Neurons in the area postrema are the only catecholamine-synthesizing cells in the medulla or pons with projections to the rostral ventrolateral medulla (C1-area) in the rabbit

We have identified, in the rabbit medulla and pons, neurons which project to the C1-region of the rostral ventrolateral medulla. By combining tyrosine hydroxylase immunohistochemistry with retrograde transport of Fluoro-Gold we determined whether any of the retrogradely labelled neurons synthesize catecholamines. The only doubly labelled cells were located in the area postrema. No other group of catecholamine-synthesizing neurons in either the medulla or the pons was found to project to the C1-area of the rostral ventrolateral medulla. Pharmacological agents which lower arterial pressure by stimulating adrenoceptors in the rostral ventrolateral medulla may act on receptors which are not innervated by catecholamine-synthesizing perikarya located outside the C1-region.     

Evaluation of vinorelbine in persistent or recurrent squamous cell carcinoma of the cervix: a Gynecologic Oncology Group study

PURPOSE: Vinorelbine is being explored by the Gynecologic Oncology Group (GOG) for its possible use in advanced or recurrent squamous cell carcinoma of the uterine cervix. The objective of this Phase II trial was to evaluate a days 1 and 8 every-21-days schedule and determine its activity in patients who had failed standard chemotherapy. PATIENTS AND METHODS: Eligible patients with measurable disease and satisfactory baseline bone marrow, liver, and kidney functions were treated with vinorelbine 30 mg/m(2) given on days 1 and 8 every 21 days. A two-stage sampling design was used, proceeding to a second stage accrual if sufficient activity was documented in the first 25 patients. RESULTS: The study did proceed to the second stage and accrued 44 patients. There were six objective responses (one complete, five partial) for a response rate of 13.7% (95% confidence interval: 5.2-27.4%). There were three patients with response in extra-pelvic sites (including the complete response) and three with response in the pelvis. The overall frequency of grades 3 and 4 neutropenia was 41%, whereas neuropathy was reported in 27% and was severe in three. Treatment-related pain, very severe in two instances, was also reported in 27%. CONCLUSION: Vinorelbine has moderate activity in a pretreated population with squamous cell carcinoma of the cervix. Accordingly, vinorelbine in this days 1 and 8 schedule is being studied further in combination with cisplatin by the GOG.     

Cisplatin and irinotecan in squamous cell carcinoma of the cervix: a phase II study of the Gynecologic Oncology Group

OBJECTIVE: To evaluate the combination of cisplatin and irinotecan as first-line treatment of patients with advanced, persistent, or recurrent squamous cell carcinoma of the cervix. METHODS: Patients with no prior treatment for metastatic disease, presence of measurable tumors, performance status of 0 or 1, and adequate bone marrow, renal, and hepatic functions were potentially eligible for this trial. Cisplatin and irinotecan were given weekly at starting doses of 25 and 65 mg/m(2), respectively, for three consecutive weeks. Cycles were to be repeated every 28 days with dose adjustments as required. Patient accrual was based on a two-stage design with at least seven responses out of 28 patients in the first stage required to proceed to a second stage of accrual seeking a response rate of 40% or better. RESULTS: Of 34 patients entered onto the study, 31 were eligible and 27 were evaluable for response. Ten had received prior chemoradiation containing cisplatin. Among the five (two complete and three partial) observed responses, two were in the subset of patients who had received prior chemoradiation. This level of activity was deemed insufficient to warrant a second stage of accrual. Predominant toxicities were myelosuppression and gastrointestinal symptoms, although six patients experienced none of these adverse effects. CONCLUSION: At these doses, weekly cisplatin and irinotecan failed to demonstrate sufficient activity to undertake a phase III study. Although not apparent in this study, prior chemoradiation may affect response to platinum-based combinations and its impact should be considered in the design of future trials.     

Effects of heparin-mediated extracorporeal low-density lipoprotein precipitation beyond lowering proatherogenic lipoproteins--reduction of circulating proinflammatory and procoagulatory markers

In addition to hypercholesterolemia, proinflammatory and prothrombotic markers have been suggested to play an important role in atherogenesis. We examined whether heparin-mediated extracorporeal low-density lipoprotein precipitation (HELP) therapy modulates the circulating levels of proinflammatory and prothrombotic markers. Twenty-two coronary heart disease (CHD) patients undergoing regular HELP-apheresis (18 males, 4 females, mean age 57.3 +/- 10.9 years) were enrolled in this study. A single HELP therapy treatment significantly decreased the circulating levels of high sensitivity C-reactive protein (hs-CRP), soluble vascular adhesion molecule-1 (sVCAM-1), soluble E-selectin, lipopolysaccharide binding protein (LBP), endothelin-1 (ET-1), and monocyte chemoattractant protein-1 (MCP-1) on average by 67, 37, 24, 27, 24, and 15%, respectively. Prothrombotic factors including fibrinogen, tissue factor (TF), soluble CD40 ligand (sCD40L), and homocysteine were decreased by 66, 27, 16, and 22%, respectively. In accordance with previous studies HELP therapy reduced total cholesterol, low density lipoprotein (LDL) cholesterol, and Lp(a) mass by 50, 61, and 62%, respectively. Our data suggest that simultaneous reduction of proinflammatory and prothrombotic factors together with atherogenic lipoproteins by HELP-apheresis may contribute to improvement of endothelial dysfunction and thereby inhibit progression of atherosclerotic lesions and stabilize the existing plaque.     

Evaluation of vinorelbine in persistent or recurrent nonsquamous carcinoma of the cervix: a Gynecologic Oncology Group Study

OBJECTIVE: The Gynecologic Oncology Group (GOG) has studied a number of drugs to determine their activity in patients with previously treated squamous and nonsquamous cancer arising in the uterine cervix. A Phase II study with intravenous vinorelbine was initiated for this purpose in patients with Stage IVB, recurrent, or persistent nonsquamous carcinomas who had received one prior chemotherapy or were not eligible for other studies. METHODS: Eligible patients had to have measurable disease, GOG performance status of 0-2 and adequate bone marrow, liver, and renal function. The treatment consisted of vinorelbine 30 mg/m(2) on days 1 and 8, repeated every 21 days. Tumor measurements and toxicities were recorded every treatment cycle. RESULTS: Thirty patients were enrolled with 28 patients deemed eligible and evaluable. Only two confirmed partial responses (7.1%) were noted. Neutropenia was the most common toxicity with 9 of 28 (32%) experiencing either grade 3 or 4 changes. Anemia was severe in seven. Neuropathy was more than mild in three patients. Severe events, such as fatigue, hypertension, or pulmonary changes attributed to drug administration, occurred only in one or two instances. CONCLUSION: With the dose schedule and assessment criteria employed, vinorelbine had only minimal activity in nonsquamous cancer of the cervix.     

Phase II evaluation of topotecan in carcinosarcoma of the uterus: a Gynecologic Oncology Group study

OBJECTIVES: To estimate the antitumor activity of topotecan in patients with persistent or recurrent carcinosarcoma (malignant mixed mullerian tumors) of the uterus and to determine the nature and degree of toxicity of topotecan in this cohort of patients. MATERIALS AND METHODS: Eligible patients had measurable advanced or recurrent carcinosarcoma of the uterus. Topotecan at a target dose of 1.5 mg/m(2) was administered IV daily for 5 days, every 3 weeks, until progression of disease or adverse affects prohibited further therapy. RESULTS: Twenty-seven member institutions entered 51 patients. Of the patients entered, 48 were eligible. Patient characteristics included a median age of 65, with 33% having prior radiation and 92% having prior chemotherapy. Twenty-six patients (54%) had a performance status (PS) of 0, 18 (38%) had a PS of 1, and four (8%) had a PS of 2. Patients received from 1 to 21 (with a median of 2) courses of treatment. The most frequently observed grade 4 toxicities were neutropenia seen in 35 (73%) patients, leukopenia in 14 (29%), and thrombocytopenia in 10 (21%). Three (6%) patients developed neutropenic sepsis and died shortly after their first treatment cycle. There were five (10%) complete responses; 13 (27%) patients maintained stable disease, 26 (54%) experienced increasing disease, and reassessment did not occur in four (8%). CONCLUSION: Topotecan at this dose and schedule does not appear to have major activity in patients with advanced or recurrent uterine carcinosarcoma previously treated with chemotherapy.     

Phase II trial of dacarbazine, mitomycin, doxorubicin, and cisplatin with sargramostim in uterine leiomyosarcoma: a Gynecologic Oncology Group study

OBJECTIVE: Following a reported 23% response rate (RR) for mitomycin (M), doxorubicin (A), and cisplatin (P) and preliminary data suggesting a superior RR for dacarbazine (D) + MAP + sargramostim, the Gynecologic Oncology Group (GOG) conducted a phase II trial of DMAP + sargramostim in patients with advanced uterine leiomyosarcoma. METHODS: Eligibility required measurable disease, a GOG performance score of 0-2, and recovery from surgery/radiotherapy. Treatment consisted of sargramostim 250 microg/m2 SC q 12 h days -6 through -3, followed by D 750 mg/m2 IV over 2 h, M 6 mg/m2 IV, A 40 mg/m2 IV and P 60 mg/m2 IV over 2 h on day 1, followed by sargramostim 250 microg/m2 SC days 2-15. Cycles were repeated q 28 days (if ANC > or = 1500/microl and platelets > or = 100,000/microl) until disease progression or toxicity prevented further therapy. Doses were to be reduced by 20% for grade 4 neutropenia >7 days or any grade 4 thrombocytopenia and by 10% for a 1- to 2-week treatment delay for myelosuppression. RESULTS: One of 19 patients who entered the study was ineligible. Eighteen patients received a median of 3.5 cycles (range: 1-6 cycles) of therapy. The overall RR was 27.8% (5.6% complete and 22.2% partial responses). Percent of patients with grade 3 or 4 toxicities included 78% neutropenia, 94% thrombocytopenia, 61% anemia, 44% GI, 28% infection, and 17% azotemia. CONCLUSIONS: DMAP + sargramostim produced a 27.8% RR, but its complexity and toxicity precluded further investigation, and the study was closed after the first stage of accrual.     

Spinal 5-HT2A receptors regulate cutaneous sympathetic vasomotor outflow in rabbits and rats; relevance for cutaneous vasoconstriction elicited by MDMA (3,4-methylenedioxymethamphetamine, "Ecstasy") and its reversal by clozapine

We determined whether spinal 5-hydroxytryptamine 2A (5-HT2A) receptors contribute to resting cutaneous sympathetic vasomotor activity, and to increases in activity elicited by electrical stimulation of the medullary raphe/parapyramidal region, and whether these receptors are involved in the cutaneous vasoconstricting action of systemically administered MDMA (3,4-methylenedioxymethamphetamine, "Ecstasy") and its reversal by clozapine. Experiments were conducted in urethane-anesthetized rabbits and rats. Administration of the 5-HT2A antagonist, trans-4-((3Z)3-[(2-Dimethylaminoethyl)oxyimino]-3-(2-fluorophenyl)propen-1-yl)-phenol, hemifumarate (SR 46349B, 0.1 mg/kg, i.v.) inhibited resting ear pinna sympathetic vasomotor nerve discharge and reduced the extent to which raphe/parapyramidal electrical stimulation caused ear pinna (rabbit) and tail (rat) artery blood flow to fall. Clozapine (0.125-0.5 mg/kg, i.v.) also reduced the fall in ear pinna blood flow elicited by raphe/parapyramidal stimulation. In rabbits, after inactivation of raphe/parapyramidal function by local microinjection of muscimol (1 nmol in 100 nl), the 5-HT2A agonist R(-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride (DOI, 50 microg/kg, i.v.) increased ear pinna sympathetic nerve activity from 3+/-2% to 129+/-5% of pre-muscimol levels (P<0.01, n=6), and this increase was abolished by section of the ipsilateral cervical sympathetic nerve trunk. MDMA (2 mg/kg, i.v.) after muscimol decreased ear pinna blood flow from 33+/-10 to 2+/-1 cm/s (P<0.01, n=5) and increased ear pinna sympathetic nerve activity from 8+/-4% to 120+/-41% of pre-muscimol levels (P<0.01, n=6). The MDMA-elicited increase in nerve activity was abolished by SR 46349B. Data suggest that spinal 5-HT2A receptors contribute to sympathetically induced cutaneous vasoconstriction regulated by raphe/parapyramidal neurons in the brainstem, and that these receptors contribute to the cutaneous vasoconstricting action of MDMA and its reversal by clozapine.     

Loss of brainstem serotonin- and substance P-containing neurons in Parkinson's disease.

Using postmortem immunohistochemical analysis, we have identified degeneration of several different neuronal cell groups in the brainstem of patients dying with idiopathic Parkinson's disease. We report the first chemically identified loss of presumed serotonin neurons in the median raphe nucleus of the pons and of substance P-containing preganglionic neurons in the dorsal motor vagal nucleus. This evidence is concordant with other evidence that the primary neuropathological process is not confined either to a single pathway or to neurons containing a particular transmitter. Rather it appears that Parkinson's disease affects several classes of neurons in localized areas of the brainstem.