Paracetamol (acetaminophen) pharmacodynamics: interpreting the plasma concentration.

Interpretation of analgesic and antipyretic responses documented after paracetamol administration is confused because response is not directly related to concentration in the blood, but rather to an effect compartment. The effect compartment does not have real measurable concentrations, but concentrations equate approximately to those observed in the cerebrospinal fluid. A time delay exists before drug reaches the effect compartment, and the equilibration half-time between the central and effect compartment is described by a single first-order parameter (Teq or T(1/2)keo), reported to be approximately 1 h for paracetamol. Paediatric analgesic studies are limited because they have only explored postoperative pain after tonsillectomy or day-stay surgery. Other pain types and pain confounders have not been investigated. Adult studies are also similarly limited. Studies investigating antipyresis have not explored the maximum response, limiting the precision of any EC(50) estimate. The influence of the cyclical nature of fever or initial temperature is seldom accounted for in antipyretic studies. Target effect compartment concentrations of 5 mg/l for fever and 10 mg/l for pain do not seem unreasonable on the basis of current literature. Speed of onset may be shortened by giving a larger initial dose or improving absorption characteristics. Consequent plasma concentration achieved, differences in effect compartment equilibration times, and the shape of the effect compartment concentration-response curve help to explain differences between common analgesic/antipyretic drugs.

Immunosuppressive proteins secreted by the gastrointestinal nematode parasite Heligmosomoides polygyrus.

Experiments are described in which the conditions for the production, assay and isolation of immunomodulatory factors from the excretory-secretory (ES) products of Heligmosomoides polygyrus have been standardized. For the inhibition of an in vitro antibody response to keyhole limpet haemocyanin, immunosuppressive activity was most reproducibly produced by 10-20-day-old adult worms maintained in culture for 24 h. This activity was relatively stable at room temperature, at 50 degrees C and pH 2, but was destroyed by boiling. Immunosuppressive activity was eluted from Sephadex G-100 in fractions preceding those containing the bulk of ES proteins, and resolved on sodium dodecyl sulphate-polyacrylamide gel electrophoresis with molecular masses of 67, 54 and 20 kDa. The relative purity of these factors was confirmed by iso-electric focusing, where immunosuppressive activity was associated with proteins of pI values of approximately 4.2 and 4.35.

Comparison of a medium supplement--'Nu-Serum'--and foetal calf serum in RPMI 1640 used for the murine allogeneic mixed lymphocyte reaction.

A commercially available medium supplement, Nu-Serum, was compared with foetal calf serum for its ability to support the murine allogeneic mixed lymphocyte reaction. Nu-Serum supported proliferation whilst at the same time producing significantly lower counts in unstimulated cultures. There was considerably less batch-to-batch variation with Nu-Serum than with foetal calf serum, which obviated the need for pretesting in order to find a suitable batch.

An experimental model of chronic renal failure in mice.

Chronic renal failure (CRF) was induced in CBA/J mice by a combination of surgery and diathermy to the right kidney followed 2 weeks later by complete removal of the left kidney. This procedure resulted in a progressive rise in blood urea nitrogen (BUN) levels accompanied by a fall in packed cell volume (PCV). In a typical group of mice BUN rose to 156.9 +/- 9.1 mg/100 ml and PCV fell to 36.4 +/- 1.9%, 8 weeks after removal of the left kidney, compared to 23.3 +/- 2.8 mg/100 ml and 51.6 +/- 2.1%, respectively, in normal mice. These changes were accompanied by other serum abnormalities in potassium, sodium, calcium, phosphate, chloride, and silicon levels. The surviving renal tissue showed histological changes, and skeletal changes were also evident on radiological examination. Mice in CRF had an increased mean survival time of tail skin allografts and a significant reduction in thymus weight, supporting the use of this model to investigate the well-documented phenomenon of immunosuppression in human patients with uremia.

Sleep and birbiturates: some experiments and observations.

To determine the effect of barbiturates on sleep two subjects, after a control period, received 200 mg. of sodium amylobarbitone for 26 nights. All night sleep records taken during this period showed that the barbiturate shortened the delay to sleep, increased the total sleep period, lengthened the delay to rapid eye movement (R.E.M.) sleep, and depressed R.E.M. sleep. After five nights R.E.M. sleep returned to baseline values -that is, showed tolerance. On stopping the drug withdrawal phenomena were seen, even to this small dose of the drug.In a second experiment a subject dependent on 600 mg. of Tuinal was found to have low normal R.E.M. sleep while on drugs. On withdrawal, delay to sleep increased and total sleep time fell. R.E.M. sleep was doubled and the delay to R.E.M. became abnormally short.These findings suggest that hypnotics allow sleep to be "borrowed," and that patients should be supported while they are being withdrawn.