Biomedical subjects

I Rossi

Publications and source records attributed to I Rossi.

At least 37 records · Page 2Linked to original sources

PubMed1998

Down regulation of major histocompatibility complex class I expression in mammary carcinoma of HER-2/neu transgenic mice.

Transgenic mice carrying the HER-2/neu proto-oncogene under tissue-specific transcriptional control of a mammary tumor virus long terminal repeat (Tg-MMTVneu mice) spontaneously develop mammary carcinomas. HER-2/neu is a tumor antigen that can be recognized by cytotoxic T lymphocytes if tumor cells present the appropriate major histocompatibility complex (MHC) class I glycoproteins. The purpose of this work was to assess whether mammary carcinomas arising in Tg-MMTVneu mice correctly expressed MHC (H-2q) class I gene products. We analyzed by flow cytometry 51 primary tumors from 19 transgenic mice. About one-half of the tumors showed a reduced expression of class I antigens. All tumors were highly positive for membrane neu. Some mice had multiple mammary carcinomas with widely different MHC expression levels, and most mice had at least one tumor with a low expression. Treatment with gamma-interferon of carcinoma cells cultured in vitro induced a strong reexpression of H-2q antigens. Our results suggest that the immune response activated in vivo by HER-2/neu-positive tumors can lead to the emergence of escape variants characterized by a down-regulation of MHC class I products.

Animals↗

PubMed1998

Interleukin 12-mediated prevention of spontaneous mammary adenocarcinomas in two lines of Her-2/neu transgenic mice.

The ability of interleukin (IL)-12 to prevent tumors when administered to individuals with a genetic risk of cancer was studied in two lines of transgenic mice expressing rat HER-2/neu oncogene in the mammary gland. Female BALB/c (H-2(d)) mice carrying the activated HER-2/ neu oncogene show no morphological abnormalities of the mammary gland until 3 wk of age. They then progress through atypical hyperplasia to in situ lobular carcinoma and at 33 wk of age all 10 mammary glands display invasive carcinomas. Adult FVB mice (H-2(q)) carrying the HER-2/neu protooncogene develop mammary carcinomas with a longer latency (38-49 wk) and a lower multiplicity (mean of 2.6 tumors/mice). Treatment with IL-12 (5 daily intraperitoneal injections, 1 wk on, 3 wk off; the first course with 50 ng IL-12/day, the second with 100 ng IL-12/day) begun at 2 wk of age in BALB/c mice and at 21 wk of age in FVB mice markedly delayed tumor onset and reduced tumor multiplicity. Analogous results were obtained in immunocompetent and permanently CD8(+) T lymphocyte-depleted mice. In both transgenic lines, tumor inhibition was associated with mammary infiltration of reactive cells, production of cytokines and inducible nitric oxide synthase, and reduction in microvessel number, in combination with a high degree of hemorrhagic necrosis.

Animals↗

PubMed1998

Interleukin 12 gene therapy of MHC-negative murine melanoma metastases.

Immunological gene therapy of cancer relies heavily on the activation of T cells, but tumors with defects in MHC gene expression are not recognized by MHC-restricted T cells. To investigate the potential of cytokine genes for the therapy of MHC-negative tumors, we transduced B78H1, a class I-negative murine melanoma clone, with a polycistronic vector carrying murine interleukin (IL)-12 genes. The clones studied produced 400-25,000 pg/ml IL-12; their in vitro growth properties were similar to those of parental cells. A complete inhibition of growth was observed in vivo both after s.c. and i.v. administration of all IL-12 clones. IL-12-transduced cells were also used as a therapeutic vaccine in mice bearing micrometastases by nontransduced parental cells. A significant (80-90%) reduction in the number of lung nodules was obtained. Immunohistochemical analysis and studies in immunocompromised hosts showed that T cells and natural killer cells had a significant role in the elimination of IL-12-releasing cells. In situ hybridization with cytokine probes detected a strong increase in the proportion of leukocytes positive for IFN-gamma, tumor necrosis factor alpha, IL-1beta, and IFN-inducible protein 10 at the site of rejection of IL-12-engineered tumor cells. However, it was clear that the loss of in vivo growth was also due to T-cell- and natural killer cell-independent factors, possibly related to the antiangiogenic properties of IL-12. In conclusion, tumor therapy based on IL-12 gene transduction was effective on a MHC-negative metastatic tumor, suggesting a possible application to MHC-defective human neoplasms.

Animals↗

PubMed1998

Sulfonylurea effects on acid and pepsinogen secretion in isolated rabbit gastric glands.

The influence of different sulfonylureas on the rate of acid and pepsinogen secretion was studied in isolated rabbit gastric glands. Neither tolbutamide (10-500 microM), chlorpropamide (10-500 microM), glibenclamide (1-50 microM) nor glipizide (1-50 microM) exerted a secretory effect. In contrast, gliquidone caused a marked and dose-dependent stimulation of acid production in gastric glands incubated under basal conditions and potentiated the stimulatory effect of both histamine and carbachol. Gliquidone also increased the rate of pepsinogen release in gastric glands incubated either under basal conditions or in the presence of cholecystokinin-octapeptide or isoproterenol. The secretory effects of gliquidone were associated with a significant increase in the glandular content of cyclic AMP, caused by a competitive inhibition of low-Km cyclic AMP phosphodiesterase. Our results indicate that, among the assayed sulfonylureas, only gliquidone, in the micromolar range, stimulates acid and pepsinogen secretion through a cyclic AMP-dependent mechanism.

3',5'-Cyclic-AMP Phosphodiesterases↗

PubMed1998

The immune response elicited by mammary adenocarcinoma cells transduced with interferon-gamma and cytosine deaminase genes cures lung metastases by parental cells.

The parental cells of the TSA murine mammary adenocarcinoma (TSA-pc) were transfected with both the interferon-gamma (IFN-y) gene and the cytosine deaminase (CD) suicide gene to obtain a therapeutic vaccine active against TSA-pc lung metastases. Even in the absence of treatment with the prodrug 5-fluorocytosine (5-FC), the local growth of double transfectants (CD-y clones) was inhibited by a marked recruitment of granulocytes and macrophages. In mice harboring TSA-pc micrometastases, therapeutic vaccination with either IFN-gamma or CD single transfectants reduced the number of lung nodules, whereas CD-gamma double transfectants abrogated metastasis growth in up to 80% of mice. Treatment of mice with 5-FC did not alter the curative efficacy of CD-gamma double-transfectant cells. By contrast, in mice vaccinated with CD single-transfectant cells, 5-FC treatment caused a significant loss of their curative activity. Host T cells played an active role in the cure of lung metastases, because vaccination of nude mice with CD-gamma cells was uneffective.

Adenocarcinoma↗

PubMed1998

Selective impairment of endothelium-mediated vasodilation in liver transplant recipients with cyclosporin A-induced hypertension.

Arterial hypertension is commonly observed in orthotopic liver transplantation (OLT) recipients receiving cyclosporin A (CsA), but the precise pathogenetic mechanisms remain partially unknown. The aim of this study was to investigate endothelium-dependent and -independent dilation and adrenergic constriction of resistance vessels of OLT recipients treated with CsA. Vascular reactivity was examined in 22 OLT patients, 10 with and 12 without arterial hypertension, and in 10 control subjects by assessing the forearm blood flow response to the brachial artery infusion of increasing concentrations of methacholine chloride, sodium nitroprusside, and phenylephrine. In 10 OLT patients, the response to methacholine was also examined after acetylsalicylate. The ratio of serum nitrite and nitrate to serum creatinine was lower (P < .05) in OLT patients with hypertension than in nonhypertensive patients and controls. Basal forearm flow was similar in the three groups. Methacholine vasodilation was impaired in the hypertensive patients as shown by a lower maximum forearm vasodilator response and a shift in the dose response curve to methacholine to the right compared with the nonhypertensive OLT patients and the controls. The response to methacholine was not modified after salicylate. Forearm flow response to nitroprusside was similar in the three groups. No differences between the patients and the controls were found in the maximum forearm flow contraction in response to phenylephrine. An impairment in endothelium-dependent vasodilation could mediate arterial hypertension in OLT patients immunosuppressed with CsA.

Adult↗

PubMed1998

Inhibition of lung colonisation of a mouse mammary carcinoma by therapeutic vaccination with interferon-alpha gene-transduced tumor cells.

A spontaneously metastatic murine mammary adenocarcinoma, TSA, has been transduced with the gene for interferon alpha1 (IFN-alpha). Transfectants were used for the immunotherapy of mice bearing lung colonies induced by the intravenous inoculation of non-transduced parental cells. A significant reduction in the number of tumor colonies was obtained when repeated subcutaneous administrations of mitomycin C-blocked transfectant cells were given, commencing 3 days after an intravenous challenge with TSA cells. Intraperitoneal vaccination induced a stronger anti-tumor response than subcutaneous vaccination, and the proportion of tumor-free mice reached 50%. The potency of IFN-alpha transfectants was similar to that of IFN-gamma transfectants previously obtained from TSA. Admixture of IFN-alpha and IFN-gamma transfectant cells in the same vaccine did not increase the curative effect over that of single vaccines. In nude mice vaccination with IFN-alpha or IFN-gamma transfectants did not lead to a reduction in the number of lung colonies, indicating that an intact T cell response was required for the therapeutic effect observed in immunocompetent mice.

Adenocarcinoma↗

PubMed1998

Wild-type p53-mediated down-modulation of interleukin 15 and interleukin 15 receptors in human rhabdomyosarcoma cells.

We recently reported that rhabdomyosarcoma cell lines express and secrete interleukin 15 (IL-15), a tightly regulated cytokine with IL-2-like activity. To test whether the p53-impaired function that is frequently found in this tumour type could play a role in the IL-15 production, wild-type p53 gene was transduced in the human rhabdomyosarcoma cell line RD (which harbours a mutated p53 gene), and its effect on proliferation and expression of IL-15 was studied. Arrest of proliferation was induced by wild-type p53; increased proportions of G1-arrested cells and of apoptotic cells were observed. A marked down-modulation of IL-15 expression, at both the mRNA and protein level, was found in p53-transduced cells. Because a direct effect of IL-15 on normal muscle cells has been reported, the presence of IL-15 membrane receptors was studied by cytofluorometric analysis. Rhabdomyosarcoma cells showed IL-15 membrane receptors, which are down-modulated by wild-type p53 transfected gene. In conclusion, wild-type p53 transduction in human rhabdomyosarcoma cells induces the down-modulation of both IL-15 production and IL-15 receptor expression.

Cell Division↗

PubMed1998

Comparison of the clientele of an anonymous HIV test centre and persons tested in the general population.

This study compares the clientele of a Swiss anonymous test centre with the general population tested. Information was obtained through similar questionnaires submitted to two samples of HIV-tested people aged from 17 to 45 years: the first administered in the context of a general population telephone survey (n = 245) and the second completed during face-to-face interviews of the clientele of an anonymous test centre (n = 250). The test centre sample has higher proportions of younger and single people. Attenders for anonymous testing were more likely to have acquired a new regular partner during the year preceding the interview (48.0% versus 14.4%). These differences remain when controlling for age and gender. Decision to test comes mostly from the respondent's own initiative, but suggestion from a doctor is more frequent in the general population (23.8% versus 0.8%), whereas suggestion from partner or friends is more frequent in the anonymous centre (44.4% versus 3.0%). The anonymous test centre clientele is not different from the general population tested except for the relational situation and origin of decision for testing. The test centre has become a place where the general population finds a response to a situation-specific need for HIV testing.

Adolescent↗

PubMed1998

Expression of functional CD40 on human osteosarcoma and Ewing's sarcoma cells.

CD40, a membrane glycoprotein of the tumor necrosis factor receptor family, is expressed by several tumor types, including B-cell lymphomas, carcinomas, and melanoma, but little is known concerning its expression by sarcoma. We used flow cytometry to analyze the expression of CD40 in human cell lines derived from 12 osteosarcomas, 6 Ewing's sarcomas, and 5 rhabdomyosarcomas. Detectable CD40 levels ranging from low to very high were found in one-third of osteosarcomas, whereas five of six Ewing's sarcomas expressed intermediate levels of CD40; all rhabdomyosarcomas were CD40-negative. At the tissue level, two of eight primary high-grade osteosarcomas showed CD40-positive immunostaining. Osteosarcoma cells and Ewing's sarcoma cells expressing CD40 were treated with recombinant soluble CD40 ligand to analyze CD40 function. Treatment with soluble CD40 ligand increased the level of apoptotic cells and stimulated the transcription of matrix metalloproteinase 9 gene, enhancing matrix metalloproteinase 9 enzyme secretion. The results indicate that in human osteosarcoma and Ewing's sarcoma, CD40 is a functional receptor whose engagement can have opposite effects on tumor cell survival and malignancy.

Apoptosis↗

PubMed1998

[Evaluation of the hemodynamic effects of tumor necrosis factor alpha factor in rats with portal hypertension using the radioactive microsphere technique].

UNLABELLED: This study was aimed at investigating the effects of blocking circulating TNF on the hyperdynamic circulatory state developed in rats with portal vein stenosis (PVS), and the factors mediating the hemodynamic action of this cytokine in this setting. MATERIALS AND METHODS: Murine antiTNF polyclonal antibodies (100 microgram) or placebo were intravenously injected into PVS rats (n = 24) before and 4 days after PVS. Hemodynamic studies were performed the day after the last antiTNF injection. RESULTS: Short-term TNF inhibition led to reductions in cardiac index (p < 0.05) and portal venous inflow (p < 0.01), and significant increases in splanchnic and systemic vascular resistances. Portal pressure was unchanged, but portal-systemic shunting was decreased (p < 0.05). CONCLUSION: TNF plays a key role in promoting the development of the hyperdynamic state of portal hypertension. The effect of TNF is mediated through an increased release of nitric oxide.

Animals↗

PubMed1997

Expression of interleukin 15 (IL-15) in human rhabdomyosarcoma, osteosarcoma and Ewing's sarcoma.

Interleukin 15 (IL-15) is a recently discovered cytokine that stimulates lymphocyte proliferation and migration via a trimeric receptor sharing the beta and gamma signal transducing chains with the IL-2 receptor. IL-15 is typically produced by normal cells that do not release IL-2, but little information is currently available on human tumors. To assess whether human musculo-skeletal sarcomas produce IL-15, we analyzed surgical specimens and cell lines obtained from rhabdomyosarcoma, osteosarcoma and Ewing's sarcoma. IL-15 mRNA was present in 9/9 surgical specimens (3 Ewing's sarcomas, 5 osteosarcomas and 1 rhabdomyosarcoma). The analysis of a panel of cell lines (7 derived from Ewing's sarcoma, 12 from osteosarcoma and 5 from rhabdomyosarcoma) showed that all rhabdomyosarcoma and osteosarcoma cell lines expressed IL-15 mRNA at levels ranging from low to high, while Ewing's sarcoma cells contained little or no IL-15 message. ELISA assays showed IL-15 release in a subset of rhabdomyosarcomas and osteosarcomas, but not in Ewing's sarcoma. The highest production of IL-15, in the picogram/ml range, was found in rhabdomyosarcoma cell lines RH30 and RD.

Enzyme-Linked Immunosorbent Assay↗

PubMed1997

Accuracy of portal and forearm blood flow measurements in the assessment of the portal pressure response to propranolol.

BACKGROUND/AIMS: The portal pressure response to propranolol varies significantly in individual patients with cirrhosis. At present, propranolol responders can be identified only by measuring the hepatic venous pressure gradient. The aims of this study were: 1) to investigate whether the noninvasive monitoring of portal blood flow by pulsed Doppler ultrasound and forearm blood flow by strain-gauge plethysmography can predict the hepatic venous pressure gradient response to propranolol in patients with cirrhosis, and 2) to analyze the factors that may influence this response. METHODS: Hemodynamic measurements were undertaken in 80 patients with cirrhosis before and after receiving propranolol (0.15 mg/kg i.v., n = 60) or placebo (n = 20). RESULTS: No changes were observed in the placebo group. Propranolol lowered (p < 0.01) hepatic venous pressure gradient from 17.6 +/- 3.8 to 14.7 +/- 3.8 mmHg, portal blood flow from 1122 +/- 363 to 897 +/- 332 ml/min and forearm blood flow from 7.52 +/- 3.1 to 6.12 +/- 2.3 ml/min%. Changes in hepatic venous pressure gradient were correlated (p < 0.01) with those of portal blood flow (r = 0.82) and forearm blood flow (r = 0.54). The reduction in hepatic venous pressure gradient was > 20% in 23 patients ("responders"). The accuracy of portal Doppler flowmetry in identifying responders was higher than that of forearm plethysmography (88.3 vs. 68.3%, p < 0.05). Multivariate analysis proved that previous variceal bleeding was the only factor independently associated with a lack of response to propranolol (relative risk 3.42, 95% CI 1.5-7.4, p < 0.01). Hepatic venous pressure gradient reduction by propranolol was higher in non-bleeders than in bleeders (-19.9 +/- 9.4 vs. -11.3 +/- 8.6%, p < 0.01). CONCLUSIONS: Portal Doppler ultrasound can be used as a reliable surrogate indicator of the hepatic venous pressure gradient response to acute propranolol administration. In addition, our study indicates that this response is mainly influenced by previous variceal hemorrhage.

Adrenergic beta-Antagonists↗

PubMed1996

Expression of transduced carcinoembryonic antigen gene in human rhabdomyosarcoma inhibits metastasis.

Carcinoembryonic antigen (CEA) is a highly glycosylated cell surface glycoprotein belonging to the immunoglobulin superfamily. CEA has been involved in vitro in adhesion mechanisms, but little is known about the function of this glycoprotein in vivo in normal tissue differentiation and malignancy. With regard to the relationship between CEA expression and tissue differentiation, it has been reported that transfection of the CEA gene in rat L6 myoblasts results in a complete block of myogenic differentiation. To extend investigations to the transformed myogenic counterpart and examine CEA effects on differentiation and malignancy outside the colon system, we have transfected the human CEA gene in human rhabdomyosarcoma cells. Human rhabdomyosarcoma cells transfected with the CEA gene correctly expressed membrane CEA anchored via glycosylphosphatidylinositol and secreted CEA in the medium. CEA gene transfer in human rhabdomyosarcoma cells, which display a limited differentiation ability, does not further inhibit myogenic differentiation or alter in vitro proliferation or natural killer sensitivity. CEA transfection does not affect s.c. growth in nude mice, but the ectopic expression of CEA in human rhabdomyosarcoma cells can strongly inhibit their metastatic ability to lungs and adrenals after i.v. injection. The impairment of metastatic potential correlates with a reduction in the homotypic adhesion properties of the cells. These data suggest that CEA, in some systems, can interfere with intercellular adhesion and, at least for cells not metastatic to the liver, can act as an anti-metastatic molecule.

Adrenal Gland Neoplasms↗

PubMed1996

Antisense epidermal growth factor receptor transfection impairs the proliferative ability of human rhabdomyosarcoma cells.

Human rhabdomyosarcoma cells express membrane epidermal growth factor receptor (ECF-R), which could confer responsiveness to EGF and transforming growth factor-alpha (TGF-alpha) of autocrine or paracrine origin. To study the role played by this growth factor circuit in the proliferation and differentiation of myogenic neoplastic cells, human rhabdomyosarcoma EGF-R-expressing cells (RD/18 clone) have been transfected with a plasmid containing a fragment of the EGF-R cDNA in the antisense orientation. In vitro growth and differentiative ability were studied on six antisense-transfected clones (AS) in comparison to parental RD/18 cells and to cells transfected with the plasmid containing only the neomycin resistance gene (NEO). A reduced EGF-R membrane expression was found in AS clones by decreased immunofluorescence with an anti-EGF-R monoclonal antibody. All AS transfectants had a greatly impaired proliferative ability, even when cultured in fetal bovine serum-containing medium. Proliferation of AS clones was completely blocked in medium supplemented with 2% horse serum. The differentiation ability of AS clones was heterogeneous, ranging from clones with a percentage of myosin-positive cells higher than controls to clones with a negligible myosin expression. Therefore, the growth impairment determined by the loop interruption is not sufficient to switch on the differentiation program. The role played by EGF-R in the proliferation of human rhabdomyosarcoma cells suggests that this receptor could constitute a target for a therapeutic approach.

Animals↗

PubMed1996

Therapy of murine mammary carcinoma metastasis with interferon gamma and MHC gene-transduced tumour cells.

Gene-transfected tumour cells were used to cure mice bearing lung metastases by the parental, non-transduced mammary adenocarcinoma (TSA-pc). Repeated subcutaneous (s.c.) administrations of mitomycin C (MitC)-treated interferon gamma (IFN-gamma) transfectants induced a 90% inhibition in the number of lung metastases. Therapeutic effect required an intact T-cell response, as shown by the lack of efficacy in nude mice. Autocrine stimulation by IFN-gamma induces specific modifications in the phenotype of transfectants that acquire a high metastatic ability and show a high expression of IFN-responsive genes; these two features were exploited to design two experimental protocols to obtain an improvement of the therapeutic effect. The increased metastatic ability of IFN-gamma transfectants was used to deliver IFN-gamma selectively to the lungs of mice bearing TSA-pc pulmonary metastases. A significant therapeutic effect was obtained when TSA-pc experimental metastases were treated by repeated intravenous (i.v.) injections of MitC IFN-gamma transfectants. Since i.v. administrations of IFN-gamma transfectants did not induce immune memory, the therapeutical effect appeared to depend on the inflammatory-like response activated by local IFN release. To exploit the autocrine stimulation of IFN-sensitive genes an IFN-gamma transfectant clone was subjected to a second transfection with an allogeneic class I MHC gene (H-2K(b) or H-2D(h)). IFN-gamma plus MHC double transfectants maintained IFN-gamma release, showed a very high expression of the MHC gene products, stimulated both macrophages and T cells, and were less tumorigenic in immunocompetent mice than the parent IFN-gamma clone. Therapeutic efficacy of double transfectant IFN-gamma plus H-2D(b) cells against TSA-pc was superior to single transfectants, showing that the reaction elicited by genetically engineered cells can be selectively tuned to increase therapeutic efficacy.

Adenocarcinoma↗

PubMed1996

Expanded CD4+CD45RO+ phenotype and defective proliferative response in T lymphocytes from patients with Crohn's disease.

BACKGROUND & AIMS: An abnormal immune response may play a pathogenic role in Crohn's disease. The aim of this study was to determine the role of regulatory T cells in Crohn's disease. METHODS: T-cell phenotype and function were studied in blood lymphocytes from patients with Crohn's disease and a control group consisting of healthy donors and patients with ulcerative colitis. RESULTS: Flow cytometric studies showed a significant increase in the percentage of CD3+DR+ and CD4+CD45RO+ T cells in patients with Crohn's disease. T cells from patients with Crohn's disease and ulcerative colitis showed a defective proliferative response after stimulation with surface mitogenic ligands (phytohemagglutinin and anti-CD28 or anti-CD3 antibodies). Soluble interleukin-2 receptor alpha was augmented in the Crohn's disease and ulcerative colitis groups. In the Crohn's disease group, impairment of T-lymphocyte proliferation was normalized by exogenous interleukin 2, although endogenous interleukin-2 production and interleukin-2 receptor alpha expression were normal. CONCLUSIONS: An in vivo expansion of CD4+ T lymphocytes with memory phenotype and impaired T-cell proliferation that can be restored by pharmacological amounts of interleukin 2 was found in patients with Crohn's disease. There is a severe immunodisturbance in the T-cell compartment of patients with either clinically active or inactive Crohn's disease.

Adult↗

PubMed1995

Continuous prazosin administration in cirrhotic patients: effects on portal hemodynamics and on liver and renal function.

BACKGROUND & AIMS: Hepatic vascular resistance is influenced by alpha-adrenergic tone. The aim of this study was to investigate the effects of continuous blockade of alpha-adrenoceptors with prazosin on hemodynamics, liver function, and renal function and whether the association of propranolol or furosemide enhances the portal pressure lowering effect of prazosin. METHODS: Cirrhotic patients with portal hypertension were studied at baseline and after a 3-month course of prazosin (n = 18) or placebo (n = 10). RESULTS: No changes were observed in the placebo group. Prazosin decreased the hepatic venous pressure gradient (HVPG) while increasing hepatic blood flow. Liver function improved as shown by an increase in hepatic and intrinsic hepatic clearances of indocyanine green and galactose elimination capacity. A significant reduction in mean arterial pressure and systemic vascular resistance was associated with increases in plasma renin activity and aldosterone concentration and a decrease in glomerular filtration rate. The plasma volume increased significantly, and 6 patients developed edema. The association of propranolol (n = 8) but not furosemide (n = 7) to prazosin increased the reduction in HVPG and attenuated the increase in plasma renin activity. CONCLUSIONS: In cirrhotic patients, continuous prazosin administration reduces portal pressure and improves liver perfusion and function but favors sodium and water retention. The association of propranolol enhances the decrease in portal pressure, suggesting a potential benefit from this combined therapy.

Adrenergic alpha-Antagonists↗