Estimation of drug receptor occupancy when non-displaceable binding differs between brain regions – extending the simplified reference tissue model

AimThe simplified reference tissue model (SRTM) is used for estimation of receptor occupancy assuming that the non-displaceable binding in the reference region is identical to the brain regions of interest. The aim of this work was to extend the SRTM to also account for inter-regional differences in non-displaceable concentrations, and to investigate if this model allowed estimation of receptor occupancy using white matter as reference. It was also investigated if an apparent higher affinity in caudate compared with other brain regions, could be better explained by a difference in the extent of non-displaceable binding.MethodsThe analysis was based on a PET study in six healthy volunteers using the 5-HT_1B receptor radioligand [¹¹C]-AZ10419369. The radioligand was given intravenously as a tracer dose alone and following different oral doses of the 5-HT_1B receptor antagonist AZD3783. Non-linear mixed effects models were developed where differences between regions in non-specific concentrations were accounted for. The properties of the models were also evaluated by means of simulation studies.ResultsThe estimate (95% CI) of Ki_PL was 10.2 ng ml⁻¹ (5.4, 15) and 10.4 ng ml⁻¹ (8.1, 13.6) based on the extended SRTM with white matter as reference and based on the SRTM using cerebellum as reference, respectively. The estimate (95% CI) of Ki_PL for caudate relative to other brain regions was 55% (48, 62%).ConclusionsThe extended SRTM allows consideration of white matter as reference region when no suitable grey matter region exists. AZD3783 affinity appears to be higher in the caudate compared with other brain regions.     

Pharmacokinetics and Toxicity of Sodium Selenite in the Treatment of Patients with Carcinoma in a Phase I Clinical Trial: The SECAR Study

Background: Sodium selenite at high dose exerts antitumor effects and increases efficacy of cytostatic drugs in multiple preclinical malignancy models. We assessed the safety and efficacy of intravenous administered sodium selenite in cancer patients’ refractory to cytostatic drugs in a phase I trial. Patients received first line of chemotherapy following selenite treatment to investigate altered sensitivity to these drugs and preliminary assessment of any clinical benefits. Materials and Methods: Thirty-four patients with different therapy resistant tumors received iv sodium selenite daily for consecutive five days either for two weeks or four weeks. Each cohort consisted of at least three patients who received the same daily dose of selenite throughout the whole treatment. If 0/3 patients had dose-limiting toxicities (DLTs), the study proceeded to the next dose-level. If 2/3 had DLT, the dose was considered too high and if 1/3 had DLT, three more patients were included. Dose-escalation continued until the maximum tolerated dose (MTD) was reached. MTD was defined as the highest dose-level on which 0/3 or 1/6 patients experienced DLT. The primary endpoint was safety, dose-limiting toxic effects and the MTD of sodium selenite. The secondary endpoint was primary response evaluation. Results and Conclusion: MTD was defined as 10.2 mg/m², with a calculated median plasma half-life of 18.25 h. The maximum plasma concentration of selenium from a single dose of selenite increased in a nonlinear pattern. The most common adverse events were fatigue, nausea, and cramps in fingers and legs. DLTs were acute, of short duration and reversible. Biomarkers for organ functions indicated no major systemic toxicity. In conclusion, sodium selenite is safe and tolerable when administered up to 10.2 mg/m² under current protocol. Further development of the study is underway to determine if prolonged infusions might be a more effective treatment strategy.     

Standard-dose anti-CD20 antibody rituximab has efficacy in chronic lymphocytic leukaemia: results from a Nordic multicentre study

OBJECTIVES: This prospective multicentre study was conducted to assess the efficacy of the monoclonal anti-CD20 antibody rituximab in patients with chronic lymphocytic leukaemia (CLL). Secondary objectives were defined as the tolerability and feasibility of rituximab in patients with CLL. METHODS: Twenty-four heavily pretreated patients with CLL were treated with a standard dose of 375 mg m-2 of rituximab given once weekly for four doses. RESULTS: The overall response rate was 35% and all the responses were partial as defined by the revised NCI criteria. In 17 (85%) of 20 patients with initially measurable peripheral lymph nodes the size of lymph nodes decreased by at least 50%, while an improvement of the bone marrow infiltration was observed only in two (11%) of 18 evaluable patients. The median duration of the overall response was 12.5 wk. Rituximab was relatively well tolerated. Although side-effects were common (75%) they were usually mild or moderate. There was only one grade 3 adverse event and no grade 4 events. CONCLUSIONS: Standard-dose rituximab has activity in heavily pretreated patients with CLL, although the response is mainly limited to the lymph nodes and of short duration. Since rituximab has in vitro synergism with chemotherapeutic agents and is well tolerated by CLL patients, it is reasonable to investigate rituximab in combination with other treatments.     

The diterpene glycoside, rebaudioside A, does not improve glycemic control or affect blood pressure after eight weeks treatment in the Goto-Kakizaki rat

The plant, Stevia rebaudiana Bertoni (SrB), has been used for the treatment of diabetes in traditional medicine. Previously, we have demonstrated that long-term administration of the glycoside stevioside has insulinotropic, glucagonostatic, anti-hyperglycemic and blood pressure-lowering effects in type 2 diabetic animal models. The aim of this study was to elucidate if long-term administration of rebaudioside A, another glycoside isolated from the plant SrB, could improve glycemic control and lower blood pressure in an animal model of type 2 diabetes. We divided male Goto-Kakizaki (GK) rats into two groups which were fed a standard laboratory chow diet for eight weeks. The diet was supplemented with oral rebaudioside A (0.025 g/kg BW/day) in the experimental group. Blood glucose, weight, blood pressure and food intake were measured weekly. Animals were equipped with an intra-arterial catheter, and at week eight the conscious rats underwent an intra-arterial glucose tolerance test (IAGTT) (2.0 g/kg BW). During the IAGTT, the level of glucose, glucagon, and insulin responses did not differ significantly between the two groups. Fasting levels of glucose, glucagon, insulin or levels of blood lipids did not differ between the groups throughout the study period. We observed no effect on blood pressure or weight development. In conclusion, oral supplementation with rebaudioside A (0.025 g/kg BW/day) for eight weeks did not influence blood pressure or glycemic control in GK rats. Rebaudioside A failed to show the beneficial effects in diabetic animals previously demonstrated for stevioside.     

Islet antibodies and remaining beta-cell function 8 years after diagnosis of diabetes in young adults: a prospective follow-up of the nationwide Diabetes Incidence Study in Sweden

Objectives. To establish the prevalence of remaining β‐cell function 8 years after diagnosis of diabetes in young adults and relate the findings to islet antibodies at diagnosis and 8 years later. Design. Population‐based cohort study. Setting. Nationwide from all Departments of Medicine and Endocrinology in Sweden. Subjects. A total of 312 young (15–34 years old) adults diagnosed with diabetes during 1987–88. Main outcome measure. Plasma connecting peptide (C‐peptide) 8 years after diagnosis. Preserved β‐cell function was defined as measurable C‐peptide levels. Three islet antibodies – cytoplasmic islet cell antibodies (ICA), glutamic acid decarboxylase antibodies and tyrosine phosphatase antibodies – were measured. Results. Amongst 269 islet antibody positives (ab⁺) at diagnosis, preserved β‐cell function was found in 16% (42/269) 8 years later and these patients had a higher body mass index (median 22.7 and 20.5 kg m^?2, respectively; P = 0.0003), an increased frequency of one islet antibody (50 and 24%, respectively; P = 0.001), and a lower prevalence of ICA (55 and 6%, respectively; P = 0.007) at diagnosis compared with ab⁺ without remaining β‐cell function. Amongst the 241 patients without detectable β‐cell function at follow‐up, 14 lacked islet antibodies, both at diagnosis and at follow‐up. Conclusions. Sixteen per cent of patients with autoimmune type 1 diabetes had remaining β‐cell function 8 years after diagnosis whereas 5.8% with β‐cell failure lacked islet autoimmunity, both at diagnosis and at follow‐up.     

Psychosocial functioning in the obese before and after weight reduction: construct validity and responsiveness of the Obesity-related Problems scale

OBJECTIVE: The Obesity-related Problems scale (OP) is a self-assessment module developed to measure the impacts of obesity on psychosocial functioning. Our principal aim was to evaluate the construct validity and responsiveness of the OP scale. Our specific aims were to test: (1). the psychometric performance of OP; (2). if OP scores differed by gender and weight category; (3). if OP scores are inversely related to mental well-being; (4). if weight reduction in the obese is accompanied by improvements in psychosocial functioning (OP). SUBJECTS: Four samples were used: 6863 subjects in the SOS cross-sectional study; 2128 in the SOS intervention study; 1017 nonobese in the SOS reference study; and 3305 obese subjects in the XENDOS study. MEASUREMENTS: Psychosocial functioning was measured by OP. Overall mood was measured by MACL. Anxiety and depression symptoms were measured by HAD. RESULTS: Psychometric testing provided strong support for the construct validity of OP. Factor analysis confirmed the homogeneity of the construct and multitrait/multi-item scaling analysis demonstrated strong item-convergent/discriminant validity. Reliability coefficients were high and floor and ceiling effects were small. Psychometric results were cross-validated and replicated in subgroups by gender, age and body mass index (BMI). As expected, large differences in OP were observed between obese and nonobese (P<0.0001). Obese women reported more weight-related psychosocial problems than obese men (P<0.0001). Psychosocial disturbances (OP) among the obese were significantly related to poor mood (MACL; P<0.0001) and anxiety and depression symptoms (HAD; P<0.0001). Change in OP over time was strongly correlated with weight loss (P<0.0001). A distinct dose-response effect between weight reduction and improvements in OP was demonstrated. Scores on psychosocial functioning (OP) and mental well-being (MACL, HAD) in nonobese (BMI<30) surgical patients at 4-y follow-up were equal to scores observed in nonobese reference subjects (NS). CONCLUSION: OP is a psychometrically valid obesity-specific measure suitable for evaluating HRQL effects of obesity interventions. The negative impact of obesity on psychosocial functioning is considerable and disturbances are connected with poor mental well-being. Weight reduction in the obese is followed by improvements in both psychosocial functioning and mental well-being.     

Different regulation of p27 and Akt during cardiomyocyte proliferation and hypertrophy

Postnatal cardiomyocytes normally grow by hypertrophy but show a limited proliferate response to certain stimuli. Although the proliferative capacity declines shortly after birth, neonatal cardiomyocytes can grow both by hypertrophy and by proliferation. Therefore, we have used neonatal cardiomyocytes to investigate the molecular differences between hypertrophic and proliferative growth of cardiomyocytes. Stimulation of neonatal cardiomyocytes with angiotensin II mainly induced hypertrophy, whereas PDGF only had a minor effect on the size of the myocytes. In contrast, PDGF induced significant proliferation in the cardiomyocyte cultures whereas angiotensin II treatment only resulted in a small increase in the number of cells. Measurement of cyclin D-dependent kinase specific phosphorylation of pRb by immunohistochemistry showed that, both stimuli activate the G1 phase of the cell cycle. By western blotting we found that PDGF-induced proliferation correlates with activation of Akt, inactivation of GSK-3β and downregulation of the cyclin-dependent kinase inhibitor p27, whereas angiotensin II only had a small effect on Akt, GSK-3β and p27. Our data support the hypothesis that, the hypertrophic and proliferative responses are both activated by G1 cell cycle molecules. The difference between the two responses appears to be that high amounts of p27 are present during hypertrophic growth, whereas proliferation involves downregulation of p27 and GSK-3β activity and upregulation of Akt.     

Small and large fiber sensory polyneuropathy in type 2 diabetes: Influence of diagnostic criteria on neuropathy subtypes

Diabetic polyneuropathy (DPN) can be classified based on fiber diameter into three subtypes: small fiber neuropathy (SFN), large fiber neuropathy (LFN), and mixed fiber neuropathy (MFN). We examined the effect of different diagnostic models on the frequency of polyneuropathy subtypes in type 2 diabetes patients with DPN. This study was based on patients from the Danish Center for Strategic Research in Type 2 Diabetes cohort. We defined DPN as probable or definite DPN according to the Toronto Consensus Criteria. DPN was then subtyped according to four distinct diagnostic models. A total of 277 diabetes patients (214 with DPN and 63 with no DPN) were included in the study. We found a considerable variation in polyneuropathy subtypes by applying different diagnostic models independent of the degree of certainty of DPN diagnosis. For probable and definite DPN, the frequency of subtypes across diagnostic models varied from: 1.4% to 13.1% for SFN, 9.3% to 21.5% for LFN, 51.4% to 83.2% for MFN, and 0.5% to 14.5% for non‐classifiable neuropathy (NCN). For the definite DPN group, the frequency of subtypes varied from: 1.6% to 13.5% for SFN, 5.6% to 20.6% for LFN, 61.9% to 89.7% for MFN, and 0.0% to 6.3% for NCN. The frequency of polyneuropathy subtypes depends on the type and number of criteria applied in a diagnostic model. Future consensus criteria should clearly define sensory functions to be tested, methods of testing, and how findings should be interpreted for both clinical practice and research purpose.