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.     

Block of potassium channels and facilitation of acetylcholine release at the neuromuscular junction by the venom of the scorpion, Pandinus imperator

Venom from the scorpion Pandinus imperator potently and selectively blocks voltage-gated K+ channels in bullfrog neurones (Pappone, P. A. and Cahalan, M. D. 1987, J. Neurosci. 7, 3300-3305). Its effects on neuromuscular transmission have now been assessed. Twitch tension studies on chick biventer cervicis preparations showed that the venom (1 microgram/ml and above) significantly augmented responses to nerve but not muscle stimulation; there was little change in postjunctional sensitivity to cholinoceptor agonists or K+-induced depolarization. Electrophysiological studies on mouse triangularis sterni preparations revealed that the venom had no effect on spontaneous transmitter release, but increased evoked transmitter release. Extracellular recordings of nerve terminal action potentials showed that the venom selectively reduced the component of the waveform associated with K+ currents. These results confirm that this venom can selectively block neuronal K+ currents, and they show that this can facilitate the release of acetylcholine at the neuromuscular junction.     

Plasma uric acid in patients receiving anticonvulsant monotherapy

In newly diagnosed adult patients with epilepsy followed prospectively on monotherapy, carbamazepine and phenytoin were associated with a fall in plasma uric acid, but sodium valproate and phenobarbitone were associated with a rise in plasma uric acid. The mechanisms and significance of these findings are discussed.     

Hemispheric activation vs spatio-motor cueing in visual neglect: a case study

We report a case of mild visuo-spatial neglect consequent upon right-hemisphere stroke. At the time of testing, the patient had a complete left visual field deficit but only a very slight left hemiparesis. Under conventional testing conditions, line bisection performed with the right hand showed more severe left neglect than when performed with the left hand. This pattern of performance could, however, be modified, both quantitatively and qualitatively, by changing the starting position of the patient's hand when bisecting horizontal lines. The results suggest that spatio-motor cueing has a more profound effect upon task performance than does differential hemispheric activation per se. We also provide a demonstration that, in a normal subject, the starting position of the hand is likewise a crucial determinant of task performance. In this case, however, there is also an interaction between the hand (and hence hemisphere) deployed and the position of that hand in space.     

Area variation of avoidable causes of death in Auckland, 1977-85

An area analysis is presented of deaths in Auckland that were ostensibly avoidable, by appropriate medical intervention and treatment. Mortality data from the National Health Statistics Centre for the period 1977-85 were used in the analysis. The definition of an avoidable death was based on the International Classification of Diseases (ICD) code using established criteria. Eight percent of deaths of people under 65 years of age met the criteria. The basic spatial entity for the analysis is the census area unit and maps of Auckland are presented to show the distribution of avoidable mortality. It is found that there are significant and consistent spatial variations. Three areas with avoidable mortality that is generally higher than elsewhere are apparent: in south Auckland; to the north-west of the central urban sector centered on Grey Lynn; and in the eastern parts of the central sector from Glenn Innes to Onehunga.     

Adrenocortical carcinoma and sudden death

A 26-year-old man who presented with a 2-year history of intermittent gynecomastia with recent onset of fever, night sweats, and abdominal distension was found to have a left-sided adrenocortical carcinoma with metastases to the liver and spine. Sudden death occurred 1 month after his presentation. At autopsy a saddle pulmonary thromboembolus was found occluding the pulmonary outflow tract, with smaller more peripheral pulmonary thromboemboli. No tumor deposits were identified in the thromboemboli. The thromboemboli had arisen from a tongue of tumor that had grown through the left adrenal vein into the inferior vena cava. Despite a high rate of angio-invasion there are very few reports of sudden death resulting from this phenomenon in patients with adrenocortical carcinoma.     

Physical-activity-assessment measures compared in a biethnic rural population: the San Luis Valley Diabetes Study

We evaluated the consistency of three questionnaire methods of assessing work and leisure activity in the rural biethnic population of the San Luis Valley Diabetes Study. A 7-d physical activity recall (PAR), a ranking of usual activity, and a history of usual participation in vigorous activity were used. Energy expenditure (kJ.kg-1.wk-1) (EE) was estimated from PAR. Subjects were 503 adults [49% non-Hispanic white (NHW), 51% Hispanic]. Physical activity at work rather than leisure-time activity largely determined total energy expenditure. Average EE at work increased with work rank for all subjects combined [mean EE (SEE) for rank 1 (low) = 324.2 (24.4), rank 4 (high) = 874.0 (102.1)] and within sex, ethnic, and occupational subgroups. Leisure EE increased with leisure rank only for NHW men and employed women. Similar patterns were observed in comparisons of PAR data with history of vigorous activity. Further development and validation of instruments appropriate for use across population subgroups are needed.