Development of everolimus, a novel oral mTOR inhibitor, across a spectrum of diseases.

Development of everolimus, a novel oral mTOR inhibitor, across a spectrum of diseases.

Ann N Y Acad Sci. 2013 May 9;

Authors: Lebwohl D, Anak O, Sahmoud T, Klimovsky J, Elmroth I, Haas T, Posluszny J, Saletan S, Berg W

Abstract
Everolimus is a potent, oral inhibitor of the mammalian target of rapamycin (mTOR) that has been investigated in multiple clinical development programs since 1996. A unique collaboration between academic and pharmaceutical experts fostered research that progressed rapidly, with simultaneous indication findings across numerous tumor types. Initially developed for the prophylaxis of organ transplant rejection, everolimus has demonstrated efficacy and safety for the treatment of patients with various types of cancer (renal cell carcinoma, neuroendocrine tumors of pancreatic origin, and breast cancer) and for adult and pediatric patients with tuberous sclerosis complex. The FDA approval of everolimus for these diseases has addressed several unmet medical needs and is widely accepted by the medical community where treatment options may be limited. An extensive clinical development program is ongoing to establish the role of everolimus as monotherapy, or in combination with other agents, in the treatment of a broad spectrum of malignancies.

PMID: 23659703 [PubMed - as supplied by publisher]

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Development of everolimus, a novel oral mTOR inhibitor, across a spectrum of diseases.

Development of everolimus, a novel oral mTOR inhibitor, across a spectrum of diseases.

Ann N Y Acad Sci. 2013 May 9;

Authors: Lebwohl D, Anak O, Sahmoud T, Klimovsky J, Elmroth I, Haas T, Posluszny J, Saletan S, Berg W

Abstract
Everolimus is a potent, oral inhibitor of the mammalian target of rapamycin (mTOR) that has been investigated in multiple clinical development programs since 1996. A unique collaboration between academic and pharmaceutical experts fostered research that progressed rapidly, with simultaneous indication findings across numerous tumor types. Initially developed for the prophylaxis of organ transplant rejection, everolimus has demonstrated efficacy and safety for the treatment of patients with various types of cancer (renal cell carcinoma, neuroendocrine tumors of pancreatic origin, and breast cancer) and for adult and pediatric patients with tuberous sclerosis complex. The FDA approval of everolimus for these diseases has addressed several unmet medical needs and is widely accepted by the medical community where treatment options may be limited. An extensive clinical development program is ongoing to establish the role of everolimus as monotherapy, or in combination with other agents, in the treatment of a broad spectrum of malignancies.

PMID: 23659703 [PubMed - as supplied by publisher]

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Efficacy and safety of short-term use of COX-2 inhibitors in patients after an acute stroke with musculoskeletal pain.

Efficacy and safety of short-term use of COX-2 inhibitors in patients after an acute stroke with musculoskeletal pain.

Ann Indian Acad Neurol. 2013 Jan;16(1):47-52

Authors: Rabadi MH, Rabadi FM, Hallford G, Aston CE

Abstract
OBJECTIVE: Musculoskeletal pain commonly occurs in the elderly, many of whom are also prone to suffer from strokes. We studied whether short-term use (? 4 weeks) of cyclooxygenase-2 (COX-2) inhibitors for musculoskeletal pain in stroke patients helped them to participate in their therapies and was safe and efficacious.
MATERIALS AND METHODS: Three hundred and three patients admitted consecutively with first ischemic stroke were studied. Two cohorts were defined, based on whether patients with acute stroke had sufficient musculoskeletal pain that warranted oral COX-2 inhibitors (COX-2 group) or not (case-matched controls). Primary efficacy measures were change in Fugl-Meyer (F-M) pain score and change in total functional independence measure (TFIM) scores on discharge from hospital. Safety was judged by the incidence of vascular episodes during the study period.
RESULTS: From the original 303 patients, 64 patients in the COX-2 group were matched with 64 patients in the non-COX-2 group. The groups were matched for age (�5 years), gender, and admission TFIM score (� 5 points). Baseline characteristics between the 2 groups were similar. The primary and secondary outcome measures were similar between the 2 groups, except for ambulation endurance, which favored the non-COX-2 group (P < 0.03). Greater change in the pain score (less pain) was found in the COX-2 group; this effect was strongest in patients who were independent prior to their stroke (on post hoc analysis). There were too few adverse events in either group of any significance.
CONCLUSIONS: The short-term use of COX-2 inhibitors reduced musculoskeletal pain in acute stroke patients, improved functional motor outcome, and were found to be safe.

PMID: 23661962 [PubMed - in process]

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Efficacy and safety of short-term use of COX-2 inhibitors in patients after an acute stroke with musculoskeletal pain.

Efficacy and safety of short-term use of COX-2 inhibitors in patients after an acute stroke with musculoskeletal pain.

Ann Indian Acad Neurol. 2013 Jan;16(1):47-52

Authors: Rabadi MH, Rabadi FM, Hallford G, Aston CE

Abstract
OBJECTIVE: Musculoskeletal pain commonly occurs in the elderly, many of whom are also prone to suffer from strokes. We studied whether short-term use (? 4 weeks) of cyclooxygenase-2 (COX-2) inhibitors for musculoskeletal pain in stroke patients helped them to participate in their therapies and was safe and efficacious.
MATERIALS AND METHODS: Three hundred and three patients admitted consecutively with first ischemic stroke were studied. Two cohorts were defined, based on whether patients with acute stroke had sufficient musculoskeletal pain that warranted oral COX-2 inhibitors (COX-2 group) or not (case-matched controls). Primary efficacy measures were change in Fugl-Meyer (F-M) pain score and change in total functional independence measure (TFIM) scores on discharge from hospital. Safety was judged by the incidence of vascular episodes during the study period.
RESULTS: From the original 303 patients, 64 patients in the COX-2 group were matched with 64 patients in the non-COX-2 group. The groups were matched for age (�5 years), gender, and admission TFIM score (� 5 points). Baseline characteristics between the 2 groups were similar. The primary and secondary outcome measures were similar between the 2 groups, except for ambulation endurance, which favored the non-COX-2 group (P < 0.03). Greater change in the pain score (less pain) was found in the COX-2 group; this effect was strongest in patients who were independent prior to their stroke (on post hoc analysis). There were too few adverse events in either group of any significance.
CONCLUSIONS: The short-term use of COX-2 inhibitors reduced musculoskeletal pain in acute stroke patients, improved functional motor outcome, and were found to be safe.

PMID: 23661962 [PubMed - in process]

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Incidence and risk of treatment-related mortality in cancer patients treated with the mammalian target of rapamycin inhibitors.

Incidence and risk of treatment-related mortality in cancer patients treated with the mammalian target of rapamycin inhibitors.

Ann Oncol. 2013 May 8;

Authors: Choueiri TK, Je Y, Sonpavde G, Richards CJ, Galsky MD, Nguyen PL, Schutz F, Heng DY, Kaymakcalan MD

Abstract
BACKGROUND: Inhibition of the mammalian target of rapamycin (mTOR) is an established treatment for multiple malignancies. We carried out an up-to-date meta-analysis to determine the risk of fatal adverse events (FAEs) in cancer patients treated with mTOR inhibitors. PATIENTS AND METHODS: PubMed, conferences and clinicaltrials.gov databases were searched for articles reported from January 1966 to June 2012. Eligible studies were limited to approved mTOR inhibitors (everolimus and temsirolimus) and reported on patients with cancer, randomized design and adequate safety profiles. Data extraction was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. RESULTS: In all, 3193 patients from eight randomized, controlled trials (RCTs) were included, 2236 from everolimus trials and 957 from temsirolimus trials. The relative risk (RR) of FAEs related to mTOR inhibitors use was 2.20 (95% CI, 1.25-3.90; P = 0.006) compared with control patients. On subgroup analysis, no difference in the rate of FAEs was found between everolimus and temsirolimus or between tumor types [renal cell carcinoma (RCC) versus non-RCC]. No evidence of publication bias was observed. CONCLUSION: The use of mTOR inhibitors is associated with a small but higher risk of FAEs compared to control patients. In the appropriate clinical scenario, the use of these drugs remains justified in their approved indications.

PMID: 23658373 [PubMed - as supplied by publisher]

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Optimizing megakaryocyte polyploidization by targeting multiple pathways of cytokinesis.

Related Articles

Optimizing megakaryocyte polyploidization by targeting multiple pathways of cytokinesis.

Transfusion. 2012 Nov;52(11):2406-13

Authors: Avanzi MP, Chen A, He W, Mitchell WB

Abstract
BACKGROUND: Large-scale in vitro production of platelets (PLTs) from cord blood stem cells is one goal of stem cell research. One step toward this goal will be to produce polyploid megakaryocytes capable of releasing high numbers of PLTs. Megakaryocyte polyploidization requires distinct cytoskeletal and cellular mechanisms, including actin polymerization, myosin activation, microtubule formation, and increased DNA production. In this study we variably combined inhibition of these principal mechanisms of cytokinesis with the goal of driving polyploidization in megakaryocytes.
STUDY DESIGN AND METHODS: Megakaryocytes were derived from umbilical cord blood and cultured with reagents that inhibit distinct mechanisms of cytokinesis: Rho-Rock inhibitor (RRI), Src inhibitor (SI), nicotinamide (NIC), aurora B inhibitor (ABI), and myosin light chain kinase inhibitor (MLCKI). Combinations of reagents were used to determine their interactions and to maximize megakaryocyte ploidy.
RESULTS: Treatment with RRI, NIC, SI, and ABI, but not with MLCKI, increased the final ploidy and RRI was the most effective single reagent. RRI and MLCKI, both inhibitors of MLC activation, resulted in opposite ploidy outcomes. Combinations of reagents also increased ploidy and the use of NIC, SI, and ABI was as effective as RRI alone. Addition of MLCKI to NIC, SI, and ABI reached the highest level of polyploidization.
CONCLUSION: Megakaryocyte polyploidization results from modulation of a combination of distinct cytokinesis pathways. Reagents targeting distinct cytoskeletal pathways produced additive effects in final megakaryocyte ploidy. The RRI, however, showed no additive effect but produced a high final ploidy due to overlapping inhibition of multiple cytokinesis pathways.

PMID: 22612069 [PubMed - indexed for MEDLINE]

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Protein tyrosine phosphatase encoded in Cotesia plutellae bracovirus suppresses a larva-to-pupa metamorphosis of the diamondback moth, Plutella xylostella.

Protein tyrosine phosphatase encoded in Cotesia plutellae bracovirus suppresses a larva-to-pupa metamorphosis of the diamondback moth, Plutella xylostella.

Comp Biochem Physiol A Mol Integr Physiol. 2013 May 4;

Authors: Kim J, Hepat R, Lee D, Kim Y

Abstract
Parasitization by an endoparasitoid wasp, Cotesia plutellae, inhibits a larva-to-pupa metamorphosis of the diamondback moth, Plutella xylostella. This study tested an inhibitory effect of C. plutellae bracovirus (CpBV) on the metamorphosis of P. xylostella. Parasitized P. xylostella exhibited significantly reduced prothoracic gland (PTG) development at the last instar compared to nonparasitized larvae. Expression of the ecdysone receptor was markedly suppressed during the last instar larvae parasitized by C. plutellae. By contrast, expression of the insulin receptor significantly increased in the parasitized larvae. Microinjection of CpBV significantly inhibited the larva-to-pupa metamorphosis of nonparasitized larvae in a dose-dependent manner. Injection of CpBV also inhibited the expression of the ecdysone receptor and increased the expression of the insulin receptor. Individual CpBV segments were transiently expressed in its encoded genes in nonparasitized larvae and screened to determine antimetamorphic viral gene(s). Out of 21 CpBV segments, two viral segments (CpBV-S22 and CpBV-S27) were proved to inhibit larva-to-pupa metamorphosis by transient expression assay. RNA interference of each gene encoded in the viral segments was applied to determine antimetamorphic gene(s). Protein tyrosine phosphatase, early expressed gene, and four hypothetical genes were selected to be associated with the antimetamorphic activity of CpBV. These results suggest that antimetamorphosis of P. xylostella parasitized by C. plutellae is induced by inhibiting PTG development and subsequent ecdysteroid signaling with viral factors of CpBV.

PMID: 23651929 [PubMed - as supplied by publisher]

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