Population pharmacokinetics of tanezumab in phase 3 clinical trials for osteoarthritis pain

AimsThe aims were to 1) develop the pharmacokinetics model to describe and predict observed tanezumab concentrations over time, 2) test possible covariate parameter relationships that could influence clearance and distribution and 3) assess the impact of fixed dosing vs. a dosing regimen adjusted by body weight.MethodsIndividual concentration–time data were determined from 1608 patients in four phase 3 studies conducted to assess efficacy and safety of intravenous tanezumab. Patients received two or three intravenous doses (2.5, 5 or 10 mg) every 8 weeks. Blood samples for assessment of tanezumab PK were collected at baseline, 1 h post‐dose and at weeks 4, 8, 16 and 24 (or early termination) in all studies. Blood samples were collected at week 32 in two studies. Plasma samples were analyzed using a sensitive, specific, validated enzyme‐linked immunosorbent assay.ResultsA two compartment model with parallel linear and non‐linear elimination processes adequately described the data. Population estimates for clearance (CL), central volume (V ₁), peripheral volume (V ₂), inter‐compartmental clearance, maximum elimination capacity (VM) and concentration at half‐maximum elimination capacity were 0.135 l day^–1, 2.71 l, 1.98 l, 0.371 l day^–1, 8.03 μg day^–1 and 27.7 ng ml^–1, respectively. Inter‐individual variability (IIV) was included on CL, V ₁, V ₂ and VM. A mixture model accounted for the distribution of residual error. While gender, dose and creatinine clearance were significant covariates, only body weight as a covariate of CL, V ₁ and V ₂ significantly reduced IIV.ConclusionsThe small increase in variability associated with fixed dosing is consistent with other monoclonal antibodies and does not change risk : benefit.     

Secondary correction of the unilateral cleft nose deformity with an endonasal technique

Summary Malposition of the nasal bone, septum and the alar cartilage are striking features of the unilateral cleft nose deformity. An endonasal technique (the extramucosal) was used in 26 patients, aged 13–38 (median 19), to correct aesthetic and functional problems. Twenty-four patients were secondary and two were tertiary. The patients were followed from 1–9 years. The pathological anatomy of the septum varied considerably, so different types of septoplasties had to be done. In 20 patients, satisfactory aesthetic and functional results were obtained in one operation. Secondary corrections were indicated in six patients. In cases with no gross scarring in or around the alar cartilage, the form and position of this cartilage will be more normal once the alar cartilages have been undermined and the deviation of the nasal bone and the septum is corrected.     

Attempt at predicting paraphrenic outcome in young, first admitted schizophrenic patients

A sample of 110 consecutive first admission young schizophrenic patients treated between 1964 and 1967 was rediagnosed in 1981. Among 92 survivors, 27 could be labelled as paraphrenics. From information available at inception 97 variables were coded covering such areas as personality, previous disturbances, age and type of onset, and symptoms around admission. Sixty-three out of 97 variables were hypothesized to differentiate, at admission, future paraphrenics from the rest of the sample. Paraphrenics were found to have had less contact disturbance, better self-esteem, less neurotic symptoms in adolescence and childhood, and less complaints of unhappiness when growing up. They had more regressive and paranoid symptoms at admission, were older at onset of the disease, which was more acute, more often connected with precipitating events, and confusion. Certain non-regressive symptoms such as brooding, anhedonia and concentration difficulties were less common. A discriminant analysis yielded a proportion of correct predictions = 0.64 (p less than 0.05). The results are in accordance with the theory of more favourable energetic and organizational capacity in paranoid schizophrenics as compared with non-paranoids.     

Mechanisms of pulmonary dysfunction after on-pump and off-pump cardiac surgery: a prospective cohort study

Background  

Pulmonary dysfunction following cardiac surgery is believed to be caused, at least in part, by a lung vascular injury and/or atelectasis following cardiopulmonary bypass (CPB) perfusion and collapse of non-ventilated lungs.     

Treatment of myofascial trigger points in common shoulder disorders by physical therapy: A randomized controlled trial [ISRCTN75722066]

Background  

Shoulder disorders are a common health problem in western societies. Several treatment protocols have been developed for the clinical management of persons with shoulder pain. However available evidence does not support any protocol as being superior over others. Systematic reviews provide some evidence that certain physical therapy interventions (i.e. supervised exercises and mobilisation) are effective in particular shoulder disorders (i.e. rotator cuff disorders, mixed shoulder disorders and adhesive capsulitis), but there is an ongoing need for high quality trials of physical therapy interventions. Usually, physical therapy consists of active exercises intended to strengthen the shoulder muscles as stabilizers of the glenohumeral joint or perform mobilisations to improve restricted mobility of the glenohumeral or adjacent joints (shoulder girdle). It is generally accepted that a-traumatic shoulder problems are the result of impingement of the subacromial structures, such as the bursa or rotator cuff tendons. Myofascial trigger points (MTrPs) in shoulder muscles may also lead to a complex of symptoms that are often seen in patients diagnosed with subacromial impingement or rotator cuff tendinopathy. Little is known about the treatment of MTrPs in patients with shoulder disorders.     

Ideological framework and health development in Tanzania 1961-2000

At independence in 1961, Tanzania inherited a classic economic structure from Britain. The most immediate aims of the new government included replacing the colonial administration with trained nationals, radical change of the development philosophy and strategies and development of self-reliance in all development sectors. The Arusha Declaration of 1967 was the turning point in Tanzania and achievements in all the sectors can be measured against targets established soon after. This paper examines development in the health sector within the wider national framework.     

Legg-Calvé-Perthes disease in hemophilia: incidence and etiologic considerations

A review of hip radiographs of patients with severe hemophilia showed Legg-Calvé-Perthes disease in four of 63 patients examined before the era of specific treatment. In another series of 44 patients receiving prophylactic treatment, there was no evidence of Legg-Calvé-Perthes disease. A case report of a boy with severe hemophilia with hip joint bleeding that caused joint capsule distention and greatly increased intracapsular pressure is presented. Based on our findings, and previously published results, we suggest that Legg-Calvé-Perthes disease in hemophilia is caused by increased intracapsular pressure secondary to hemarthrosis.     

Stress protection by external fixation of the rabbit tibia

Osteopenia of the tibia and femur caused by an external fixator in the tibia was studied in 14 rabbits. Eight rabbits were treated with a complete unilateral external fixator in one tibia, whereas the other tibia served as control. The other 6 animals had one leg operated on with inserting of all the pins but without the frame. This technique was chosen to compare osteopenia caused by stress protection and the effect of the pins. After 6 weeks, we found a 7 percent reduction in the bone mineral content in the tibial diaphyseal segment between the pins of the external fixator and no bone loss in the tibia that were operated on with only pins. In the femurs, there was a smaller decrease in the bone mineral content: respectively 3.2 percent (complete frame) and 2.9 percent (only pins). On all the operated on tibiae, there was an increase in the bone mineral content around the pins both proximally and distally.