Sixty-one 2nd, 74 3rd and 49 4th year medical students who attended the role play sessions and the OSCE were randomly selected. Their performances were assessed by clinical examiners and clinical experts and compared with a reference group of 6th year graduated students. Additionally, the scores of a questionnaire on study load and appreciation were collected. RESULTS: The level of the pharmacotherapeutic skills of the 4th year students who followed the pharmacotherapy context-learning programme was not far below that of 6th year graduates who had finished their clinical clerkships, but had not followed the pharmacotherapy programme. The time spent on the programme was about 1% of the total study load per year. The students appreciated the role play sessions and OSCE by around 80% and 99% of the maximum possible scores. CONCLUSIONS: Preclinical pharmacotherapy context learning has a modest but positive effect on learning cognitive pharmacotherapeutic skills, i.e. choosing a drug treatment and determining patient information. This effect has been obtained with role play sessions, a suboptimal form of context learning, with a minimal study load and a high appreciation by students.

Curriculum development in pharmacotherapy: testing the ability of preclinical medical students to learn therapeutic problem solving in a randomized controlled trial.

AIMS: To determine whether preclinical medical students are able to learn therapeutic problem solving simultaneously with gaining knowledge of pharmacology. METHODS: A randomized controlled pre/post-test study among 85 3rd year preclinical medical students from two medical faculties in Amsterdam. In addition to the normal curriculum, the study group followed a course, which was a copy of the obligatory training in cognitive therapeutic skills for 5th year students who had gained knowledge first, followed by applying the knowledge. Before, immediately after and 9 months after the training both the study group and a control group took a test (T0, T1, T2). The level of knowledge and cognitive therapeutic skills were assessed. As a reference, 38 5th year students also took the tests. RESULTS: On T0 the levels of cognitive therapeutic skills of the study and control groups were similar (26.7% and 27.4% of the required level for graduation, respectively). On T1 and T2, the study group scored significantly higher compared with the control group: 46.0/36.7% and 41.3/36.3%, respectively (P<0.05). In comparison with T0, the scores of the study group on T1 increased significantly and showed no significant decline on T2. There were no differences between the groups with respect to the level of knowledge in any of the three tests. The level of cognitive therapeutic skills in the 5th year reference group increased slightly but not significantly from 40.3% to 44.5% after the training; the level of knowledge increased significantly from 48.8% to 68.0%. CONCLUSIONS: Preclinical medical students are able to learn cognitive therapeutic skills simultaneously with gaining knowledge of pharmacology.

Initial phase of chronic medication use; patients' reasons for discontinuation.

AIM: The aim of this study was to gain more insight into patients' reasons for discontinuing chronic medication. METHODS: Electronic medication overviews recorded by a pharmacy were analysed with respect to patients' return behaviour during 3 months following their first prescription. Patients who did not return in time were interviewed by telephone to find out their reasons for either returning too late or not returning at all to the pharmacy to collect their repeat medication. RESULTS: Of 232 first-time chronic medication prescriptions, 132 were not collected at all (46.1%) or too late (11%). These prescriptions involved 121 patients, 113 (93.4%) of whom participated in the telephone interview. Twenty patients returned too late to collect their repeat prescriptions, largely because they had forgotten to take their medication according to schedule (n=13). Ninety-three patients did not return to the pharmacy at all because of side-effects (24.5%), inefficacy (16.4%), medication not intended for chronic use (15.3%) and absence of need for continued use (14.3%). CONCLUSIONS: About 50% of patients who have been prescribed chronic medication for the first time stop using their drugs within a matter of months. Perceived drug side-effects, drug ineffectiveness and personal considerations related to use and a lack of need of treatment were the main reasons for discontinuing chronic drug therapy. This kind of noncompliance may result in an increased health risk as well as constituting a waste of a large amount of money. Adequate patient counselling and shared decision-making between doctors and patients are needed to prevent the unnecessary cessation of chronic drug therapy.

Discontinuation symptoms in users of selective serotonin reuptake inhibitors in clinical practice: tapering versus abrupt discontinuation.

OBJECTIVE: Tapering of selective serotonin reuptake inhibitor (SSRI) therapy, as opposed to abrupt discontinuation, has been recommended by several guidelines and in the literature in order to diminish the occurrence of discontinuation symptoms. However, the evidence of a favourable effect of tapering is limited, and it is unclear how patients ought to discontinue SSRIs in daily life. The aim of this study was to examine the way in which patients discontinue SSRI therapy in clinical practice and to compare the effect of tapering with that of abrupt discontinuation on the occurrence of discontinuation symptoms. METHODS: Patients (n = 74) who recently discontinued SSRI therapy completed a questionnaire containing questions about discontinuation symptoms (DESS events), the prescribed SSRI, reasons for discontinuation, way of discontinuation, knowledge of discontinuation symptoms, impact on daily life and patient counseling and education. The number of DESS events was compared among groups (abrupt discontinuation versus tapering; age; male versus female; paroxetine versus other SSRIs; knowledge of discontinuation symptoms at start of therapy versus lack of knowledge). RESULTS: A total of 66 patients were eligible for analysis. Of all patients ending SSRI therapy, 21% abruptly discontinued therapy. There was a significant difference in the number of DESS events between abrupt discontinuation and tapering of SSRI therapy (12.0 versus 5.9). There was also a tendency for an adverse effect of lack of knowledge of discontinuation symptoms at the start of therapy on the number of DESS events (8.9 versus 5.5). CONCLUSION: One in five patients abruptly discontinued their SSRI therapy in clinical practice. Abrupt discontinuation caused a larger increase in the number of discontinuation symptoms than tapering. We therefore advise tapering SSRI therapy in clinical practice to prevent unnecessary adverse effects of discontinuation.

Increased psychotropic drug consumption by children in the Netherlands during 1995-2001 is caused by increased use of methylphenidate by boys.

OBJECTIVE: The aim of the study was to determine the changes in consumption of psychotropic drugs by children aged less than 18 years during the years 1995 to 2001 in the Netherlands. METHODS: The year prevalence of antipsychotics, benzodiazepines, antidepressants and psychostimulants for boys and girls under 18 years was determined using electronic pharmacy dispensing records obtained from the PHARMO database. RESULTS: The overall prevalence of psychotropic drugs increased from 11.1 per 1000 in 1995 to 22.9 per 1000 in 2001. This increase could almost completely be attributed to the increase in the use of psychostimulants, i.e. methylphenidate, which increased from 1.7 per 1000 children in 1995 to 10.0 per 1000 in 2001. For the other psychotropic drugs, no or only a small increase was seen. For both boys and girls, the use of psychostimulants was highest in the age group of 5-14 years. CONCLUSION: During the years 1995-2001, the consumption of psychotropic drugs by children in the Netherlands has more than doubled. This increase could largely be attributed to an increased use of the psychostimulant methylphenidate by boys of the age 5-14 years.

Communicating with patients the second time they present their prescription at the pharmacy. Discovering patients' drug-related problems.

OBJECTIVE: To assess the effect of a short inquiry the second time that the prescription was presented at the pharmacy (SP) counter on the detection of drug related-problems as perceived by patients in a community pharmacy. The implementation of the SP procedure is also described. METHOD: At SP patients were asked to give a short description of their experience with their newly prescribed drug. Patients' drug-related problems were recorded on a SP form and were categorised into three groups: side effects, inefficacy, and problems with use or instruction. Data were also matched with drug categories. The ATC classification was used. A comparison with a control pharmacy was made. MAIN OUTCOME MEASURES: Drug experience, patients' drug-related problems, side effects, inefficacy, problems with the use or instruction. RESULTS: Data from 700 SP forms showed that in 78% of cases patients did not have problems with the use of their new drugs. In the remainder of cases (22%), drug-related problems mainly concerned side effects (49%; 76 out of 156) and complaints about the drugs not being as effective as expected (inefficacy: 49%; 77 out of 156). In the control pharmacy no drug-related problems were detected in 30 SP contacts. Patients using gastrointestinal drugs reported fewer side effects than patients using cardiovascular drugs. Patients using respiratory drugs reported more often that the drug was not effective than patients using cardiovascular drugs. CONCLUSION: It was concluded that the SP procedure encourages patients to report their drug problems at the counter in the pharmacy.

The influence of calcium antagonists on the adenine nucleotide metabolism in the guinea-pig working heart during ischaemia and reperfusion.

With the aim of gaining more insight into the metabolism of adenine nucleotides in working normoxic guinea-pigs and in hearts subjected to 45 min of global ischaemia and subsequent reperfusion for 25 min, we evaluated the effect of nifedipine, verapamil, diltiazem, bepridil, CERM 11956, lidoflazine, mioflazine and dipyridamole on the adenine nucleotide catabolite levels in these hearts. The drugs were applied at the concentrations that reduced the aortic dP/dt of normoxic working hearts by 10% (EC10) and 30% (EC30). In globally ischaemic hearts there was a large accumulation of adenine nucleotide catabolites. Inosine proved to be the major catabolite. The drugs, with the exception of bepridil, CERM 11956 and dipyridamole (3 mumol/l), decreased the accumulation of catabolites. In hearts treated with mioflazine and dipyridamole the amount of adenosine increased. A deficit in the balance between adenine nucleotides and catabolites indicated that in globally ischaemic hearts there was a large accumulation of inosine monophosphate. Indeed, a substantial amount of inosine monophosphate was determined in untreated hearts, and hearts treated with nifedipine (EC30) and mioflazine (EC10). During the first 5 min of reperfusion a large quantity of catabolites, mainly inosine, was washed out. During 20 min of subsequent reperfusion in untreated hearts and in nifedipine and mioflazine-treated hearts the efflux of catabolites returned to normoxic values. Similar to the effect in ischaemic hearts, in early perfusate from lidoflazine, mioflazine and dipyridamole-treated hearts the adenosine/inosine ratio was increased.(ABSTRACT TRUNCATED AT 250 WORDS)

The influence of nifedipine and mioflazine on mitochondrial calcium overload in normoxic and ischaemic guinea-pig hearts.

The influence of nifedipine (20 nM) and mioflazine (300 nM), i.e. concentrations inducing a 60-70% recovery of cardiac function during reperfusion of globally ischaemic guinea-pig working hearts, on the mitochondrial calcium content was investigated in normoxic, globally ischaemic and reperfused globally ischaemic guinea-pig working hearts. Mitochondrial calcium was determined electronmicroscopically with oxalate-pyroantimonate method. In normoxic hearts both nifedipine and mioflazine reduced the mitochondrial calcium content. Global ischaemia for 45 min and subsequent reperfusion for 25 min resulted in a pronounced mitochondrial calcium overload and damage to the cellular structure. In ischaemic and in reperfusion hearts the drugs maintained mitochondrial calcium at pre-ischaemic levels and decreased the damage to the cellular structure.

Differences between negative inotropic and vasodilator effects of calcium antagonists acting on extra- and intracellular calcium movements in rat and guinea-pig cardiac preparations.

In order to get more insight into the utilization of calcium in the mammalian heart and the influence of calcium antagonists on this process we have evaluated the negative inotropic and vasodilator effect of nifedipine, diltiazem, verapamil, bepridil and lidoflazine as well as of the intracellularly acting calcium antagonists ryanodine and TMB-8 in the presence of 0.9 and 1.8 mmol/l calcium in rat Langendorff hearts. The effect of ryanodine was also studied in guinea-pig Langendorff hearts. In addition, in rat and guinea-pig papillary muscles the effect of these drugs on the force of contraction was examined. With the exception of ryanodine and TMB-8 all calcium antagonists induced a pronounced coronary vasodilator effect. The rank order of potency for this effect was: nifedipine greater than verapamil = diltiazem = bepridil = lidoflazine in the presence of 0.9 mmol/l calcium. At a calcium concentration of 1.8 mmol/l nifedipine and verapamil proved more potent, whereas diltiazem was less active. All calcium antagonists completely suppressed the development of the left ventricular pressure. At a calcium concentration of 0.9 mmol/l the potency order for this effect was: ryanodine greater than nifedipine = verapamil greater than diltiazem = bepridil = lidoflazine greater than TMB-8. In the presence of 1.8 mmol/l calcium the concentration-response curves for reduction of the left ventricular pressure by nifedipine, verapamil and diltiazem slightly shifted to the right. In contrast to all calcium antagonists investigated, in guinea-pig Langendorff hearts ryanodine only partially decreased the left ventricular pressure.(ABSTRACT TRUNCATED AT 250 WORDS)

The differential effect of calcium antagonists on the positive inotropic effects induced by calcium and monensin in cardiac preparations of rats and guinea-pigs.

It was the aim of the present study to gain more insight into the role of extracellular calcium and of calcium from intracellular sources in the development of contractile force in the mammalian heart. In rat Langendorff hearts the effect of nifedipine, verapamil, diltiazem, bepridil and lidoflazine as well as of the intracellularly acting calcium antagonists ryanodine and TMB-8 on the increase of the left ventricular pressure induced by calcium and the sodium ionophore monensin, respectively, was studied. In rat and guinea-pig papillary muscles the influence of nifedipine, ryanodine and lidoflazine on the effect of monensin on the force of contraction was evaluated. Calcium and monensin concentration-dependently increased the left ventricular pressure in rat Langendorff hearts. The calcium-induced effect was characterized by a sharp initial rise of the left ventricular pressure which stabilized at a lower level while monensin elicited a gradual rise of the left ventricular pressure. Nifedipine, verapamil and diltiazem, applied at the EC50 and the EC80 for the reduction of the left ventricular pressure under control conditions, shifted the concentration-response curves for calcium and monensin into the right. Ryanodine, TMB-8, lidoflazine and bepridil, applied at the EC50, displaced the concentration-response curves for calcium and monensin to the right but reduced the maximal increase of the left ventricular pressure. At the EC80, these drugs almost completely abolished the positive inotropic effects elicited by calcium and monensin, respectively. In rat papillary muscles monensin did not influence the basal force of contraction. A clear positive inotropic effect was only observed in the presence of nifedipine.(ABSTRACT TRUNCATED AT 250 WORDS)