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Selinexor in combination with topotecan in patients with advanced or metastatic solid tumors: Results of an open-label, single-center, multi-arm phase Ib study.
Thein, KZ, Piha-Paul, SA, Tsimberidou, A, Karp, DD, Janku, F, Zarifa, A, Shah, J, Milton, DR, Bean, S, McQuinn, L, et al
Investigational new drugs. 2021;(5):1357-1365
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Abstract
Background Selinexor, a first-in-class, oral selective inhibitor of nuclear export (SINE) compound inhibits Exportin-1(XPO1), had demonstrated synergistic activity with many chemotherapies and conferred in vivo antitumor efficacy in hematologic as well as solid tumors. Methods This open-label, single-center, multi-arm phase 1b study used a standard 3 + 3 design and a "basket type" expansion. Selinexor with intravenous topotecan was given in one of the 13 parallel arms. Patients with advanced or metastatic relapsed/refractory solid tumors following prior systemic therapy, or in whom the addition of selinexor to standard chemotherapy deemed appropriate, were eligible. Results Fourteen patients with the median age of 61 years (range, 22-68years) were treated, and the most common cancer types were gynecological cancers; ovarian (n = 5), endometrial (n = 2), and 1 each with fallopian tube and vaginal cancers. Of the 14 patients treated, 12 (86 %) had at least one treatment-related adverse event (TRAE). The most common TRAEs were anemia (71 %), thrombocytopenia (57 %), hyponatremia (57 %), vomiting (57 %), fatigue (50 %), nausea (50 %), and neutropenia (36 %). Two patients had dose limiting toxicities. One patient dosed at selinexor 80 mg had grade 3 nausea and vomiting and one patient dosed at selinexor 60 mg experienced grade 4 neutropenia and thrombocytopenia. Of the 13 efficacy evaluable patients, one (8 %) with endometrial cancer achieved unconfirmed partial response (uPR) and the time-to-treatment failure (TTF) was 48 weeks, whereas 6 of the 13 (46 %) patients had stable disease (SD) contributing to the clinical benefit rate of 46 %. The median TTF for all patients was 9 weeks (range, 2-48weeks). Conclusions Once weekly selinexor in combination with topotecan was viable and showed some preliminary tumor efficacy. The recommend phase 2 dose of selinexor was 60 mg once weekly in combination with IV topotecan.Trial registration: NCT02419495. Registered 14 April 2015, https://clinicaltrials.gov/ct2/show/NCT02419495.
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The response of patients with bile acid diarrhoea to the farnesoid X receptor agonist obeticholic acid.
Walters, JR, Johnston, IM, Nolan, JD, Vassie, C, Pruzanski, ME, Shapiro, DA
Alimentary pharmacology & therapeutics. 2015;(1):54-64
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Abstract
BACKGROUND Bile acid diarrhoea is a common cause of chronic diarrhoea, occurring as a primary condition or secondary to ileal disease or resection. Many patients have reduced levels of the ileal hormone fibroblast growth factor 19 (FGF19), an inhibitory regulator of hepatic bile acid synthesis, secreted in response to farnesoid X receptor (FXR) activation. AIM: To investigate whether obeticholic acid, a potent FXR agonist, could increase FGF19 in patients with bile acid diarrhoea, and produce clinical benefits. METHODS After a 2 week run-in when bile acid sequestrants were discontinued, patients with previously diagnosed primary bile acid diarrhoea (n = 10), secondary bile acid diarrhoea (n = 10) or idiopathic chronic diarrhoea (n = 8), received oral obeticholic acid 25 mg daily for 2 weeks. Serum FGF19, total bile acids and 7α-OH-4-cholesten-3-one (C4) were measured, symptoms recorded and a diarrhoea index calculated. RESULTS In primary bile acid diarrhoea, obeticholic acid increased median fasting FGF19 (133-237 pg/mL, P = 0.007) and significantly reduced fasting C4 and bile acid responses. Improvements occurred in median stool frequency (-24% after 2 weeks treatment, P = 0.03), stool form (-14%, P = 0.05) and diarrhoea index (-34%, P = 0.005). In the secondary bile acid diarrhoea group, significant clinical improvements were found predominantly in patients with shorter ileal resections. Symptoms of abdominal pain and urgency improved. FGF19 and bile acids changed in the control group, without significant clinical improvement. Total and LDL-cholesterol increased and triglycerides decreased. Obeticholic acid treatment was well tolerated. CONCLUSIONS This proof-of-concept study indicates that obeticholic acid stimulates FGF19, reduces bile acid synthesis and produces clinical benefits in bile acid diarrhoea. FXR agonists have therapeutic potential in chronic diarrhoea. EudraCT 2011-003777-28; Clinical Trials: NCT01585025.
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Bisphosphonate treatment does not affect serum levels of osteoprotegerin and RANKL in hypercalcemic cancer patients.
Zojer, N, Brenner, K, Beke, D, Kudlacek, S, Hawa, G, Woloszczuk, W, Hofbauer, LC, Pecherstorfer, M
Anticancer research. 2005;(5):3607-12
Abstract
Bisphosphonates are the standard treatment for hypercalcemia of malignancy. We hypothesized that bisphosphonate treatment and the subsequent fall in serum calcium might induce changes in the RANK/RANKL/OPG system, which plays a pivotal role in the regulation of bone resorption. Soluble RANKL and OPG levels were measured in the serum of 15 hypercalcemic patients at baseline and on 5 consecutive days following treatment with the amino-bisphosphonate ibandronate. At day 0, the median soluble OPG level was elevated (p=0.0021) in the hypercalcemic group as compared to normal controls, while the median serum RANKL level was not significantly different. Ibandronate treatment and the resulting decrease (p<0.0001) in serum calcium levels did not affect the serum concentrations of OPG, serum RANKL, or the serum RANKL/OPG ratio. In comparison with day 0, these factors did not change significantly at any time-point analyzed.
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Peroxisome proliferator activated receptor delta genotype in relation to cardiovascular risk factors and risk of coronary heart disease in hypercholesterolaemic men.
Skogsberg, J, McMahon, AD, Karpe, F, Hamsten, A, Packard, CJ, Ehrenborg, E, ,
Journal of internal medicine. 2003;(6):597-604
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Abstract
OBJECTIVES Peroxisome proliferator activated receptor delta (PPARD) is a transcription factor implicated in the regulation of genes involved in cholesterol metabolism. We recently discovered a common polymorphism in the 5'-untranslated region (5'-UTR) of the human PPARD, +294T/C, that is associated with an increased plasma low-density lipoprotein cholesterol (LDL-C) concentration in healthy subjects. Whether the +294C allele is associated with LDL-C elevation independently of the background lipoprotein phenotype and whether it confers increased risk of coronary heart disease (CHD) is unknown. Against this background, we investigated the relationships between the PPARD polymorphism and plasma lipoprotein concentrations and the risk for contracting CHD in the West of Scotland Coronary Prevention Study (WOSCOPS). DESIGN A nested case-control study of participants in a randomized double-blind placebo-controlled trial of pravastatin in mildly-to-moderately hypercholesterolaemic men. SUBJECTS A total of 580 cases of incident CHD and 1160 individuals who remained free of CHD (controls). MAIN OUTCOME MEASURES Plasma lipoprotein concentrations and risk of CHD according to PPARD genotype. RESULTS Individuals carrying the rare PPARD +294C allele had a significantly lower high-density lipoprotein cholesterol (HDL-C) concentration than subjects homozygous for the common T-allele. Homozygous carriers of the C-allele also showed a tendency towards higher risk of CHD compared with homozygous carriers of the T-allele. In addition, a gene-gene interaction involving the PPARD polymorphism and the PPAR alpha L162V polymorphism may influence the plasma LDL-C concentration. CONCLUSIONS PPARD plays a role in cholesterol metabolism in man.
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Misoprostol as agonist of IP2 receptor.
Goszcz, A, Bierón, K, Grodzińska, L
Journal of physiology and pharmacology : an official journal of the Polish Physiological Society. 2002;(4 Pt 1):635-41
Abstract
Fourteen patients with peripheral vascular disease received 200 microg of misoprostol 3 times a day during one month. The therapy with misoprostol caused clinical and biochemical improvement in all 14 patients. An elongation of pain free and maximum walking distance, shortening of pain duration and increase in arterial blood flow in both calves were observed. At the same time an activation of the fibrinolytic system, rise in the platelet aggregate ratio and increase in cAMP levels were noticed. It is suggested that misoprostol in human being caused rather activation of IP2 receptor.