Robin Stull

Malignant Pheochromocytoma: Effective Treatment with a Combination of Cyclophosphamide, Vincristine, and Dacarbazine

STUDY OBJECTIVE To determine the efficacy and toxicity of combination chemotherapy in patients with advanced, malignant pheochromocytoma. DESIGN Nonrandomized, single-arm trial. SETTING Governmental medical referral center. PATIENTS Fourteen patients with malignant pheochromocytoma confirmed by histologic tests. All patients had metastatic disease and elevated urinary catecholamine secretion. INTERVENTIONS After optimization of antihypertensive therapy, patients received cyclophosphamide, 750 mg/m2 body surface area on day 1; vincristine, 1.4 mg/m2 on day 1, and dacarbazine, 600 mg/m2 on days 1 and 2, every 21 days. MEASUREMENTS AND MAIN RESULTS Combination chemotherapy with cyclophosphamide, vincristine, and dacarbazine produced a complete and partial response rate of 57% (median duration, 21 months; range, 7 to more than 34). Complete and partial biochemical responses were seen in 79% of patients (median duration, more than 22 months; range, 6 to more than 35). All responding patients had objective improvement in performance status and blood pressure. Toxicity included expected hematologic, neurologic, and gastrointestinal effects of chemotherapy without serious sequelae. There were four minor hypotensive episodes and one minor hypertensive episode. CONCLUSIONS Combination chemotherapy with cyclophosphamide, vincristine, and dacarbazine is effective for advanced malignant pheochromocytoma. Urinary catecholamines are useful to ascertain biochemical response to therapy.

Clonidine Suppression Testing in Essential Hypertension

To assess the contribution of sympathetic outflow to blood pressure in patients with essential hypertension, we measured blood pressure and plasma norepinephrine responses to clonidine, an antihypertensive agent that decreases central sympathetic outflow, in 44 patients and in 41 normotensive control subjects of similar age. Among the hypertensive patients, the resting level of plasma norepinephrine was significantly related to the decrease in mean arterial pressure 3 hours after a single oral dose of clonidine 300 micrograms (r = 0.62, p less than 0.001). The magnitude of the depressor response in the patients also was correlated significantly with the decrease in plasma norepinephrine after clonidine (r = 0.60, p less than 0.001). These results suggest that increased sympathetic outflow plays a pathophysiologic role in some patients with essential hypertension.

Levels of Catechols in Epileptogenic and Nonepileptogenic Regions of the Human Brain

Abstract: Recent reports about tyrosine hydroxylase and α1‐adrenoceptors in epileptic foci have suggested increased regional catecholaminergic activity, which may serve a compensatory, inhibitory role. We measured levels of catechols, including the precursor 3,4‐dihydroxyphenylalanine (Dopa) and the catecholamines dopamine (DA) and nor‐epinephrine (NE), in surgically removed foci identified by electrocorticography and in nonepileptogenic sites from 23 patients with intractable temporal lobe epilepsy. The following values (mean ± 1 SD) were obtained: DOPA = 142 ± 60 ng/g of protein in the focus vs. 115 ± 39 ng/g in the nonfocus (p < 0.01); DA = 168 ± 85 vs. 106 ± 54 ng/g (p < 0.001); and NE = 267 ± 117 vs. 181 ± 80 ng/g (p < 0.001). The results are consistent with increased catecholaminergic activity in epileptic foci.

Steady-state dopamine clearance in critically ill infants and children

Little is known about dopamine pharmacokinetics in pediatric patients, especially in critically ill infants and children who often receive treatment with dopamine. Arterial plasma concentrations of dopamine were measured in 27 patients who were hemodynamically stable and received dopamine for at least one hour. The dopamine levels were measured using liquid chromatography with electrochemical detection. Dopamine clearance averaged 96.2 +/- 55.4 ml/kg.min in 13 patients in the neonatal ICU, and 58.8 +/- 51 ml/kg.min in 14 patients in the pediatric ICU. Six patients had renal (BUN greater than 25 mg/dl, or creatinine greater than 1.2 mg/dl) or hepatic (liver enzymes greater than 3 times normal) dysfunction. Dopamine clearance in these patients (25.1 +/- 17.2 ml/kg.min) was substantially lower than in the other patients (p less than .01). Neither postnatal nor gestational age correlated with dopamine clearance. Substantial interindividual variation was observed in steady-state dopamine clearance in critically ill infants and children, and plasma dopamine could not be predicted accurately from the dopamine infusion rate. Because of the more than three-fold prolongation of dopamine clearances in patients with hepatic or renal dysfunction, these patients may be more likely to suffer toxic effects of dopamine at the usual drug infusion rates.

Plasma 3, 4-Dihydroxyphenylalanine (Dopa) and Catecholamines in Neuroblastoma or Pheochromocytoma

Excerpt Neuroblastomas and benign and malignant pheochromocytomas are tumors of neural-crest origin that have different clinical characteristics: neuroblastomas are aggressive tumors that occur in ...

Angiotensin II increases cytosolic calcium and stimulates catecholamine release in cultured bovine adrenomedullary cells

In bovine adrenomedullary cells in primary culture, angiotensin II (AII) elicited virtually immediate, dose-related increments in cytosolic calcium [( Ca++]i) measured by the Quin 2 technique and stimulated approximately proportional secretion of norepinephrine, epinephrine, and dopamine measured by liquid chromatography with electrochemical detection. Peak responses of [Ca++]i to AII were similar to peak responses to nicotine or KCl. Pre-treatment with verapamil or washing the cells in calcium-free medium attenuated the stimulatory effect of AII on [Ca++]i. Pre-treatment with nicotine, which temporarily inactivates cholinergic receptor-activated calcium channels, did not affect [Ca++]i responses to AII. The results indicate functional effects of AII on cultured chromaffin cells. The mechanism of cellular activation by AII appears to include increases in [Ca++]i due to opening of membrane calcium channels which may be unrelated to cholinergic receptor-operated calcium channels.

Estimation of intrasynaptic norepinephrine concentrations in humans.

Levels of synaptic cleft norepinephrine associated with pressor responses were estimated in humans by measuring blood pressure and arterial plasma norepinephrine during norepinephrine infusion and during yohimbine-induced release of endogenous norepinephrine. Linear pressor response-log norepinephrine concentration relationships were observed during the infusions. At a pressor response of 20 mm Hg, arterial norepinephrine averaged 3647 pg/ml. The pressor-log norepinephrine relationship was shifted more than fivefold to the left during combined ganglionic, alpha 2-adrenergic receptor, and Uptake1 (neuronal norepinephrine uptake) blockade: arterial norepinephrine averaged 684 pg/ml at a 20 mm Hg pressor response. During yohimbine-induced release of endogenous norepinephrine in desipramine-pretreated subjects, arterial norepinephrine averaged 467 pg/ml at a 20 mm Hg pressor response. Since the norepinephrine concentration in the synaptic clefts must have been between the values for plasma norepinephrine during its infusion and during its endogenous release, we estimated that in healthy people, a 20 mm Hg sympathetically mediated pressor response is associated with about a 560 pg/ml (3.3 nM) concentration of norepinephrine in the average neuroeffector junction.

Cerebrospinal fluid and serum levels of dopa, catechols, and monoamine metabolites in patients with epilepsy.

Summary: We measured CSF and serum concentrations of monoamines and monoamine metabolites in normal control subjects and in patients with partial epilepsy between and less than 2 h after complex partial seizures (CPS) or secondarily generalized tonic‐clonic seizures (SGTCs). After SGTCs, concentrations of norepinephrine in CSF were significantly higher (p < 0.05) than interictal concentrations, concentrations after PSs, and concentrations in control subjects. Serum epinephrine levels also were significantly higher after SGTCs than interictal and control subjects’levels. CSF HVA levels were significantly higher after PSs than interictal or control subjects’levels. CSF concentrations of norepinephrine and its intraneuronal metabolite, dihydroxyphenylglycol, were highly correlated, both interictally and following SGTCs, whereas correlations between serum and CSF levels of these catechols generally were not statistically significant. The results indicate that seizures are associated with release of catecholamines in the central nervous system.

Plasma catecholamine and hemodynamic responses during isoproterenol infusions in humans

We infused isoproterenol (ISO) intravenously into 23 subjects (3.5, 7, 14, and 35 ng/kg/min for 20 minutes at each dose) and measured venous plasma concentrations of ISO and the circulatory and plasma norepinephrine (NE) and epinephrine (E) responses. At the lowest dose, venous plasma ISO averaged 48 pg/ml and was associated with increased heart rate (9%; P < 0.001), cardiac index (20%; P < 0.001), and stroke volume (9%; P < 0.02) and decreased total peripheral resistance index (−21%; P < 0.001). Linear concentration‐response relationships were observed between plasma ISO and cardiac index and between plasma ISO and heart rate. Plasma NE increased as a function of plasma ISO (mean increase 81% at 35 ng/kg/min), whereas plasma E was unchanged or decreased. The results indicate that circulatory effects of ISO are detectable in humans at plasma concentrations in the range of physiologic levels of E. Since ISO increases plasma NE, ISO may act presynaptically to enhance NE release from sympathetic nerve terminals and thereby stimulate a‐adrenoceptors indirectly. ISO does not appear to stimulate secretion from the adrenal medulla or corelease of E with NE from sympathetic nerve endings.

Role of CRH in Glucopenia‐lnduced Adrenomedullary Activation in Rats

Acute glucoprivation profoundly stimulates hypothalamic‐pituitary‐adrenocortical (HPA) and adrenomedullary outflows. Whether these responses reflect a single central mechanism regulated by corticotropin‐releasing hormone (CRH) has been unclear. This study examined the role of endogenous CRH in HPA and adrenomedullary responses to hypoglycemia in Sprague‐Dawley rats, by using anti‐CRH immune serum or a CRH antagonist (α‐helical h/r CRH9–41, and in Lewis rats, a strain characterized by deficient hypothalamic CRH responses during stress. In conscious Sprague‐Dawley rats with indwelling arterial and venous cannulas, insulin (0.3 U/kg) was injected iv, and responses of serum glucose concentrations and plasma levels of corticotropin (ACTH) and catechols (including epinephrine, EPI; norepinephrine, NE; dihydroxyphenylalanine, DOPA; dihydroxyphenylglycol, DHPG; and dihydroxyphenylacetic acid, DOPAC) were assessed, with or without pretreatment with anti‐CRH immune serum (0.5 or 1.0ml iv or 10μI icv) or α‐helical h/r CRH9–41 (130 nmol iv or 13 nmol icv). Responses to insulin (1.0 U/kg iv) were also measured in conscious juvenile Lewis and Fischer 344/N rats. Insulin‐induced hypoglycemia markedly increased plasma levels of EPI and ACTH in all groups. Pretreatment iv with 1.0ml of anti‐CRH immune serum blocked the ACTH response to insulin but failed to attenuate the EPI response, α‐helical h/r CRH9_41, whether given iv or icv, failed to alter ACTH or EPI responses to insulin, although the antagonist did block EPI responses to icv CRH. Hypoglycemia elicited similar increments in ACTH levels in Lewis rats and Fischer 344/N control rats; and although Lewis rats had lower baseline EPI and smaller responses of NE, DHPG, DOPA, and DOPAC levels, the groups did not differ in proportionate increments in EPI levels. The results indicate that the ACTH response to hypoglycemia depends on availability of CRH outside the blood‐brain barrier—presumably in the pituitary gland. The findings with icv α‐helical h/r CRH9_41 can be explained by failure of the antagonist to reach effective concentrations at central sites of action of endogenous CRH, or by mechanisms other than CRH release determining the adrenomedullary response to hypoglycemia. Lewis rats seem to have less adrenomedullary secretion at baseline and smaller responses of NE synthesis and release during hypoglycemia than do Fischer 344/N rats. Neurochemical evidence for differential adrenomedullary and sympathoneural responses during hypoglycemia in all three rat strains is inconsistent with Cannons view of a functionally unitary sympathoadrenal system. Since Lewis and Fischer 344/N rats had similar proportionate responses of both ACTH and EPI levels during hypoglycemia, either Lewis rats have deficient CRH responses to some stressors but not to others, or else pituitary‐adrenocortical and adrenomedullary responses in this setting depend on mechanisms other than CRH release in the brain. Both explanations are inconsistent with the doctrine of non‐specificity, the main tenet of Selyes stress theory.