An inventory of collaborative medication reviews for older adults - evolution of practices.

BACKGROUND: Collaborative medication review (CMR) practices for older adults are evolving in many countries. Development has been under way in Finland for over a decade, but no inventory of evolved practices has been conducted. The aim of this study was to identify and describe CMR practices in Finland after 10 years of developement. METHODS: An inventory of CMR practices was conducted using a snowballing approach and an open call in the Finnish Medicines Agency's website in 2015. Data were quantitatively analysed using descriptive statistics and qualitatively by inductive thematic content analysis. Clyne et al's medication review typology was applied for evaluating comprehensiveness of the practices. RESULTS: In total, 43 practices were identified, of which 22 (51%) were designed for older adults in primary care. The majority (n = 30, 70%) of the practices were clinical CMRs, with 18 (42%) of them being in routine use. A checklist with criteria was used in 19 (44%) of the practices to identify patients with polypharmacy (n = 6), falls (n = 5), and renal dysfunction (n = 5) as the most common criteria for CMR. Patients were involved in 32 (74%) of the practices, mostly as a source of information via interview (n = 27, 63%). A medication care plan was discussed with the patient in 17 practices (40%), and it was established systematically as usual care to all or selected patient groups in 11 (26%) of the practices. All or selected patients' medication lists were reconciled in 15 practices (35%). Nearly half of the practices (n = 19, 44%) lacked explicit methods for following up effects of medication changes. When reported, the effects were followed up as a routine control (n = 9, 21%) or in a follow-up appointment (n = 6, 14%). CONCLUSIONS: Different MRs in varying settings were available and in routine use, the majority being comprehensive CMRs designed for primary outpatient care and for older adults. Even though practices might benefit from national standardization, flexibility in their customization according to context, medical and patient needs, and available resources is important.

Internet as a source of medicines information (MI) among frequent internet users.

BACKGROUND: The internet is widely and increasingly used to search for health information. Previous studies have focused mainly on health information on the internet and not specifically on medicines information (MI). OBJECTIVES: The aim of this study was to explore the internet as a source of MI compared to other sources of MI; to identify those who use the internet as a source of MI; and to describe patterns of use of the internet as a source of MI. METHODS: A cross-sectional design employed a web-based questionnaire posted by patients' and other organizations as well as pharmacies on their websites during six weeks in the beginning of 2014. Logistic regression analysis was used to assess associations of background variables to the use of different MI sources. RESULTS: The most frequently used MI sources among respondents (n = 2489) were package leaflets (90%), pharmacists (83%), physicians (72%), and the internet (68%). According to a multivariate analysis, internet use for MI was associated with female gender, age <65 years, higher education, daily use of the internet, and continuous use of vitamins or herbals. MI was most commonly searched from a Finnish health portal (56%) and websites of pharmacies (41%). Of the respondents, nearly half (43%) used search engines to find information from the internet. The names of the medicinal product, symptom or disease were the most commonly used search terms. CONCLUSIONS: Well-educated, young women tend to search MI on the internet. Health care professionals should discuss reliable MI websites and tools that can help patients evaluate the reliability of information.

Medication review practices in European countries.

BACKGROUND: Medication review procedures have been developed in many countries to improve rational and safe medication use. The similarities, comprehensiveness, and effectiveness of these procedures has not been assessed, or compared. OBJECTIVE: The aim of this study was to explore medication review practices in European countries. METHODS: An online survey was sent to 32 European countries (all 28 European Union countries and 4 other European countries) by email to one person in each country known to be aware of medication review practices in their country in May 2011. The informants were identified through Pharmaceutical Group of European Union. To complement and validate the information received through Pharmaceutical Group of European Union, medication review experts involved in Pharmaceutical Care Network Europe were contacted. The survey assessed comprehensiveness of the medication review procedures classified according to 3 types in terms of settings; access to patient clinical information; patient involvement; availability of documentation and information; collaboration with the physician; quality control, and training required. RESULTS: Almost two thirds (64%) of the 25 European countries which responded (response rate 78%) indicated having at least one type of medication review procedure in their country. In the community setting prescription (type I) and adherence (type II) medication reviews were the most common (established in 9 and 11 countries, respectively). More comprehensive type III clinical medication reviews requiring access to clinical patient information were still rare, and just being established in 6 countries. CONCLUSIONS: Medication review procedures are becoming common in health care throughout Europe, however improving their comprehensiveness would require better access to patient information for those professionals conducting clinical medication reviews. In addition to benchmarking, the inventory can enhance cooperation between countries and stakeholders involved in medication review practice development nationally and internationally.

Evaluation of the cytotoxicity of selected systemic and intravitreally dosed drugs in the cultures of human retinal pigment epithelial cell line and of pig primary retinal pigment epithelial cells.

The cytotoxicity of the selected systemic and intravitreally dosed drugs tamoxifen, toremifene, chloroquine, 5-fluorouracil, gentamicin and ganciclovir was studied in retinal pigment epithelium (RPE) in vitro. The cytotoxicity was assayed in the human RPE cell line D407 and the pig RPE cell culture using the WST-1 test, which is an assay of cell proliferation and viability. The effects of experimental conditions on the WST-1 test (cell density, serum content in the culture medium, the exposure time) were evaluated. The EC50 values in tamoxifen-treated D407 cells ranged between 6.7 and 8.9 micromol/l, and in pig RPE cells between 10.1 and 12.2 micromol/l, depending on the cell density used. The corresponding values for toremifene were 7.4 to 11.1 micromol/l in D407 cells and 10.0 to 11.6 micromol/l in pig RPE cells. In chloroquine-treated cells, the EC50 values were 110.0 micromol/l for D407 cells and 58.4 micromol/l for pig RPE cells. Gentamicin and ganciclovir did not show any toxicity in micromolar concentrations. The exposure time was a significant factor, especially when the drug did not induce cell death, but was antiproliferative (5-fluorouracil). Serum protected the cells from the toxic effects of the drugs. Both cell cultures were most sensitive to tamoxifen and toremifene, and next to chloroquine. The drug toxicities obtained in the present study were quite similar in both cell types; that is, the pig RPE cells and the human D 407 cell line, despite the differences in, for example, the growth rate and melanin contents of the cell types. Owing to the homeostatic functions important for the whole neuroretina, RPE is an interesting in vitro model for the evaluation of retinal toxicity, but, in addition to the WST-1 test, more specific tests and markers based on the homeostatic functions of the RPE are needed.

Interferon-alpha and 13-cis-retinoic acid as maintenance therapy after high-dose combination chemotherapy with growth factor support for small cell lung cancer--a feasibility study.

This randomized phase II multi-center study was designed to determine the time to progression, duration of response and the feasibility of an intensified maintenance regime consisting of a combination of interferon (IFN)-alpha and retinoic acid after high-dose combination chemotherapy and radiotherapy in patients with small cell lung cancer. The patients received four courses of combination chemotherapy consisting of ifosfamide, carboplatin and etoposide, with higher doses of ifosfamide and carboplatin given in the first course, with routine growth factor support. Responding patients were then randomly assigned to one of three maintenance therapy arms. All patients with limited disease (LD) were given thoracic radiotherapy before maintenance therapy and those who had also achieved a complete response (CR) or minimal residual disease (MRD) received prophylactic cranial irradiation. In Arm 1 patients received IFN-alpha-2a, 6 MIU s.c. TIW for 4 weeks, followed by 3 MIU s.c. TIW, and 13-cis-retinoic acid 1 mg/kg/day p.o. BID daily. In Arm 2 patients received trophosphamide 100-150 mg/day p.o. BID. No maintenance treatment was given in Arm 3, the control group. Maintenance therapy was continued for 1 year. Eighty-five patients were treated according to the protocol. Twenty-one patients achieved CR, four achieved MRD and forty-two achieved partial responses to chemotherapy and radiotherapy. Sixty patients (71%) were randomly assigned for maintenance treatment. Median survival was 17.1 months in the IFN-alpha-retinoic acid arm, 12.4 months in the trophosphamide arm and 13.5 months in the control arm. One-year survival rates were 82, 56 and 55%, respectively. Duration of response was 6.5, 5.5 and 4.7 months, respectively. Time to progression was 8.6, 8.0 and 6.8 months, respectively The differences were not statistically significant. The IFN-alpha-retinoic acid maintenance treatment was well tolerated. Patients who received IFN-alpha-retinoid maintenance therapy lived longer after the onset of progressive disease. The treatment regime was effective, feasible and well tolerated.

Phase II study of vinorelbine and gemcitabine for inoperable stage IIIB-IV non-small-cell lung cancer.

PURPOSE: To evaluate the efficacy of the combination of vinorelbine and gemcitabine as a non-platinum chemotherapy regimen in patients with inoperable locally-advanced or metastatic non-small-cell lung cancer (NSCLC). Efficacy was assessed primarily in terms of response rate, and secondarily in terms of toxicity, time to progression and survival. PATIENTS AND METHODS: Patients with cytologically- or histologically-proven stage IIIB-IV NSCLC, bi-dimensionally measurable lesions, adequate haematological, hepatic and renal function, WHO performance status < or = 2 and no previous chemotherapy or radiotherapy were eligible. The first 12 patients were entered in a pilot study and received vinorelbine (VNR) 30 mg/m2 on days 1, 8, 15 and 22, and gemcitabine (GEM) 1000 mg/m2 on days 1, 8 and 15, of a 28-day cycle. Subsequently, patients were entered in a phase II trial of VNR 35 mg/m2 and GEM 1200 mg/m2 on days 1 and 15 of each 28-day cycle. Treatment consisted of three cycles of the chemotherapy, with a further three cycles for those patients who achieved stable disease or a complete or partial response (CR/PR) to the first three cycles. Patients who had achieved CR or PR after six cycles continued with the treatment until relapse. RESULTS: The dosage and scheduling of VNR and GEM in the pilot study resulted in neutropenia necessitating reductions or delays in treatment, and consequently low dose intensity. The schedule was thus modified to VNR 35 mg/m2 and GEM 1200 mg/m2 on days 1 and 15 of each 28-day cycle for the phase II trial. Thirty-three patients were enrolled in the phase II trial, and 28 were evaluable for response. The overall intent-to-treat response rate of all 45 patients was 40% (18 of 45), comprising 4 CR (9%) and 14 PR (31%). For the 28 evaluable patients who received the fortnightly chemotherapy the response rate was 46% (13 of 28), CR 11% (3 of 28) and PR 36% (10 of 28). Seven patients (25%) had stable disease. The one-year cumulative survival rate for the 33 patients receiving the fortnightly chemotherapy was 24% and median time-to-progression 4 months (range 1-16 months). Median survival for these patients was eight months. Nine out of twelve patients in the pilot study (75%) suffered grade 3-4 neutropenia. There was one toxic death, attributed to neutropenic fever and sepsis, and two cases of pulmonary embolism. One patient suffered Grade 4 thrombocytopenia. Only eight patients (24%) on the fortnightly schedule suffered grade 3-4 neutropenia, resulting in dose reductions or delays for three of them (9%). None of the patients on the fortnightly schedule suffered thrombocytopenia or anaemia. CONCLUSIONS: The fortnightly schedule of gemcitabine and vinorelbine was a well-tolerated out-patient regimen, producing response and survival rates comparable to those of cisplatin combination regimens, but with a more favourable toxicity profile. Gemcitabine and vinorelbine should now be tested in a triplet combination with a taxane as the third drug, or against a platinum-containing regimen in a phase III study.

High-dose methotrexate in combination with interferons in the treatment of malignant pleural mesothelioma.

Twenty six patients with pleural mesothelioma of UICC stage I-IV excluding M1 disease (46% of whom had stage I disease and 38% stage III disease) were treated intravenously with high dose MTX (3 g) and calcium folinate rescue three times at intervals of 2 weeks and three times at intervals of 3 weeks. Natural interferon (IFN)-alpha (3 MIU days 2-10) and recombinant IFN-gamma1b (50 microg m(-2) on days 2, 6 and 10) were injected subcutaneously after each MTX dose. At the end of MTX treatment the IFNs were continued as maintenance therapy until disease progression. Seven partial responses were observed among 24 patients evaluable for response (response rate 29%, 95% confidence interval 13-51%). Median duration of response was 10 months (range 3-24 months). Median survival was 17 months and 1-year and 2-year survival rates 62% and 31% respectively. The toxicity of the chemo-immunotherapy was acceptable. Treatment was stopped in one patient who developed grade IV neurological toxicity. MTX dose reductions were rare (two patients with grade 1-2 renal toxicity). The combination of high dose MTX and IFN-alpha and IFN-gamma is active against malignant pleural mesothelioma and well-tolerated. The survival rates are encouraging.

Concomitant chemotherapy and IFN-alpha for small cell lung cancer: a randomized multicenter phase III study.

Patients with any stage of small cell lung cancer were given low-dose interferon-alpha (IFN-alpha) from the first day of treatment as long as possible irrespective of changes in treatment dictated by disease progression. All patients received 6 cycles of the chemotherapy (CT): cisplatin 70 mg/m2 i.v. day 1 and etoposide 100 mg/m2 i.v. days 1, 2, 3 every 28 days. Seventy-eight patients were assigned to arm 1: CT alone, 75 patients to arm 2: CT + natural IFN-alpha (3 MU three times a week i.m.), and 66 patients to arm 3: CT + recombinant IFN alpha-2a (3 MU three times a week i.m.). There was no difference in median survival between the arms (10.2 months, 10.0 months, 10.1 months, respectively), p = 0.32. The 2-year survival rates were 15%, 3%, and 11%, respectively. Grade 3 and 4 leukopenia occurred more frequently in the IFN arms than in the CT alone arm and resulted in dose reductions. Antibodies occasionally developed to recombinant IFN. We conclude that IFN-alpha can be administered concomitantly with chemotherapy but is probably better kept for maintenance therapy so that optimal full doses of induction CT can be given.

Expression of cytochrome P450 genes encoding enzymes active in the metabolism of tamoxifen in human uterine endometrium.

Long-term tamoxifen therapy is associated with increased risk of uterine endometrial cancer and benign alterations. Tamoxifen is metabolized to reactive intermediates by endometrial tissue, and tamoxifen therapy-induced DNA adducts have been found in human endometrium. Since metabolic activation is often catalyzed by cytochrome P450 (CYP) enzymes, the expression profile of individual xenobiotic-metabolizing CYP genes was studied in human uterine endometrium by reverse transcriptase-polymerase chain reaction. The following CYP mRNAs were detected: CYP2B6, CYP2C, CYP2E1, CYP3A4, CYP3A5, CYP4B1, and CYP11A. Amplification of CYP1A1, CYP1A2, CYP2A6, CYP2D6, CYP2F1, CYP3A7, and CYP19 was not found. CYP3A5 and CYP4B1 transcripts were found only in samples from premenopausal women. These data suggest that the human endometrial epithelium has the potential of producing CYP enzymes known to generate genotoxic intermediates from tamoxifen and metabolites that affect oestrogen receptors.

Expression of CYP1B1 in human adult and fetal tissues and differential inducibility of CYP1B1 and CYP1A1 by Ah receptor ligands in human placenta and cultured cells.

Expression of the Ah receptor-regulated cytochrome P4501B1 (CYP1B1) gene was studied in human adult and fetal tissues and cells in culture by reverse transcriptase-coupled polymerase chain reaction (RT-PCR). In adults, CYP1B1 mRNA was detected in liver, lymphocytes, cells of bronchoalveolar lavage samples and uterine endometrium, but not in lung. The level of expression was very low in adult liver and only three out of six fetal livers expressed CYP1B1. Extrahepatic fetal tissues, especially brains and kidneys, expressed high levels of CYP1B1. CYP1B1 mRNA was constitutively detected at a low level in first trimester and full-term placental samples. A competitive RT-PCR assay was developed to assess the regulation of CYP1B1. CYP1B1 mRNA was not induced in placenta by maternal cigarette smoking. Inducibility of CYP1B1 in cells in culture by the Ah receptor ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin was studied in primary fibroblasts and chorion carcinoma cell line JEG-3 having different CYP1A1 induction properties. Inducibility of CYP1B1 was found to be regulated independently from CYP1A1. In JEG-3 cells CYP1A1 mRNA was induced up to 9000-fold, while the expression of CYP1B1 was not affected. Expression of Ah receptor and Ah receptor nuclear translocator (regulators of the CYP1 family) was determined in human placenta and in the JEG-3 cell line. Expression of these transcription factors was found neither to be co-regulated nor affected by Ah receptor ligands. This study provides evidence that in addition to the Ah receptor complex, other cell-specific factors modulate the response of CYP1B1 and CYP1A1 to Ah receptor ligands.

Interferon maintenance therapy for small cell lung cancer: improvement in long-term survival.

Two hundred thirty-seven patients with small cell lung cancer (SCLC), who had responded to induction chemotherapy and radiotherapy, were randomly assigned to receive low-dose natural interferon-alpha (nIFN alpha) for 6 months; or 6 cycles of maintenance chemotherapy (CAP); or no maintenance therapy (control group). Although there was no difference in median survival between the groups, there was a significant difference (p = 0.04) in the long-term survival of patients with limited disease, in favour of nIFN alpha maintenance therapy. This finding is now confirmed by a further analysis of the most recent data. Ten percent of patients in the IFN group survived for five years or more, but the 5-year-survival rate in the CAP and control groups was only two percent. All long-term survivors had good performance status. The majority had limited disease and had achieved a complete response to the induction therapy. These results suggest that interferon-alpha improves the long-term survival of SCLC patients for whom other prognostic factors are favorable.

Altered fractionation of hemithorax irradiation for pleural mesothelioma and failure patterns after treatment.

Malignant pleural mesothelioma is a rare malignancy with a bleak prognosis. The role of radiotherapy has not yet been clarified. Our aim was to study the effect of altered fractionation on mesothelioma. We have treated 57 patients, 41 males and 16 females, with hemithorax irradiation with six different fractionation schedules. All the patients have been included in a combined modality program consisting of surgery followed by chemotherapy and finally by hemithorax irradiation. The radiotherapy schedules used were: I. Conventional fractionation of 20 Gy in 10 fractions over 12 days. II. Split-course radiotherapy 55 Gy in 25 fractions of 2.2 Gy over 7 weeks (a two weeks rest halfways) followed by a boost dose of 15 Gy over 8 days to the major tumour area. III. Hyperfractionation of 70 Gy over 7 weeks, 1.25 Gy BID with a 6-h interval and a 10-day rest halfways. IV. Combined hyperfractionation and hypofractionation, 35 Gy hyperfractionation in 28 fractions (1.25 Gy BID with a 6-h interval) over three weeks followed by 36 Gy hypofractionation 9 fractions of 4 Gy given every other day over 3 weeks to the major tumour areas only. V. Hypofractionation of 38.5 Gy over 15 days (9 x 3.5 Gy). VI. Combined conventional radiotherapy and hypofractionation with 20 Gy given conventionally in 10 fractions followed by 10 fractions of 3 Gy over two weeks, overall time 4 weeks. The 2-year survival rate of all patients was 21% and the 5-year survival rate 9%. Two patients are still alive more than 6 and 9 years after radiotherapy. Progression occurred after surgery in four patients, during and after chemotherapy in 22 patients and after completed radiotherapy in 29 patients. The pattern of progression was similar in each treatment group.

Interstitial radiotherapy of 25 parasellar/clival meningiomas and 19 meningiomas in the elderly. Analysis of short-term tolerance and responses.

I-125 seeds were permanently implanted into 25 parasellar-clival meningiomas (median age of patients, 56 y) and 19 globoid meningiomas in the elderly (median age of patients, 77 y) using stereotactic technique and 3-D dose planning. Total dose at the tumour margin was increased during the series from 100 Gy to 150 Gy. The procedure caused no mortality and no serious bleeding, but injury to the III cranial nerve due to puncture occurred in one (4%) of the 25 parasellar-clival meningiomas. In two (4.5%) of the 44 cases the postoperative CT scan showed a misplaced seed, located at the tumour surface. Nonenhancing hypodense rings developed around the seeds ('hot spots') with a median diameter of 10.5 mm at 12 months corresponding to a median initial activity of 8.7 mCi. In general, meningiomas responded by slow reduction in volume. The parasellar-clival meningiomas were followed-up for a median of 19 months (6-32), and so far 4 tumours have shrunk moderately, 13 slightly, and 5 not at all. Pre-operative III, V or VI cranial nerve signs were present in 17 patients and subsided in 8 of them. On the other hand, facial numbness developed or increased in 9 of the 25 patients, indicating that the V nerve is rather sensitive to this type of irradiation. In the 19 meningiomas of the elderly, the median follow-up time was 14 months (5-26). The median relative tumour volume was 46% at 12 months. Accounting for tumour-related deaths only, the actuarial survival rate was 78% at 12 months and 62% at 24 months. In general, brain oedema persisted despite reduction in tumour volume. Stereotactic implantation of I-125 seeds into intracranial meningiomas is relatively safe. Interstitial radiotherapy represents a potential tool in the control of medium-sized intracranial meningiomas with minimal brain oedema, but its long-term impact and untoward effects remain to be followed-up.

Randomised, controlled study of intratumoral recombinant gamma-interferon treatment in newly diagnosed glioblastoma.

The effect of intratumoral recombinant interferon gamma (rIFN-gamma) as adjuvant to open cytoreduction and external irradiation of 60 Gy on survival in adults with a newly diagnosed high-grade cerebral glioma was studied. The patients were randomised during surgery into the rIFN-gamma group (n = 14) or the control group (n = 17), and the latter received a subcutaneous reservoir of rIFN-gamma injections. Intratumoral rIFN-gamma was given three times a week for 4 weeks until radiotherapy, escalating the dose from 5 micrograms to 50 micrograms. Both groups received external whole-brain irradiation of 40 Gy and a local boost of 20 Gy. After radiotherapy, rIFN-gamma was continued with 50 micrograms twice a week up to 9 weeks. The patients received no chemotherapy. Intratumoral rIFN-gamma was tolerated well with transient fever only. There were 12 glioblastomas (GBs) in the control group and nine in the rIFN-gamma group with completed irradiation. The patients were followed clinically and by computerised tomography (CT) every third month until death. Tumour responses were seen in three interferon-treated (one still alive 45 months after operation) and in two conventionally treated patients. The progression of the tumour volumes on CT did not differ between the IFN-treated and control groups. There were no differences in the survival times. Median survival of the rIFN-gamma-treated patients was 54 weeks (95% CI 35-68) and of the control patients 55 weeks (95% CI 41-77). Intratumoral rIFN-gamma given in the study doses does not seem to inhibit tumour growth or improve the prognosis of patients with high-grade glioma.

Radioimmunoimaging of non-small cell lung cancer with 111In- and 99mTc-labeled monoclonal anti-CEA-antibodies.

Radiolabeled monoclonal anti-CEA antibodies were used for radioimmunolocalization (RIL) of non-small cell lung cancer; in 30 patients with 111In labeled anti CEA F(ab')2 fragment (BW 431/31) and in 16 with 99mTc-labeled intact MoAb (BW 431/26). RIL results were compared with those of other imaging modalities. Paraffin sections from some patients were also studied immunohistochemically using anti-CEA antibody. Patients with 111In labeled MoAB were imaged twice 1-4 days after injection and for image enhancement pulmonary and liver/spleen subtraction were performed. Twenty-seven of 28 primary tumors were positive and metastases were detected in all patients. The total number of lesions was 78 of which 61 (78%) could be detected by RIL. For verification CT was applied to the study of 46 lesions detected by RIL. We found 6 unknown lesions subsequently verified histologically. Using subtraction techniques we detected 9 lesions in 4 patients, later verified as pulmonary metastases, not detected in unprocessed images. Pleural, mediastinal and pericardial lesions were also better delineated in subtracted images than in unprocessed images. Imaging of non-small cell lung cancer with 99mTc-labeled MoAB was performed twice 4-24 h after injection. RIL results were compared with other imaging methods; CT US, conventional radiography, and immunohistochemistry. Twelve out of 16 patients with suspected or known lung cancer had positive immunoscintigrams; 19 of 25 lesions could be detected by RIL. There were 5 false positive and 2 true negative findings. Immunoperoxidase (IP) stainings of paraffin sections of the tumours from 7 patients were performed using two different anti-CEA antibodies; BW 431/26 and ZCEA1. None of the seven tumors examined by immunohistochemistry were negative when stained by BW 431/26, which was the antibody used for immunoscintigraphy.