The pharmacokinetics of lignocaine in humans during a computer-controlled infusion.

Several types of chronic pain syndromes are effectively treated with sodium channel blockers such as lignocaine. Further investigation of this therapeutic modality would be facilitated by refinement of the parameters describing lignocaine distribution and elimination. This would allow precise lignocaine infusion by a computer-controlled infusion to attain and maintain stable target lignocaine concentrations. Arterial blood samples were obtained at frequent intervals during a computer-controlled infusion of lignocaine in 12 adult human volunteers. Plasma lignocaine concentrations of 1, 2, 3, 4 and 5 microg/ml were targeted for 15 min at each concentration. A three-compartment mammillary pharmacokinetic model best described the resulting concentration vs time profile. A population pharmacokinetic analysis was performed using three different techniques; the two-stage, pooled and mixed effects modelling. There was marked overshoot of the plasma concentration above the target prior to refinement of the pharmacokinetic parameters. The best parameters of a three-compartment mammillary model fit to the measured concentration using the pooled data approach were: V(1) = 7.44, V(2) =11.5 and V(3) = 97.71; Cl(1) = 0.585, Cl(2) = 2.23 and Cl(3) =1.64 l/min. Similarly calculated parameters using NONMEM were V(1) = 6.99, V(2) =12.2 and V(3) =1341; Cl(1) = 0.703, Cl(2) =1.24 and Cl(3) =1.49 l/min. The addition of age as a covariate of the pharmacokinetic parameters improved the model in both cases. Height, lean body mass and body surface area as covariates of the pharmacokinetic parameters did not improve the predicted value of the model. Prospective testing of the pharmacokinetic parameters will be required to define whether they function well. The refinement of pharmacokinetic parameters for the computer-controlled intravenous infusion of lignocaine will facilitate further research in pain therapy. Published lignocaine pharmacokinetic values have a relatively large central volume of distribution, and hence, when implemented as a computer-controlled infusion, result in dramatic overshoot shortly after targeting a higher plasma concentration. In light of the long-lasting pain relief provided by sodium channel blockade in neuropathic pain states, overshoot of plasma concentrations must be avoided if the concentration vs effect relationship is to be defined.     

Disorders of the pyruvate dehydrogenase complex

Pyruvate dehydrogenase deficiency may be a non-specific consequence of many different neurological degenerative disorders. There are also serious methodological problems in estimating the activity of this enzyme complex.     

Persistent hyperplastic primary vitreous involving the anterior eye.

The imaging features of persistent hyperplastic primary vitreous (PHPV) affecting the posterior eye are well known. We recently encountered a patient with the anterior variant of PHPV who had MR imaging of the orbits. We present the clinical and imaging findings of this unusual entity and discuss the therapeutic options available for its management.     

Active idiopathic systemic lupus erythematosus in a 90-year-old woman requiring corticosteroid therapy.

A woman who developed multisystem systemic lupus erythematosus (SLE) at the age 80 improved with therapy, but after a hip fracture her disease flared necessitating corticosteroid treatment at age 90. This is the oldest case of active lupus ever reported, and points out the importance of not excluding active SLE as a cause of symptoms or signs even in advanced age.     

The strength of surgical repairs of the rotator cuff. A biomechanical study on cadavers.

Using 26 cadaver shoulders, we produced a standard defect in the supraspinatus tendon and performed one of three types of repair. Their strength was found by testing in tension the force required to produce a gap of 3 mm, then 6 mm, and finally total disruption of the repair. The use of a polyethylene patch to spread the forces over the lateral bone surface and of extra sutures to grasp the tendon end raised by 2.6 times the load at which a 3 mm gap in the repair occurred and by 1.7 times the load to failure.     

Progressive hind limb paralysis in mice carrying a v-Mos transgene.

To study the function of the protooncogene Mos in mouse brain development we have created a transgenic mouse model system in which an activated form of the gene, the murine retroviral v-Mos gene, is highly overexpressed in the brain. Six transgenic founder animals and mice of one established transgenic line (line TG66) displayed a progressive hind limb paralysis with onset between 18 days and 9 months. The severity of the neurological phenotype correlated with pathological alterations and the degree of v-Mos expression in the brain which varied between individual animals of line TG66. The most striking feature of the brain pathology was the presence of large, abnormal astrocytes in the cerebellum, medulla, thalamus and in the dorsal horn of the spinal cord. These areas also contained shrunken and basophilic neurons whose cytoplasm was abnormally immunoreactive for phosphorylated epitopes of neurofilaments. In addition to neuropathologic changes, these mice also displayed aberrant eye lens differentiation and absence of hair cells in the inner ear. These results establish v-Mos transgenic mice as a model system to study progressive neurodegenerative disease and provide further evidence that the Mos protein-serine/threonine kinase has a function in brain development.