Pharmacokinetics and non-analgesic effects of S- and R-ketamines in healthy volunteers with normal and reduced metabolic capacity.

OBJECTIVE: There is a growing interest in low-dose ketamine as an analgesic agent in different intractable pain conditions. Due to its narrow therapeutic window, well-defined pharmacokinetic parameters are essential for its successful use in these situations. Arterial data for ketamine or its enantiomers have not been reported before. The metabolic pathways involved in the metabolism of S- and R-ketamines are not known. METHODS: Ten healthy male volunteers received 7 mg infusions of R- and S-ketamine-hydrochloride in a randomised order over 30 min on 2 separate days. Six were extensive metabolisers, two were poor metabolisers of debrisoquine (CYP2D6) and two were poor metabolisers of mephenytoin (CYP2C19). Arterial and venous concentrations and non-analgesic side effects were measured. RESULTS: Subjective side effects were mild but more pronounced for S- than for R-ketamine. There were no salient differences between the subjects with reduced and normal metabolic capacity in pharmacokinetic parameters or in side effects. Volumes of distribution and mean residence times were 40% smaller for arterial than for venous data. The mean clearance of R-ketamine, 0.020 l min(-1) kg(-1), was slightly but significantly lower than of S-ketamine, 0.024 l min(-1) kg(-1). CONCLUSIONS: There are large differences between arterial and venous data in the pharmacokinetic parameters that are heavily dependent on distribution processes. Parameters mainly reflecting elimination, such as clearance and area under the concentration time curve, are unchanged. The choice of sampling site could be important when computer-controlled infusions are used.

The brain in healthy aged individuals: MR imaging.

Twenty-four healthy aged individuals with above-average intellectual function were studied with use of a low-field-strength (0.02-T) magnetic resonance (MR) imager. The group was carefully selected so as not to include persons with signs of arteriosclerotic diseases, major somatic disease, or a history of brain disease or dementia in the family. The width of the subarachnoid spaces and lateral ventricles, as well as the frequency and degree of brain white-matter lesions, were described with the use of a visual rating scale. White matter lesions were found in less than 9% of the subjects. The lateral brain ventricles were enlarged in 8% of all individuals and the cortical cerebrospinal fluid (CSF) spaces in more than 40% of all individuals. Moreover, T1 and T2 were estimated in different brain areas, and a positive correlation between T1 in the frontal white matter and age was found. A computer-assisted classification procedure was used to estimate brain tissue and CSF areas. The results of this procedure strongly correlated with the visually estimated ventricular size.

S-100 protein in cerebrospinal fluid after aneurysmal subarachnoid haemorrhage: relation to functional outcome, late CT and SPECT changes, and signs of higher cortical dysfunction.

The concentration of S-100 protein measured in ventricular cerebrospinal fluid (CSF) from 32 patients with subarachnoid haemorrhage (SAH) during the acute phase was related to features on admission such as the Hunt and Hess neurological scale and the amount of blood at the first computed tomography (CT). The S-100 values were also related to functional outcome assessed by the Glasgow outcome scale (GOS) at 12 months. Twenty-two patients were re-examined more than 2 years after the SAH, and the initial S-100 values were related to signs of structural brain damage at CT and single photon emission computed tomography (SPECT) and to the results of neuropsychological evaluation (NPE). NPE included standardized tests for memory functions, intellectual functions, visuo-spatial abilities, sensory-motor functions, and concept formation. Life-adjustment was assessed by two separate questionnaires. Tests for agnostic dysfunction and the Western aphasia battery test (WABT) were also performed. Patients who were functionally disabled or ultimately died had significantly higher initial CSF concentrations of S-100 protein than patients showing good recovery. Patients with low-attenuated regions and/or increased ventricular size at CT and/or regionally decreased tracer uptake on SPECT had higher S-100 levels during days 2-8 than had patients showing no such changes. Logistic and multiple regression analysis of all characteristics assessed during the acute phase after SAH showed that the CSF S-100 concentration during days 2-8 was the factor best correlated to GOS and findings on CT and/or SPECT. All patients showed varying degrees of cognitive impairment at follow-up. The results of NPE and the WABT were related to outcome assessed by GOS and to increased ventricular size on CT. Women had a stronger feeling of maladjustment, but the scores for life adjustment were otherwise not related to other outcome criteria. It is concluded that the ventricular CSF S-100 concentration during the acute phase after SAH is related not only to the functional outcome as assessed by GOS but also to signs of brain damage seen on late CT and SPECT.

Effects of growth hormone substitution on mental performance in adults with growth hormone deficiency: a pilot study.

Five patients ages 22 to 36 years with growth hormone deficiency received substitution with native human growth hormone and biosynthetic methionyl human growth hormone, 8 IU i.m. three times weekly, for two separate 4-week periods. Before and at the end of each treatment period, five psychometric tests evaluating cognitive functions were performed. The results suggest a beneficial effect of growth hormone on certain cognitive functions. The results were similar for the two hGH preparations.