PURPOSE: This trial was conducted to assess the toxicity and efficacy of 131I-Lym-1 in patients with either malignant B-cell non-Hodgkin's lymphoma (NHL) or chronic lymphocytic leukemia (CLL) using low-dose, fractionated radioimmunotherapy (RIT). MATERIALS AND METHODS: Thirty adult patients who had advanced B-cell malignancies (25 NHL and 5 CLL) had progressed despite standard therapy; 12 patients entered the trial with Karnofsky performance status (KPS) of equal to or greater than 60. Patients were treated with a series of intravenous doses of 131I-Lym-1 with a goal of reaching a cumulative dose in each patient of at least 300 mCi. All patients were Lym-1 reactive. Clinical responses and immediate toxicity were evaluable in all 30 patients and delayed toxicity in 26. RESULTS: Toxicity to Lym-1 antibody occurred with 28% of the 176 doses and was transient. Human antimouse antibodies (HAMA) were generated in 30% after a mean of 4 doses, but interrupted therapy in only 10% of the patients. Thrombocytopenia was dose-limiting; there were no deaths due to toxicity. Tumor regression occurred in 25 (83%) of the patients and was great enough, and durable enough, in 17 (57%) to qualify them as responders; 13 NHL patients and 4 CLL patients. Advanced disease often interrupted therapy prematurely. However, 18 patients received at least 180 mCi of 131I-Lym-1; 17 (94%) of these responded to the therapy. CONCLUSION: Although advanced disease often interrupted therapy prematurely, the results from 131I-Lym-1 therapy are clearly promising and warrant additional trials.

Adult↗

PubMed1998

Haemodynamic actions of insulin.

Several lines of evidence indicate a significant association between insulin and cardiovascular disease. This association might be explained by direct (cardio) vascular effects of insulin. Two hemodynamic actions of insulin are discussed in this review; it induces direct vasodilation in skeletal muscle and stimulation of the sympathetic nervous system. These closely linked effects normally offset each other. Although more insight has been obtained into responses in insulin-resistant individuals and possible mechanisms, direct evidence to support a causative role for insulin is not yet available.

Animals↗

PubMed1998

Different relationships of spillover to release of norepinephrine in human heart, kidneys, and forearm.

Spillover of norepinephrine (NE) into plasma is used frequently as an index of NE release and therefore of sympathetic nerve activity. An important limitation of NE spillover is that it reflects not only release but also uptake processes that intervene before the transmitter reaches the circulation. To overcome this limitation, we developed a method for estimating NE release based on measurements of the specific activities of [3H]NE in plasma and interstitial fluid during intravenous infusion of [3H]NE. We applied this method to examine relationships among NE release, tissue uptake, and spillover in the human heart, kidneys, and forearm. The sum of uptake and spillover of released NE provided an estimate of NE release into the interstitial fluid. In the kidneys, NE release averaged three times NE spillover, in skeletal muscle, 12 times NE spillover, and in the heart, >20 times NE spillover. Thus NE release greatly and variably exceeds NE spillover from these organs, so that assessing regional sympathetic function requires an understanding of the relationship of NE spillover to NE release.

Adult↗

PubMed1998

Heterogeneous neurochemical responses to different stressors: a test of Selye's doctrine of nonspecificity.

Selye defined stress as the nonspecific response of the body to any demand. Stressors elicit both pituitary-adrenocortical and sympathoadrenomedullary responses. One can test Selye's concept by comparing magnitudes of responses at different stress intensities and assuming that the magnitudes vary with stress intensity, with the prediction that, at different stress intensities, ratios of increments neuroendocrine responses should be the same. We measured arterial plasma ACTH, norepinephrine, and epinephrine in conscious rats after hemorrhage, intravenous insulin, subctaneous formaldehyde solution, cold, or immobilization. Relative to ACTH increments, cold evoked large norepinephrine responses, insulin large epinephrine responses, and hemorrhage small norepinephrine and epinephrine responses, whereas immobilization elicited large increases in levels of all three compounds. The ACTH response to 25% hemorrhage exceeded five times that to 10%, and the epinephrine response to 25% hemorrhage was two times that to 10%. The ACTH response to 4% formaldehyde solution was two times that to 1%, and the epinephrine response to 4% formaldehyde solution exceeded four times that to 1%. These results are inconsistent with Selye's doctrine of nonspecificity and the existence of a unitary "stress syndrome," and they are more consistent with the concept that each stressor has its own central neurochemical and peripheral neuroendocrine "signature."

Adrenocorticotropic Hormone↗

PubMed1998

Maximum-tolerated dose, toxicity, and efficacy of (131)I-Lym-1 antibody for fractionated radioimmunotherapy of non-Hodgkin's lymphoma.

PURPOSE: Lym-1, a monoclonal antibody that preferentially targets malignant lymphocytes, has induced remissions in patients with non-Hodgkin's lymphoma (NHL) when labeled with iodine 131 ((131)I). Based on the strategy of fractionating the total dose, this study was designed to define the maximum-tolerated dose (MTD) and efficacy of the first two, of a maximum of four, doses of (131)I-Lym-1 given 4 weeks apart. Additionally, toxicity and radiation dosimetry were assessed. MATERIALS AND METHODS: Twenty patients with advanced NHL entered the study a total of 21 times. Thirteen (62%) of the 21 entries had diffuse large-cell histologies. All patients had disease resistant to standard therapy and had received a mean of four chemotherapy regimens. (131)I-Lym-1 was given after Lym-1 and (131)I was escalated in cohorts of patients from 40 to 100 mCi (1.5 to 3.7 GBq)/m2 body surface area. RESULTS: Mean radiation dose to the bone marrow from body and blood (131)I was 0.34 (range, 0. 1 6 to 0.63) rad/mCi (0.09 mGy/MBq; range, 0.04 to 0.17 mGy/ MBq). Dose-limiting toxicity was grade 3 to 4 thrombocytopenia with an MTD of 100 mCi/m2 (3.7 GBq/m2) for each of the first two doses of (131)I-Lym-1 given 4 weeks apart. Nonhematologic toxicities did not exceed grade 2 except for one instance of grade 3 hypotension. Ten (71 %) of 14 entries who received at least two doses of (131)I-Lym-1 therapy and 11 (52%) of 21 total entries responded. Seven of the responses were complete, with a mean duration of 14 months. All three entries in the 100 mCi/m2 (3.7 MBq/m2) cohort had complete remissions (CRs). All responders had at least a partial remission (PR) after the first therapy dose of (131)I-Lym-1. CONCLUSION: (131)I-Lym-1 induced durable remissions in patients with NHL resistant to chemotherapy and was associated with acceptable toxicity. The nonmyeloablative MTD for each of the first two doses of (131)I-Lym-1 was 100 mCi/m2 (total, 200 mCi/m2) (3.7 GBq/m2; total, 7.4 GBq/m2).

Adult↗

PubMed1998

Catecholamines and neurocardiogenic syncope.

Explore the source record for details and available documents.

Adrenal Medulla↗

PubMed1998

Sympathetic cardioneuropathy in dysautonomias.

Explore the source record for details and available documents.

Ammonia↗

PubMed1998

Novel catecholaminergic systems. Overview.

Explore the source record for details and available documents.

Animals↗

PubMed1997

Increased survival associated with radiolabeled Lym-1 therapy for non-Hodgkin's lymphoma and chronic lymphocytic leukemia.

BACKGROUND: Because most patients with advanced non-Hodgkin's lymphoma (NHL) and chronic lymphocytic leukemia (CLL) respond to radioimmunotherapy (RIT), the study was designed to evaluate the relationship between response and survival in patients treated with radiolabeled Lym-1. METHODS: Fifty-seven patients with NHL (52) or CLL (5) were treated with radiolabeled Lym-1 antibody between 1985 and 1994. Influence of response to treatment on survival was examined directly and was also adjusted for other factors previously found to be significant predictors of survival. A multivariate model that was based on baseline Karnofsky performance status (KPS) and serum lactic dehydrogenase (LDH) predicted response and survival and was used to define risk groups. Proportional-hazards, Kaplan-Meier, and Landmark models were used to evaluate parameters for their ability to predict outcome. RESULTS: By using a proportional-hazards model with response as a time-dependent variable, overall response (P < 0.001) and complete response (P = 0.006) were predictive of increased survival in univariate analyses. Overall response continued to be significant (P = 0.02) in multivariate analyses, even when risk groups that also predicted survival were included. Median survival of responders was 84 weeks, whereas that of nonresponders was 22 weeks when the Landmark method, based on response status at 16 weeks from start of therapy, was used to generate survival curves. CONCLUSIONS: Response to treatment with radiolabeled Lym-1 was associated with increased survival, even when adjusted for baseline clinical parameters that also predicted for survival. The results provide the first unbiased evidence for survival effects of RIT in patients.

Adult↗

PubMed1997

Sympathetic cardioneuropathy in dysautonomias.

BACKGROUND: The classification of dysautonomias has been confusing, and the pathophysiology obscure. We examined sympathetic innervation of the heart in patients with acquired, idiopathic dysautonomias using thoracic positron-emission tomography and assessments of the entry rate of the sympathetic neurotransmitter norepinephrine into the cardiac venous drainage (cardiac norepinephrine spillover). We related the laboratory findings to signs of sympathetic neurocirculatory failure (orthostatic hypotension and abnormal blood-pressure responses associated with the Valsalva maneuver), central neural degeneration, and responsiveness to treatment with levodopa-carbidopa (Sinemet). METHODS: Cardiac scans were obtained after intravenous administration of 6-[18F]fluorodopamine in 26 patients with dysautonomia. Fourteen had sympathetic neurocirculatory failure--three with no signs of central neurodegeneration (pure autonomic failure), two with parkinsonism responsive to treatment with levodopa-carbidopa, and nine with central neurodegeneration unresponsive to treatment with levodopa-carbidopa (the Shy-Drager syndrome). The rates of cardiac norepinephrine spillover were estimated on the basis of concentrations of intravenously infused [3H]norepinephrine during catheterization of the right side of the heart. RESULTS: Patients with pure autonomic failure or parkinsonism and sympathetic neurocirculatory failure had no myocardial 6-[18F]fluorodopamine-derived radioactivity or cardiac norepinephrine spillover, indicating loss of myocardial sympathetic-nerve terminals, whereas patients with the Shy-Drager syndrome had increased levels of 6-[18F]fluorodopamine-derived radioactivity, indicating intact sympathetic terminals and absent nerve traffic. Patients with dysautonomia who did not have sympathetic neurocirculatory failure had normal levels of 6-[18F]fluorodopamine-derived radioactivity in myocardium and normal rates of cardiac norepinephrine spillover. CONCLUSIONS: The results of 6-[18F]fluorodopamine positron-emission tomography and neurochemical analyses support a new clinical pathophysiologic classification of dysautonomias, based on the occurrence of sympathetic neurocirculatory failure, signs of central neurodegeneration, and responsiveness to levodopa-carbidopa.

Adult↗

PubMed1997

6-[18F]fluorodopamine positron emission tomographic scanning in the assessment of cardiac sympathoneural function--studies in normal humans.

Thoracic positron emission tomographic (PET) scanning after injection of 6-[18F]fluorodopamine ([18F]-6F-DA) visualizes cardiac sympathetic innervation. We tested whether changes in curves relating myocardial [18F]-6F-DA-derived radioactivity with time (time-activity curves, TACs) can reflect changes in important aspects of cardiac sympathetic function. Thoracic PET scans were obtained after intravenous administration of [18F]-6F-DA or the perfusion imaging agent [13N]ammonia into normal volunteers. Ganglion blockade with trimethaphan (TRI) was used to decrease sympathoneural traffic, desipramine (DMI) to block neuronal uptake of catecholamines, and tyramine (TYR) to displace vesicular amines. After [18F]-6F-DA administration, myocardial concentrations of [18F]-6F-DA-derived radioactivity declined bi-exponentially from the peak value. TRI increased the y-intercept (yo) value for the early phase (p = 0.01), and DMI decreased the yo for the late phase (p = 0.01). The TRI effect did not result from increased arterial [18F]-6F-DA concentrations or from increased myocardial perfusion. TYR infusion, begun 90 min after [18F]-6F-DA administration, accelerated the decline of myocardial radioactivity by 2.6-fold (p = 0.003). Alterations in post-ganglionic sympathoneural traffic, neuronal catecholamine uptake, and vesicular turnover of monoamines produce distinct changes in myocardial TACs after [18F]-6F-DA injection. [18F]-6F-DA PET scanning may therefore enable assessments of effects of stressors, drugs, and neurocardiological disorders on specific aspects of cardiac sympathoneural function.

Adrenergic Uptake Inhibitors↗

PubMed1997

Gender differences in brain metabolic and plasma catecholamine responses to alpha 2-adrenoceptor blockade.

alpha 2-Adrenergic receptors modulate the release of several neurotransmitters implicated in the treatment and pathophysiology of mood and anxiety disorders. Significant sex differences occur in the prevalence of both disorders. To test whether gender affects alpha 2 function, the plasma catecholamine and brain metabolic responses to alpha 2 blockade were measured in male and female volunteers. Ten female and thirteen male volunteers underwent [18F]-fluorodeoxyglucose (FDG) positron emission tomography (PET) scans before and after infusion of idazoxan (200 micrograms/kg). Measures of plasma catecholamines, blood pressure, and anxiety were obtained. Norepinephrine responses were larger in males. Women showed global increases in metabolism, whereas males had no global changes and some regional decreases in FDG uptake following idazoxan administration. The differences in norepinephrine increases are consistent with previously reported effects of gender on sympathetic activation. The PET data suggest gender differences in responses to alpha 2-receptor blockade in brain as well.

Adrenergic alpha-2 Receptor Antagonists↗