Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0015672 (fatigue)
 51,768 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

GEM 231 is a second-generation antisense oligonucleotide targeted against the RIalpha regulatory subunit of cAMP-dependent protein kinase type I (PKA-I). Excessive expression of PKA-I is associated with cell proliferation and transformation, and increased levels of secreted extracellular PKA (ECPKA) are found in the serum of cancer patients. Preclinical studies have demonstrated single-agent antitumor activity of GEM 231 in a variety of human cancer xenograft models, and additive or synergistic antitumor activity has been observed with taxane and/or camptothecin-based combinations. Based on prior safety (MTD) data demonstrating dose-dependent, reversible, and cumulative transaminitis, and high peak plasma concentration (Cmax)-dependent changes in activated partial thromboplastin time (aPTT) with GEM 231 2-h twice-weekly infusions, an alternative schedule of GEM 231 given as a single agent was evaluated in patients with advanced solid tumors. Fourteen patients (median age approximately 60 yrs) with advanced solid malignancies received a total of 78 weeks of therapy. GEM 231 was infused via a CADD pump at 80 mg/m2/day (d) for 3 d/wk (n = 1), then for 5 d/wk at 80 (n = 3), 120 (n = 8), and 180 mg/m2/d (n = 2). One cycle was defined as 4 weeks of therapy. Apparent dose dependency for the occurrence of transaminitis was readily reversible. At 180 mg/m2/d, 2 of 2 patients had cycle 1 dose-limiting toxicity (DLT) transaminitis. One patient treated at 120 mg/m2/d experienced grade 3 transaminase elevations after 8 weeks of therapy, but when serum transaminase values rapidly improved he resumed treatment at 80 mg/m2/d for 6 weeks until tumor progression was documented. Another patient at 120 mg/m2/d developed grade 3 esophagitis after 3 weeks, limiting further dosing. One patient (lung cancer) demonstrated stable disease for 9 weeks. Overall, plasma aPTT was minimally prolonged and changes were transient, peaked at the end of each infusion, and were not associated with spontaneous bleeding. A constitutive symptom (e.g., low-grade fatigue) was common, cumulative, and reversible following discontinuation of therapy. Serum ECPKA was measured by enzymatic assay and Western blotting from blood drawn at the beginning and end of each infusion. Serum ECPKA levels demonstrated a trend to decline with the treatment. In addition to single agent schedules, combination trials were undertaken to assess safety and possible interaction of GEM 231 with taxanes (paclitaxel, docetaxel), given once every 3 weeks (one cycle). While trials using the 2-h twice-weekly GEM 231 infusions are ongoing, preliminary results from both studies show that it is safe to combine paclitaxel or docetaxel with GEM 231. Overall, it is also feasible to administer GEM 231 in combination with taxane or nontaxane chemotherapy (e.g., camptothecins). Phase I combination studies are currently underway to further explore the clinical, pharmacokinetic, and biologic profile of GEM 231 with chemotherapy.
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PMID:Clinical studies in patients with solid tumors using a second-generation antisense oligonucleotide (GEM 231) targeted against protein kinase A type I. 1475 40

Interferon-alpha1 (IFN-alpha1), which may have a primary role in innate immunity, differs significantly in amino-acid sequence from IFN-alpha2, the only recombinant IFN-alpha with substantial clinical evaluation. Patients with metastatic malignancies received daily subcutaneous doses of 1.5-270 mug/m(2) of recombinant IFN-alpha1b. Gene modulation, pharmacokinetics, tolerability, and disease response were determined. Significant (P<0.01) dose and gene-dependent increases of 2-10 fold occurred in IFN-stimulated genes, including four (tumor necrosis factor-related apoptosis-inducing ligand, cig 5, p56, GEM) never previously identified as increased in patients; significant increases (P<0.01) resulted at the lowest dose (1.5 microg/m(2); 1.5 x 10(4) human antiviral units/m(2)). Increases (P<0.01) were sustainable for >4 weeks. Peak levels of IFN-alpha1b were at 3 h; an increase of approximately eightfold in both C(max) and AUC occurred between 15 microg/m(2) and 270 microg/m(2). Chronic toxicities of anorexia, weight loss, and fatigue were relatively uncommon. Eighteen patients were treated for >8 weeks; none experienced >grade 1 weight loss. Three patients at the highest dose developed grade 3 fatigue after > or =3 months, which required dose reduction or discontinuation. Patient acceptability of fatigue defined a dose for initiation of Phase II trials, 270 microg/m(2). Six patients (five with renal cell carcinoma) had progression-free survival for >1 year, including two who had partial responses. IFN-alpha1b resulted in potent stimulation of IFN-regulated genes and tumor regressions in renal cell carcinoma. Unique gene modulatory effects, when coupled with the moderate severity of side effects and a potentially central role in innate immunity, provide rationale for further clinical evaluation of IFN-alpha1 in virus infections and cancer.
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PMID:Gene modulatory effects, pharmacokinetics, and clinical tolerance of interferon-alpha1b: a second member of the interferon-alpha family. 1733 65

A 61-year-old woman was introduced for consultation with a chief complaint of frequent vomiting. CT revealed a pancreatic body cancer approximately 40mm in size; an invading stenosis from the horizontal part of the duodenum to the jejunum, superior mesenteric artery, and portal vein, splenic vein obstruction, lymphadenopathy, and some ascitic fluid. We diagnosed a passage disorder due to the invasive stenosis from the horizontal part of the duodenum of the pancreatic body cancer to the jejunum, and subsequently performed a duodenum and jejunum bypass operation. We controlled cancer pain with opioid analgesia, and S-1 monotherapy was chosen as the primary chemotherapy. A tendency to increase and the cancer pain of the tumor was aggravated when 5 courses took effect, so gemcitabine plus nab-paclitaxel(GEM plus nab-PTX)therapy was chosen as the second-line chemotherapy because of adverse Grade 3 events due to difficulties with S-1 internal use. We tapered off the opioid analgesia dosage because the cancer pain was relieved after 1 course. The imaging top indicated stable disease at the end of 5 courses, but the pain was relieved so opioid pain killers were unnecessary. Foreign continuation is under treatment with 10-course GEM plus nab-PTX therapy after initial diagnosis. Currently, the patient has undergone 5 courses of S-1 for approximately 18 months, and has achieved stable disease. The only adverse events were nausea, fatigue, Grade 1 malaise, and Grade 2 alopecia, as detected with imaging.
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PMID:[A Case of Successful Treatment with Gemcitabine plus Nab-Paclitaxel Therapy for Nonresected Pancreatic Body Cancer(Stage IVb)]. 2965 Sep 39

We report a case of conversion surgery for a locally advanced unresectable(UR-LA)pancreatic cancer that was radically resected after S-1 therapy. A 65-year-old man visited a referral physician because of fatigue and liver dysfunction. A CT scan revealed a mass in the pancreatic uncinate process that was suspected to be superior mesenteric artery(SMA)infiltration and was diagnosed as UR-LA pancreatic cancer. GEM nab-PTX therapy was initiated but was discontinued after 2 courses because of adverse events. The treatment was switched to S-1 monochemotherapy. After that, the tumor did not progress for around 1.5 years, and the patient was referred to our hospital for surgical treatment. As the contact between the tumor and the SMA was considered to be less than half-round, we made a diagnosis of borderline resectable(BR-A)pancreatic cancer. Subsequently, we performed a pancreaticoduodenectomy with partial resection of the portal vein and achieved R0 resection. The patient received adjuvant chemotherapy with S-1 and showed no signs of recurrence for 10 months after surgery.
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PMID:[A Case of Conversion Surgery for an Initially Locally Advanced Unresectable Pancreatic Cancer after S-1 Chemotherapy]. 3215 96