Summary Clinical anti-tumour efficacy of anti-cancer drugs is a function of dose intensity, i.e. the concentration -time profile in tumour tissue. Hence, information on drug concentration profiles in tumours is of critical importance but appropriate methods for measurement are lacking. The aim of the present study was to obtain, by microdialysis sampling, concentration -time profiles in a solid tumour (melanoma) of a model anti-cancer drug, carboplatin, and thereby to assess the scope of microdialysis for tumour pharmacokinetic studies in man. Six patients with cutaneous melanoma metastases at the extremities or body trunk, scheduled to receive carboplatin (400 mg m 2 i.v.) were studied. Carboplatin concentrations were monitored in serum, intratumoral and subcutaneous tissue. Calibration of the microdialysis probes was carried out in vitro and in vivo with use of the retrodialysis method. Complete carboplatin concentration vs time profiles in tumour and subcutaneous tissue were obtained. Major pharmacokinetic parameters (maximum concentration, time to maximum concentration, area under the curve, elimination half-life) were calculated for tissues and tumour/ serum concentration ratios for carboplatin were derived. Mean free concentrations of carboplatin in cutaneous melanoma metastases reached only about 50-60% of total serum levels; maximal intratumoral concentrations were 7.6 (±2.0; s.e.m.) Mg ml-', mean concentrations in subcutaneous tissue were similar to those in tumour.The present study demonstrates that microdialysis is a novel tool for measuring drug concentrations in solid tumours in humans in vivo and appears to be a valuable addition for pharmacokinetic/pharmacodynamic studies in oncology.

1. Diabetic autonomic neuropathy causes loss of sympathetic cardiovascular control and is associated with increased vascular sensitivity to catecholamines. Supersensitivity to catecholamines could be due to either a postsynaptic increase in vascular sensitivity or to decreased catecholamine uptake into peripheral sympathetic nerve endings. 2. To differentiate between these possible mechanisms we have measured the responsiveness in vivo to noradrenaline and phenylephrine with local infusions into peripheral veins of diabetic patients with and without symptomatic autonomic neuropathy and of healthy control subjects. The dorsal hand vein compliance technique was used. 3. Symptomatic diabetic patients required significantly lower doses of noradrenaline for half-maximal venoconstriction (ED50) (geometric mean 2.14 ng/min) than control subjects (geometric mean 6.61 ng/min, P = 0.032), but there was no difference in the results from the phenylephrine dose-response curves between the groups. There were no differences in venous responsiveness to noradrenaline or phenylephrine between the asymptomatic diabetic group and the control group. However, in the asymptomatic diabetic group, postural blood pressure change (an index of loss of sympathetic control) was correlated with the ED50 for noradrenaline (r = 0.74, P = 0.014), but not with the ED50 for phenylephrine. In the control group the ED50 values for noradrenaline and phenylephrine were correlated with each other (r = 0.81, P = 0.0005). 4. Both vasopressor drugs act on vascular alpha-adrenoceptors, but only noradrenaline is taken up into peripheral sympathetic nerve endings. Our results suggest that, in diabetic patients, vascular supersensitivity to catecholamines is primarily determined by decreased neuronal catecholamine uptake. A postsynaptic increase in vascular alpha-adrenoceptor stimulation does not appear to be prominent in diabetic autonomic neuropathy.

Purpose Thromboxane A2 (TxA2) is implicated in the pathogenesis of various forms of drug‐induced renal damage. Based on previous functional studies, we postulated that cis‐dichlorodiammineplatinum (cisplatin) induces intrarenal TxA2 synthesis. To test this hypothesis, we measured urinary excretion of thromboxane B2 (TxB2), the stable inactive metabolite of TxA2, during and after cisplatin administration. Patients and methods The study included 16 patients with malignant disease who were scheduled to receive cisplatin (100 mg/m2) and 11 healthy subjects who received the same amount of fluid loading and the same concomitant medication as the patients but no cisplatin. Total urine output was collected in seven intervals from 24 hours before until 72 hours after the start of prehydration. Urinary immunoreactive TxB2 was measured. Results There was a marked increase (4.5 ± 1.6‐fold; mean ± SEM) in urinary TxB2 excretion in patients during and immediately after cisplatin infusion. This increase was significant compared with baseline and the control group. Conclusion High‐dose cisplatin causes an acute increase in urinary excretion of TxB2. This likely represents enhanced intrarenal synthesis of TxA2, in response to an acute damaging effect of cisplatin on the kidneys. These findings warrant further studies to evaluate the renoprotective effect of anti‐TxA2 intervention in patients receiving high‐dose cisplatin. Clinical Pharmacology & Therapeutics (1995) 58, 418–424; doi:

We studied in vivo responsiveness of venous alpha 1- and alpha 2-adrenoceptors, measuring the diameter changes in superficial veins in response to alpha-adrenergic agonists and antagonists in healthy human volunteers. The dorsal hand vein technique was used because it permits complete dose-response studies of venous constriction without confounding reflex alterations. Local infusions of all agonists studied induced dose-dependent contraction of the hand vein; the maximal effects (Emax) were: norepinephrine (88% +/- 10%), methoxamine (97% +/- 5%), phenylephrine (95% +/- 6%), clonidine 54% +/- 12%), and azepexole (68% +/- 26%). Clonidine reduced the norepinephrine-induced venoconstriction by 11% +/- 10%. Oral doses of 1 mg prazosin antagonized the venoconstriction induced by norepinephrine, methoxamine, and clonidine, but not by azepexole. Yohimbine-antagonism was observed against all agonists studied. Inhibition by yohimbine of clonidine-induced venoconstriction was irreversible over 60-180 min. Results show that the in vivo effects on veins of alpha-adrenergic agonists are in good agreement with results from in vitro experiments. Agonists with alpha 1- and alpha 2-adrenoceptor subtype selectivity cause venoconstriction in vivo, but alpha 2-receptor mediated constriction is intrinsically weaker. Clonidine acts as a partial antagonist against norepinephrine, presumably on postsynaptic alpha 2-receptors. At high doses, alpha 2-adrenoceptor subtype selectivity of clonidine and yohimbine appear to be partially lost in vivo.

Responsiveness of superficial hand veins to local infusions of noradrenaline was compared in patients with primary varicose veins and in healthy volunteers by use of the dorsal hand vein technique. Patients with varicose veins required significantly higher doses of noradrenaline for half-maximal venoconstriction than the dose required by control subjects (geometric mean, 11.6 ng/min in patients compared with 4.8 ng/min in control subjects; p = 0.006). Noradrenaline responsiveness in varicose veins was not significantly different from hand vein responsiveness in the same patients. Our findings indicate a constitutional decrease in venous alpha-adrenergic receptor responsiveness in patients with varicosities. Dilation of varicose veins does not further affect noradrenaline-induced venoconstriction.