We have studied the clinical effects and pharmacokinetics of levodopa infusions and oral therapy in seven patients with Parkinson's disease. They all showed on‐off fluctuations whilst receiving long‐term treatment with levodopa in combination with a peripheral decarboxylase inhibitor. Intravenous infusion at a constant rate for up to 16 h resulted in a smoother clinical response, and maintained plasma levodopa concentrations within narrower limits compared with conventional oral therapy. Following infusion rates of 32‐80 mg h‐1 (0.5‐1.3 mg kg‐1 h‐1) the plasma concentration associated with optimum therapeutic response lay between 0.3 and 1.6 mg l‐1. There was considerable variation in the oral absorption and elimination of levodopa, both within and between subjects. The concentration of 3‐OMe dopa in plasma hardly increased during each day's levodopa therapy. In all cases levels were greater than the maximum concentrations of levodopa, sometimes by as much as a factor of 10. In contrast to most previous reports on the pharmacokinetics of levodopa, the data presented here are consistent with a two‐compartment kinetic model. It is not known whether the difference in pharmacokinetics is due to chronic therapy or whether it is specific to those patients who show on‐ off phenomena, but such changes might be related in some way to the development of fluctuations in clinical response.

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1. The metabolism of the radiosensitizing 2-nitroimidazole, misonidazole, has been investigated in mice, rats, baboons, human volunteers, and in patients receiving radiotherapy for advanced malignant disease. 2. Plasma levels of unchanged drug and its desmethylated metabolite have been measured, and in humans there is good correlation of peak plasma concn. with drug dose. All drug-related material in plasma was accounted for as unchanged misonidazole or its desmethylated metabolite, both compounds being radiosensitizers in vitro. 3. Extensive faecal excretion of material not containing any nitro group occurred in mice, rats, and baboons dosed with radiolabelled drug. 4. Renal excretion is the preferred route of elimination in man, baboon and mouse. Nitroimidazole metabolites accounting for over half the urinary excretion in all species were identified. 5. The compound penetrates solid murine tumours in concentrations sufficient to achieve radiosensitization.

I The urinary recovery and plasma concentration of debrisoquine (D) and its metabolite 4-hydroxydebrisoquine (HD) has been studied following single and multiple oral administration of debrisoquine hemisulphate to 15 hypertensive in-patients and four normal volunteers. The distribution of D in the blood was studied after a single dose to one volunteer. The greatest concentration of the drug was in the platelet rich fraction from which it was eliminated slowly. The elimination half-lives in plasma and platelet rich plasma were 17.5 h and 56 h respectively. 7 On early multiple dosing the hypotensive response was related to high plasma D concentrations.

weeks (P< 0-01) in those who responded well and by six weeks (P<005) in those who showed no remission. Among patients with normal prolactin values the release of prolactin after thyrotrophin-releasing hormone was significantly greater in those with no remission than in those who responded to tamoxifen. Responses in those with hyperprolactinaemia were reduced to about half the control values, and again this change occurred faster in those who were successfully treated. Patients therefore seem to have a better chance of responding to antioestrogen treatment if prolactin secretion is low.