Effects of a nationwide programme: interventions to reduce perceived barriers to collaboration and to increase structural one-on-one contact

OBJECTIVE: To describe the implementation of a nationwide programme and to determine the effects of specific quality improvement (QI) interventions within this programme on perceived barriers to collaboration between general practitioner (GPs) and mental health professionals and frequency of structural one-on-one contact regarding individual patients. METHODS: The implementation of regional QI-interventions, perceived barriers to collaboration, and frequency of structural one-on-one contact, were assessed in a cohort study involving two surveys (2001 and 2003) among a random sample of 2757 GPs. RESULTS: 1336 and 1358 GPs returned baseline and follow-up questionnaires respectively. Most of the interventions were only offered to a minority of GPs. Less than 25% of GPs that had been offered interventions actually participated. The frequency of structural one-on-one contact with mental health professionals did not change, but barriers to collaboration decreased between 2001 and 2003. For GPs who actually participated in interactive small group meetings or in intervention in which mental health professionals were integrated in general practice, a reduction of perceived barriers could be observed as well as an increase in the frequency of structural one-on-one contact. CONCLUSION: Interventions that could be characterized as interactive small group meetings as well as interventions that involved the integration of mental health professionals in general practice led to a reduction of perceived barriers as well as an increase in the frequency of structural one-on-one contact. These findings add to the knowledge of which interventions have an effect on the collaboration between different health care providers.     

Fourier transform infrared spectroscopy studies of alginate-PLL capsules with varying compositions

Microencapsulation of cells is a promising approach to prevention of rejection in the absence of immunosuppression. Clinical application, however, is hampered by insufficient insight into the factors that influence the biocompatibility of the capsules. Capsules prepared of alginates with a high guluronic (G) acid content proved to be more adequate for clinical application since they are more stable, but, unfortunately, they are less biocompatible than capsules prepared of intermediate-G alginate. In order to get some insight into the physicochemical factors that influence the biocompatibility of capsules for the encapsulation of living cells, the chemical compositions of alginate[bond]Ca beads and alginate[bond]PLL capsules were studied by Fourier transform infrared spectroscopy. We found that during the transition of the alginate[bond]Ca beads to alginate[bond]PLL capsules, Ca connecting the alginate molecules, disappeared at the surface of both high-G and intermediate-G alginate[bond]PLL capsules. At the same time, it turned out that high-G alginate[bond]PLL capsules contained more hydrogen bonding than did intermediate[bond]G alginate capsules. Thus the well-known higher stability of high-G alginate[bond]PLL compared to intermediate-G alginate[bond]PLL capsules is not caused by a higher degree of binding to Ca of the alginate molecules but rather by the presence of more hydrogen bonds. Another observation was that after the transition from bead to capsule, high-G alginate[bond]PLL capsules contained 20% more PLL than the intermediate-G alginate[bond]PLL capsules. Finally, we show that in both high-G and intermediate-G alginate[bond]PLL capsules, the PLL exists in the alpha-helix, in the antiparallel beta-sheet, and in the random coil conformation. This study shows that FT-IR allows for successful analyses of the chemical factors essential for understanding differences in the biocompatibility of alginate[bond]PLL capsules.     

Phase I and pharmacokinetic study of the dolastatin 10 analogue TZT-1027, given on days 1 and 8 of a 3-week cycle in patients with advanced solid tumors.

PURPOSE: TZT-1027 [N(2)-(N,N-dimethyl-l-valyl)-N-[(1S,2R)-2-methoxy-4-[(2S)-2-[(1R,2R)-1-methoxy-2-methyl-3-oxo-3-[(2-phenylethyl)]amino]propyl]-1-pyrrolidinyl]-1-[(S)-1-methylpropyl]-4-oxobutyl]-N-methyl-l-valinamide] is a cytotoxic dolastatin 10 derivative inhibiting microtubule assembly through the binding to tubulins. The objectives of this phase I study was to assess the dose-limiting toxicities (DLT), to determine the maximum tolerated dose, and to study the pharmacokinetics of TZT-1027 when given i.v. over 60 minutes on days 1 and 8 every 3 weeks to patients with advanced solid tumors. EXPERIMENTAL DESIGN: Patients were treated with escalating doses of TZT-1027 at doses ranging from 1.35 to 2.7 mg/m(2). For pharmacokinetic analysis, plasma sampling was done during the first and second course and assayed using a validated high-performance liquid chromatographic assay with mass spectrometric detection. RESULTS: Seventeen patients received a total of >70 courses. The stopping dose was reached at 2.7 mg/m(2), with neutropenia and infusion arm pain as DLT. Neutropenia was not complicated by fever. Over all dose levels, eight patients experienced pain in the infusion arm 1 to 2 days after administration of the drug, which seemed ameliorated by adding additional flushing after drug administration. Other side effects included nausea, vomiting, diarrhea, and fatigue. One partial response lasting >54 weeks was observed in an extensively pretreated patient with metastatic liposarcoma. The pharmacokinetics of TZT-1027 suggested linearity over the dose ranges. No correlation between body surface area and absolute CL of TZT-1027 was established, vindicating that a flat dosing regimen might be used in the future. A correlation was observed between the percentage decrease in neutrophil count and the AUC of TZT-1027. CONCLUSIONS: In this study, the DLT of TZT-1027 was neutropenia and infusion arm pain. The recommended dose for phase II studies of TZT-1027 is 2.4 mg/m(2) given i.v. over 60 minutes, on days 1 and 8 every 21 days. Phase II studies have recently started.     

Population pharmacokinetic and pharmacodynamic analysis to support treatment optimization of combination chemotherapy with indisulam and carboplatin

AIMS

Indisulam and carboplatin have shown synergistic activity in preclinical studies. In a dose escalation study of the combination, a treatment delay was frequently required in a 3-weekly regimen to allow recovery from myelosuppression from previous cycles. A 4-weekly regimen was better tolerated, but had a decreased dose-intensity which may compromise efficacy. The aims of this study were (i) to develop a pharmacokinetic–pharmacodynamic (PK–PD) model to describe the myelosuppressive effect of the combination, and (ii) to use this model to select a dosing regimen for Phase II evaluation.

METHODS

Sixteen patients were treated at four different dose levels of indisulam (1-h infusion on day 1) and carboplatin (30-min infusion on day 2). Pharmacokinetic data were analysed with nonlinear mixed effects modelling. A semiphysiological model describing chemotherapy-induced myelosuppression characterized the relationship between the pharmacokinetics and the haematological toxicity of indisulam and carboplatin. A simulation study was performed to evaluate the tolerability and dose-intensity for 3-weekly and 4-weekly treatment regimens.

RESULTS

The PK–PD model described the pharmacokinetics and the myelosuppressive effect of indisulam and carboplatin. The risk of a treatment delay at cycle 2 due to myelosuppression was unacceptably high (34–65%) in a 3-weekly regimen for various dose levels (350–600 mg m⁻² indisulam in combination with carboplatin to achieve an AUC of 4–6 mg min⁻¹ ml⁻¹). This risk was acceptable for a 4-weekly regimen (9–24%), which is in line with the clinical study results.

CONCLUSIONS

This PK–PD study supports the selection of indisulam 500 mg m⁻² and a dose of carboplatin to achieve an AUC of 6 mg min⁻¹ ml⁻¹ in a 4-weekly regimen as the recommended dose for future studies.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Chemotherapy with indisulam in combination with a standard dose of carboplatin was not well tolerated in a 3-weekly regimen in a Phase I dose escalation study.
• Myelosuppression was the dose limiting toxicity.
• This pharmacokinetic–pharmacodynamic (PK–PD) study was performed to suggest a dosing regimen for the combination therapy indisulam–carboplatin that is well tolerated in patients.

WHAT THIS STUDY ADDS

• This PK–PD study supports the selection of indisulam 500 mg m⁻² and a dose of carboplatin to achieve an AUC of 6 mg min⁻¹ ml⁻¹ in a 4-weekly regimen as the recommended dose for future studies.

     

Improving primary mental health care: impact of a nationwide programme

OBJECTIVE: To determine the impact of a nationwide programme on primary mental health care practices. DESIGN: Cohort study involving two surveys conducted in 2001 and 2003. SETTING AND SUBJECTS: Random sample of 2757 general practitioners. INTERVENTION: In 2001, a nationwide programme was initiated to improve primary mental health care. The programme used a participatory approach with regional needs assessment and regional selection of the interventions. MAIN OUTCOME MEASURES: Perceived need, availability and participation in the interventions; self-reported mental health performance (self-reported diagnosis and management of mental health disorders); perceived barriers to optimal care. RESULTS: Baseline and follow-up questionnaires were returned by 1336 and 1358 general practitioners, respectively. Interventions did not entirely match general practitioners' needs. Mental health performance did not change consistently while perceived barriers to optimal care decreased considerably. Actual participation in the interventions was not associated with improved mental health performance or decreased perception of barriers. CONCLUSIONS: The application of the nationwide programme had no considerable impact on the professional practices of general practitioners with regard to mental health care. This finding challenges the assumption that a bottom-up approach to quality improvement is effective. Extensive coordination at a national level and the provision of specific supportive products and services appears to be necessary to achieve improvement.     

Phase I and pharmacokinetic study of E7070, a chloroindolyl-sulfonamide anticancer agent, administered on a weekly schedule to patients with solid tumors.

PURPOSE: E7070 is a sulfonamide that induces arrest at the G(1)-S boundary with subsequent dose and exposure-dependent apoptosis. The objectives of this study were (a) to determine the maximum-tolerated dose (MTD) and recommended safe dose (RD) of E7070 for additional evaluation, (b) to define the dose limiting toxicity(ies) [DLT(s)], (c) to study the pharmacokinetics of E7070, and (d) to seek preliminary evidence of antitumor activity. EXPERIMENTAL DESIGN: Patients with solid tumors who had either failed or were not amenable to established forms of treatment were eligible for the study. E7070 was administered i.v. at weekly intervals for 4 consecutive weeks to cohorts of 3-6 patients at each dose level. Treatment was repeated six weekly in the absence of tumor progression. A Fibonacci-like scheme was used for dose escalation. The MTD was determined in a stepwise procedure for two cohorts of patients; the "initial patient cohort" who met the original inclusion criteria (group A) and the "better prognosis cohort" (group B) who had adequate hepatic function, less extensive tumor involvement of the liver, and no more than three previous lines of chemotherapy. The RD was defined as the highest dose at which the incidence of definitely drug-related DLTs was <33%. The pharmacokinetic profile of E7070 was determined. RESULTS: Overall, 46 patients entered the study; information from 36 of the 37 patients forming group A was used to determine the overall MTD. An additional 9 patients plus 9 patients from group A who met the more restrictive inclusion criteria made up group B. The MTD was 500 mg/m(2)/week for both groups. Reversible neutropenia and thrombocytopenia were the most common DLTs. Other DLTs included stomatitis, hyperglycemia, sepsis, fever, hemorrhage, diarrhea, nausea, and fatigue. The pharmacokinetics of E7070 were nonlinear over the dose range 160-500 mg/m(2). One partial response was observed in a patient with an endometrial adenocarcinoma who had previously been treated with radiotherapy. Twelve other patients had stable disease as their best response (27%); among them. 1 patient with metastatic melanoma who received 21 cycles of therapy. CONCLUSIONS: The RD for further study of E7070 using this administration schedule is 400 mg/m(2)/week. Using this schedule, the predominant toxicity of E7070 is myelosuppression. E7070 has anticancer activity in pretreated patients.