Subject(s)
Eflornithine , Neuroblastoma , Humans , Neuroblastoma/drug therapy , Eflornithine/therapeutic use , Eflornithine/administration & dosage , Eflornithine/adverse effects , Antineoplastic Agents/adverse effects , Antineoplastic Agents/therapeutic use , Antineoplastic Agents/administration & dosageABSTRACT
Pancreatic ductal adenocarcinoma (PDAC) has an extremely poor five-year survival rate of less than 10%. Immune suppression along with chemoresistance are obstacles for PDAC therapeutic treatment. Innate immune cells, such as tumor-associated macrophages, are recruited to the inflammatory environment of PDAC and adversely suppress cytotoxic T lymphocytes. KRAS and MYC are important oncogenes associated with immune suppression and pose a challenge to successful therapies. Here, we targeted KRAS, through inhibition of downstream c-RAF with GW5074, and MYC expression via difluoromethylornithine (DFMO). DFMO alone and with GW5074 reduced in vitro PDAC cell viability. Both DFMO and GW5074 showed efficacy in reducing in vivo PDAC growth in an immunocompromised model. Results in immunocompetent syngeneic tumor-bearing mice showed that DFMO and combination treatment markedly decreased tumor size, but only DFMO increased survival in mice. To further investigate, immunohistochemical staining showed DFMO diminished MYC expression and increased tumor infiltration of macrophages, CD86+ cells, CD4+ and CD8+ T lymphocytes. GW5074 was not as effective in modulating the tumor infiltration of total CD3+ lymphocytes or tumor progression and maintained MYC expression. Collectively, this study highlights that in contrast to GW5074, the inhibition of MYC through DFMO may be an effective treatment modality to modulate PDAC immunosuppression.
Subject(s)
Carcinoma, Pancreatic Ductal/drug therapy , Eflornithine/administration & dosage , Indoles/administration & dosage , Pancreatic Neoplasms/drug therapy , Phenols/administration & dosage , Animals , Carcinoma, Pancreatic Ductal/immunology , Carcinoma, Pancreatic Ductal/metabolism , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Down-Regulation , Drug Synergism , Eflornithine/pharmacology , Gene Expression Regulation, Neoplastic/drug effects , Humans , Immunocompetence/drug effects , Immunocompromised Host/drug effects , Indoles/pharmacology , Mice , Pancreatic Neoplasms/immunology , Pancreatic Neoplasms/metabolism , Phenols/pharmacology , Proto-Oncogene Proteins c-myc/antagonists & inhibitors , Treatment Outcome , Tumor Microenvironment/drug effects , Xenograft Model Antitumor AssaysABSTRACT
BACKGROUND: Nifurtimox-eflornithine combination therapy (NECT) for the treatment of second stage gambiense human African trypanosomiasis (HAT) was added to the World Health Organization's Essential Medicines List in 2009 after demonstration of its non-inferior efficacy compared to eflornithine therapy. A study of NECT use in the field showed acceptable safety and high efficacy until hospital discharge in a wide population, including children, pregnant and breastfeeding women, and patients with a HAT treatment history. We present here the effectiveness results after the 24-month follow-up visit. METHODOLOGY/PRINCIPAL FINDINGS: In a multicenter, open label, single arm phase IIIb study, second stage gambiense HAT patients were treated with NECT in the Democratic Republic of Congo. Clinical cure was defined 24 months after treatment as survival without clinical and/or parasitological signs of HAT. Of the 629 included patients, 619 (98.4%) were discharged alive after treatment and were examined for the presence of trypanosomes, white blood cell count in cerebro-spinal fluid, and disease symptoms. The clinical cure rate of 94.1% was comparable for all subpopulations analyzed at the 24-month follow-up visit. Self-reported adverse events during follow-up were few and concerned mainly nervous system disorders, infections, and gastro-intestinal disorders. Overall, 28 patients (4.3%) died during the course of the trial. The death of 16 of the 18 patients who died during the follow-up period was assessed as unlikely or not related to NECT. Within 24 months, eight patients (1.3%) relapsed and received rescue treatment. Sixteen patients were completely lost to follow-up. CONCLUSIONS/SIGNIFICANCE: NECT treatment administered under field conditions was effective and sufficiently well tolerated, no major concern arose for children or pregnant or breastfeeding women. Patients with a previous HAT treatment history had the same response as those who were naïve. In conclusion, NECT was confirmed as effective and appropriate for use in a broad population, including vulnerable subpopulations. TRIAL REGISTRATION: The trial is registered at ClinicalTrials.gov, number NCT00906880.
Subject(s)
Antiprotozoal Agents/administration & dosage , Eflornithine/administration & dosage , Nifurtimox/administration & dosage , Trypanocidal Agents/administration & dosage , Trypanosomiasis, African/drug therapy , Adolescent , Adult , Aged , Antiprotozoal Agents/adverse effects , Child , Child, Preschool , Democratic Republic of the Congo , Drug Therapy, Combination , Eflornithine/adverse effects , Female , Follow-Up Studies , Humans , Infant , Male , Middle Aged , Nifurtimox/adverse effects , Pregnancy , Treatment Outcome , Trypanosoma brucei gambiense/drug effects , Trypanosoma brucei gambiense/genetics , Trypanosoma brucei gambiense/physiology , Trypanosomiasis, African/parasitology , Trypanosomiasis, African/pathology , Young AdultABSTRACT
The polyamine synthesis inhibitor eflornithine is a recommended treatment for the neglected tropical disease Gambian human African trypanosomiasis in late stage. This parasitic disease, transmitted by the tsetse fly, is lethal unless treated. Eflornithine is administered by repeated intravenous infusions as a racemic mixture of L-eflornithine and D-eflornithine. The study compared the in vitro antitrypanosomal activity of the two enantiomers with the racemic mixture against three Trypanosoma brucei gambiense strains. Antitrypanosomal in vitro activity at varying drug concentrations was analysed by non-linear mixed effects modelling. For all three strains, L-eflornithine was more potent than D-eflornithine. Estimated 50% inhibitory concentrations of the three strains combined were 9.1 µM (95% confidence interval [8.1; 10]), 5.5 µM [4.5; 6.6], and 50 µM [42; 57] for racemic eflornithine, L-eflornithine and D-eflornithine, respectively. The higher in vitro potency of L-eflornithine warrants further studies to assess its potential for improving the treatment of late-stage Gambian human African trypanosomiasis.
Subject(s)
Eflornithine/pharmacology , Trypanocidal Agents/pharmacology , Trypanosoma brucei gambiense/drug effects , Eflornithine/administration & dosage , Humans , Trypanocidal Agents/chemistryABSTRACT
BACKGROUND: Neuroblastoma (NB) is the most common extracranial solid tumor in children. Interference with the polyamine biosynthesis pathway by inhibition of MYCN-activated ornithine decarboxylase (ODC) is a validated approach. The ODC inhibitor α-difluoromethylornithine (DFMO, or Eflornithine) has been FDA-approved for the treatment of trypanosomiasis and hirsutism and has advanced to clinical cancer trials including NB as well as cancer-unrelated human diseases. One key challenge of DFMO is its rapid renal clearance and the need for high and frequent drug dosing during treatment. METHODS: We performed in vivo pharmacokinetic (PK), antitumorigenic, and molecular studies with DFMO/probenecid using NB patient-derived xenografts (PDX) in mice. We used LC-MS/MS, HPLC, and immunoblotting to analyze blood, brain tissue, and PDX tumor tissue samples collected from mice. RESULTS: The organic anion transport 1/3 (OAT 1/3) inhibitor probenecid reduces the renal clearance of DFMO and significantly increases the antitumor activity of DFMO in PDX of NB (P < 0.02). Excised tumors revealed that DFMO/probenecid treatment decreases polyamines putrescine and spermidine, reduces MYCN protein levels and dephosphorylates retinoblastoma (Rb) protein (p-RbSer795), suggesting DFMO/probenecid-induced cell cycle arrest. CONCLUSION: Addition of probenecid as an adjuvant to DFMO therapy may be suitable to decrease overall dose and improve drug efficacy in vivo.
Subject(s)
Antineoplastic Agents/pharmacology , Eflornithine/pharmacology , Neuroblastoma/drug therapy , Probenecid/pharmacology , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/pharmacokinetics , Cell Cycle Checkpoints/drug effects , Cell Line, Tumor , Chromatography, Liquid , Eflornithine/administration & dosage , Eflornithine/pharmacokinetics , Female , Humans , Kidney/metabolism , Mice , Mice, Nude , Neuroblastoma/pathology , Ornithine Decarboxylase Inhibitors/administration & dosage , Ornithine Decarboxylase Inhibitors/pharmacokinetics , Ornithine Decarboxylase Inhibitors/pharmacology , Probenecid/administration & dosage , Tandem Mass Spectrometry , Xenograft Model Antitumor AssaysABSTRACT
Neuroblastoma is a sympathetic nervous system tumor, primarily presenting in children under 6 years of age. The long-term prognosis for patients with high-risk neuroblastoma (HRNB) remains poor despite aggressive multimodal therapy. This report provides an update to a phase II trial evaluating DFMO as maintenance therapy in HRNB. Event-free survival (EFS) and overall survival (OS) of 81 subjects with HRNB treated with standard COG induction, consolidation and immunotherapy followed by 2 years of DFMO on the NMTRC003/003b Phase II trial were compared to a historical cohort of 76 HRNB patients treated at Beat Childhood Cancer Research Consortium (BCC) hospitals who were disease-free after completion of standard upfront therapy and did not receive DFMO. The 2- and 5-year EFS were 86.4% [95% confidence interval (CI) 79.3%-94.2%] and 85.2% [77.8%-93.3%] for the NMTRC003/003b subset vs 78.3% [69.5%-88.3%] and 65.6% [55.5%-77.5%] for the historical control group. The 2- and 5-year OS were 98.8% [96.4-100%] and 95.1% [90.5%-99.9%] vs 94.4% [89.3%-99.9%] and 81.6% [73.0%-91.2%], respectively. DFMO maintenance for HRNB after completion of standard of care therapy was associated with improved EFS and OS relative to historical controls treated at the same institutions. These results support additional investigations into the potential role of DFMO in preventing relapse in HRNB.
Subject(s)
Eflornithine/administration & dosage , Neuroblastoma/drug therapy , Child, Preschool , Disease-Free Survival , Eflornithine/therapeutic use , Female , Humans , Maintenance Chemotherapy , Male , Prognosis , Standard of Care , Treatment OutcomeABSTRACT
Human African trypanosomiasis caused by Trypanosoma brucei gambiense is a parasitic infection that usually progresses to coma and death unless treated. WHO has updated its guidelines for the treatment of this infection on the basis of independent literature reviews and using the Grading of Recommendations Assessment, Development and Evaluation methodology. The first-line treatment options, pentamidine and nifurtimoxeflornithine combination therapy, have been expanded to include fexinidazole, an oral monotherapy given a positive opinion from the European Medicines Agency. Fexinidazole is recommended for individuals who are aged 6 years and older with a bodyweight of 20 kg or more, who have first-stage or second-stage gambiense human African trypanosomiasis and a cerebrospinal fluid leucocyte count less than 100 per µL. Nifurtimoxeflornithine combination therapy remains recommended for patients with 100 leucocytes per µL or more. Without clinical suspicion of severe second-stage disease, lumbar puncture can be avoided and fexinidazole can be given. Fexinidazole should only be administered under supervision of trained health staff. Because these recommendations are expected to change clinical practice considerably, health professionals should consult the detailed WHO guidelines. These guidelines will be updated as evidence accrues.
Subject(s)
Humans , Pentamidine/administration & dosage , Trypanocidal Agents/administration & dosage , Trypanosoma brucei gambiense , Trypanosomiasis, African/drug therapy , Eflornithine/administration & dosage , Nifurtimox/administration & dosage , Nitroimidazoles/administration & dosage , Trypanosomiasis, African/parasitology , Cerebrospinal Fluid/parasitology , Drug Therapy, CombinationABSTRACT
BACKGROUND: Nifurtimox eflornithine combination therapy (NECT) to treat human African trypanosomiasis (HAT), commonly called sleeping sickness, was added to the World Health Organisation's (WHO) Essential Medicines List in 2009 and to the Paediatric List in 2012. NECT was further tested and documented in a phase IIIb clinical trial in the Democratic Republic of Congo (DRC) assessing the safety, effectiveness, and feasibility of implementation under field conditions (NECT-FIELD study). This trial brought a unique possibility to examine concomitant drug management. METHODOLOGY/PRINCIPAL FINDINGS: This is a secondary analysis of the NECT-FIELD study where 629 second stage gambiense HAT patients were treated with NECT, including children and pregnant and breastfeeding women in six general reference hospitals located in two provinces. Concomitant drugs were prescribed by the local investigators as needed. Patients underwent daily evaluations, including vital signs, physical examination, and adverse event monitoring. Concomitant medication was documented from admission to discharge. Patients' clinical profiles on admission and safety profile during specific HAT treatment were similar to previously published reports. Prescribed concomitant medications administered during the hospitalization period, before, during, and immediately after NECT treatment, were mainly analgesics/antipyretics, anthelmintics, antimalarials, antiemetics, and sedatives. Use of antibiotics was reasonable and antibiotics were often prescribed to treat cellulitis and respiratory tract infections. Prevention and treatment of neurological conditions such as convulsions, loss of consciousness, and coma was used in approximately 5% of patients. CONCLUSIONS/SIGNIFICANCE: The prescription of concomitant treatments was coherent with the clinical and safety profile of the patients. However, some prescription habits would need to be adapted in the future to the evolving available pharmacopoeia. A list of minimal essential medication that should be available at no cost to patients in treatment wards is proposed to help the different actors to plan, manage, and adequately fund drug supplies for advanced HAT infected patients. TRIAL REGISTRATION NUMBER: The initial study was registered at ClinicalTrials.gov, number NCT00906880.
Subject(s)
Eflornithine/therapeutic use , Nifurtimox/therapeutic use , Trypanocidal Agents/therapeutic use , Trypanosoma brucei gambiense , Trypanosomiasis, African/drug therapy , Democratic Republic of the Congo/epidemiology , Drug Therapy, Combination , Eflornithine/administration & dosage , Humans , Nifurtimox/administration & dosage , Treatment Outcome , Trypanosomiasis, African/epidemiologySubject(s)
Cerebellar Nuclei/pathology , Hypothalamus/pathology , Magnetic Resonance Imaging , Trypanosoma brucei gambiense , Trypanosomiasis, African/pathology , Cerebellar Nuclei/parasitology , Drug Therapy, Combination , Eflornithine/administration & dosage , Eflornithine/therapeutic use , Humans , Hypothalamus/parasitology , Male , Middle Aged , Nifurtimox/administration & dosage , Nifurtimox/therapeutic use , Trypanocidal Agents/administration & dosage , Trypanocidal Agents/therapeutic use , Trypanosomiasis, African/drug therapy , Trypanosomiasis, African/parasitologyABSTRACT
Although ovarian cancer has a low incidence rate, it remains the most deadly gynecologic malignancy. Previous work has demonstrated that the DNMTi 5-Azacytidine (5AZA-C) activates type I interferon signaling to increase IFNγ+ T cells and natural killer (NK) cells and reduce the percentage of macrophages in the tumor microenvironment. To improve the efficacy of epigenetic therapy, we hypothesized that the addition of α-difluoromethylornithine (DFMO), an ornithine decarboxylase inhibitor, may further decrease immunosuppressive cell populations improving outcome. We tested this hypothesis in an immunocompetent mouse model for ovarian cancer and found that in vivo, 5AZA-C and DFMO, either alone or in combination, significantly increased survival, decreased tumor burden, and caused recruitment of activated (IFNγ+) CD4+ T cells, CD8+ T cells, and NK cells. The combination therapy had a striking increase in survival when compared with single-agent treatment, despite a smaller difference in recruited lymphocytes. Instead, combination therapy led to a significant decrease in immunosuppressive cells such as M2 polarized macrophages and an increase in tumor-killing M1 macrophages. In this model, depletion of macrophages with a CSF1R-blocking antibody reduced the efficacy of 5AZA-C + DFMO treatment and resulted in fewer M1 macrophages in the tumor microenvironment. These observations suggest our novel combination therapy modifies macrophage polarization in the tumor microenvironment, recruiting M1 macrophages and prolonging survival. SIGNIFICANCE: Combined epigenetic and polyamine-reducing therapy stimulates M1 macrophage polarization in the tumor microenvironment of an ovarian cancer mouse model, resulting in decreased tumor burden and prolonged survival.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/pharmacology , Cystadenocarcinoma, Serous/immunology , Disease Models, Animal , Immunity, Innate/immunology , Macrophages/immunology , Ovarian Neoplasms/immunology , Tumor Microenvironment/immunology , Animals , Azacitidine/administration & dosage , Cystadenocarcinoma, Serous/drug therapy , Cystadenocarcinoma, Serous/metabolism , Cystadenocarcinoma, Serous/pathology , Eflornithine/administration & dosage , Female , Immunity, Innate/drug effects , Macrophages/drug effects , Mice , Mice, Inbred C57BL , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/metabolism , Ovarian Neoplasms/pathology , Polyamines/metabolism , Tumor Cells, Cultured , Tumor Microenvironment/drug effectsABSTRACT
PURPOSE: Glioblastoma multiforme (GBM) is the most malignant primary brain tumor with dismal prognosis. This tumor is characterized by extensive heterogeneity, thus is difficult to treat and every established or new treatment faces significant hazard of resistance. Temozolomide (TMZ), an oral alkylating agent, is the first-line treatment for GBM, but resistance to TMZ is a major problem. Herewith, we investigated the combined effect of TMZ, difluoromethylornithine (DFMO), an inhibitor of ornithine decarboxylase, and radiation in GBM cell lines. METHODS: We used the U87G, U251MG and T98G GBM cell lines. A linac 6MV accelerator (Varian Medical Systems) was used for cell irradiation. Viability and proliferation of the cells were examined with trypan blue exclusion assay, crystal violet and xCELLigence system. Cell cycle and activation of caspase-8 were evaluated with flow cytometry. RESULTS: The combination treatment resulted in a consistent higher suppression of proliferation in all cell lines treated and induced a significant higher cell cycle arrest in G2/M phase in U251MG and T98G cell lines. In U251MG cells caspase-8 was increased with each treatment alone, however the combination treatment had lower level of caspase-8 induction, suggesting a co-existence of another mechanism of cell death apart from apoptosis. In T98G cells the combination treatment increased the activation of caspase-8. CONCLUSION: Combination treatment with DFMO, TMZ and radiation significantly reduced cell viability in all cell lines tested. Given that both TMZ and DFMO can be administered orally and are related to minimal toxicities, this combination treatment may be a novel treatment strategy for GBM that deserves further investigation.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Brain Neoplasms/drug therapy , Brain Neoplasms/radiotherapy , Glioblastoma/drug therapy , Glioblastoma/radiotherapy , Cell Cycle/drug effects , Cell Cycle/radiation effects , Cell Death/drug effects , Cell Death/radiation effects , Cell Line, Tumor , Chemoradiotherapy , Eflornithine/administration & dosage , Humans , Temozolomide/administration & dosageSubject(s)
Eflornithine/administration & dosage , Hair/drug effects , Hypertrichosis/drug therapy , Postoperative Complications/drug therapy , Rhinoplasty/adverse effects , Aged , Carcinoma, Basal Cell/surgery , Dermoscopy , Esthetics , Female , Forehead/surgery , Hair/diagnostic imaging , Hair/growth & development , Humans , Hypertrichosis/diagnostic imaging , Hypertrichosis/etiology , Mohs Surgery/adverse effects , Nose/drug effects , Nose/surgery , Nose Neoplasms/surgery , Postoperative Complications/diagnostic imaging , Postoperative Complications/etiology , Rhinoplasty/methods , Skin Cream/administration & dosage , Surgical Flaps/adverse effects , Surgical Flaps/transplantation , Treatment OutcomeABSTRACT
Cancer is a set of diseases characterized by uncontrolled cell growth. In certain cancers of the gastrointestinal tract, the adenomatous polyposis coli (APC) tumor suppressor gene is altered in either germline or somatic cells and causes formation of risk factors, such as benign colonic or intestinal neoplasia, which can progress to invasive cancer. APC is a key component of the WNT pathway, contributing to normal GI tract development, and APC alteration results in dysregulation of the pathway for production of polyamines, which are ubiquitous cations essential for cell growth. Studies with mice have identified nonsteroidal anti-inflammatory drugs (NSAIDs) and difluoromethylornithine (DFMO), an inhibitor of polyamine synthesis, as potent inhibitors of colon carcinogenesis. Moreover, gene expression profiling has uncovered that NSAIDs activate polyamine catabolism and export. Several DFMO-NSAID combination strategies are effective and safe methods for reducing risk factors in clinical trials with patients having genetic or sporadic risk of colon cancer. These strategies affect cancer stem cells, inflammation, immune surveillance, and the microbiome. Pharmacotherapies consisting of drug combinations targeting the polyamine pathway provide a complementary approach to surgery and cytotoxic cancer treatments for treating patients with cancer risk factors. In this Minireview, we discuss the role of polyamines in colon cancer and highlight the mechanisms of select pharmacoprevention agents to delay or prevent carcinogenesis in humans.
Subject(s)
Colonic Neoplasms/prevention & control , Polyamines/metabolism , Animals , Anti-Inflammatory Agents, Non-Steroidal/administration & dosage , Chemoprevention , Colonic Neoplasms/metabolism , Eflornithine/administration & dosage , HumansABSTRACT
High risk neuroblastoma (HRNB) accounts for 15% of all pediatric cancer deaths. Despite aggressive therapy approximately half of patients will relapse, typically with only transient responses to second-line therapy. This study evaluated the ornithine decarboxylase inhibitor difluoromethylornithine (DFMO) as maintenance therapy to prevent relapse following completion of standard therapy (Stratum 1) or after salvage therapy for relapsed/refractory disease (Stratum 2). This Phase II single agent, single arm multicenter study enrolled from June 2012 to February 2016. Subjects received 2 years of oral DFMO (750 ± 250 mg/m2 twice daily). Event free survival (EFS) and overall survival (OS) were determined on an intention-to-treat (ITT) basis. 101 subjects enrolled on Stratum 1 and 100 were eligible for ITT analysis; two-year EFS was 84% (±4%) and OS 97% (±2%). 39 subjects enrolled on Stratum 2, with a two-year EFS of 54% (±8%) and OS 84% (±6%). DFMO was well tolerated. The median survival time is not yet defined for either stratum. DFMO maintenance therapy for HRNB in remission is safe and associated with high EFS and OS. Targeting ODC represents a novel therapeutic mechanism that may provide a new strategy for preventing relapse in children with HRNB.
Subject(s)
Eflornithine/administration & dosage , Maintenance Chemotherapy , Neuroblastoma/drug therapy , Neuroblastoma/mortality , Child, Preschool , Disease-Free Survival , Eflornithine/adverse effects , Female , Humans , Male , Survival RateABSTRACT
We conducted a retrospective study on mortality trends and risk factors in 781 naïve cases of advanced stage-2 sleeping sickness admitted between 1989 and 2012 at the National Reference Center for Human African Trypanosomiasis (HAT), Department of Neurology, Kinshasa University, Democratic Republic of Congo (DRC). Death was the outcome variable whereas age, gender, duration of disease, location of trypanosomes in body fluids, cytorachy, protidorachy, clinical status (assessed on a syndromic and functional basis) on admission, and treatment regimen were predictors in logistic regression models run at the 0.05 significance level. Death proportions were 17.2% in the standard melarsoprol schedule (3-series of intravenous melarsoprol on 3 successive days at 3.6 mg/kg/d, with a one-week interval between the series, ARS 9); 12.1% in the short schedule melarsoprol (10 consecutive days of intravenous melarsoprol at 2.2 mg/kg/d, ARS 10), 5.4% in the first-line eflornithine (14 days of eflornithine at 400 mg/kg/d in 4 infusions a day DFMO B), 9.1% in the NECT treatment regimen (eflornithine for 7 days at 400, mg/kg/d in 2 infusions a day combined with oral nifurtimox for 10 days at 15 mg/kg/d in 3 doses a day); and high (36%) in the group with select severely affected patients given eflornithine because of their clinical status on admission, at the time when this expensive drug was kept for treatment of relapses (14 days at 400 mg/kg/d in 4 infusions a day, DFMO A). After adjusting for treatment, death odds ratios were as follows: 10.40 [(95% CI: 6.55-16.51); p = .000] for clinical dysfunction (severely impaired clinical status) on admission, 2.14 [(95% CI: 1.35-3.39); p = .001] for high protidorachy, 1.99 [(95% CI: 1.18-3.37); p = .010] for the presence of parasites in the CSF and 1.70 [(95% CI: 1.03-2.81); p = .038] for high cytorachy. A multivariable analysis within treatment groups retained clinical status on admission (in ARS 9, ARS 10 and DFMO B groups) and high protidorachy (in ARS 10 and DFMO B groups) as significant predictors of death. The algorithm for initial clinical status assessment used in the present study may serve as the basis for further development of standardized assessment tools relevant to the clinical management of HAT and information exchange in epidemiological reports.
Subject(s)
Trypanosomiasis, African/epidemiology , Trypanosomiasis, African/mortality , Adolescent , Adult , Democratic Republic of the Congo/epidemiology , Disease Management , Drug Therapy, Combination , Eflornithine/administration & dosage , Eflornithine/therapeutic use , Female , Hospital Records , Humans , Male , Melarsoprol/administration & dosage , Melarsoprol/therapeutic use , Middle Aged , Multivariate Analysis , Nifurtimox/administration & dosage , Nifurtimox/therapeutic use , Recurrence , Retrospective Studies , Risk Factors , Treatment Outcome , Trypanocidal Agents/administration & dosage , Trypanocidal Agents/therapeutic use , Trypanosoma brucei gambiense/drug effects , Trypanosomiasis, African/drug therapy , Trypanosomiasis, African/parasitology , Young AdultABSTRACT
Tuberous sclerosis complex (TSC) is an autosomal dominant neurodevelopmental disorder and the quintessential disorder of mechanistic Target of Rapamycin Complex 1 (mTORC1) dysregulation. Loss of either causative gene, TSC1 or TSC2, leads to constitutive mTORC1 kinase activation and a pathologically anabolic state of macromolecular biosynthesis. Little is known about the organ-specific metabolic reprogramming that occurs in TSC-affected organs. Using a mouse model of TSC in which Tsc2 is disrupted in radial glial precursors and their neuronal and glial descendants, we performed an unbiased metabolomic analysis of hippocampi to identify Tsc2-dependent metabolic changes. Significant metabolic reprogramming was found in well-established pathways associated with mTORC1 activation, including redox homeostasis, glutamine/tricarboxylic acid cycle, pentose and nucleotide metabolism. Changes in two novel pathways were identified: transmethylation and polyamine metabolism. Changes in transmethylation included reduced methionine, cystathionine, S-adenosylmethionine (SAM-the major methyl donor), reduced SAM/S-adenosylhomocysteine ratio (cellular methylation potential), and elevated betaine, an alternative methyl donor. These changes were associated with alterations in SAM-dependent methylation pathways and expression of the enzymes methionine adenosyltransferase 2A and cystathionine beta synthase. We also found increased levels of the polyamine putrescine due to increased activity of ornithine decarboxylase, the rate-determining enzyme in polyamine synthesis. Treatment of Tsc2+/- mice with the ornithine decarboxylase inhibitor α-difluoromethylornithine, to reduce putrescine synthesis dose-dependently reduced hippocampal astrogliosis. These data establish roles for SAM-dependent methylation reactions and polyamine metabolism in TSC neuropathology. Importantly, both pathways are amenable to nutritional or pharmacologic therapy.
Subject(s)
Brain/metabolism , Metabolomics , Tuberous Sclerosis/metabolism , Animals , Brain/pathology , Cystathionine/genetics , Cystathionine beta-Synthase/genetics , DNA Methylation/genetics , Disease Models, Animal , Eflornithine/administration & dosage , Humans , Mechanistic Target of Rapamycin Complex 1/genetics , Methionine Adenosyltransferase/genetics , Mice , Neurons/metabolism , Neurons/pathology , Polyamines/metabolism , Putrescine/biosynthesis , S-Adenosylmethionine/metabolism , Tuberous Sclerosis/genetics , Tuberous Sclerosis/pathology , Tuberous Sclerosis Complex 1 Protein/genetics , Tuberous Sclerosis Complex 2 Protein/geneticsABSTRACT
BACKGROUND: While the combination of nifurtimox and eflornithine (NECT) is currently recommended for the treatment of the late stage human African trypansomiasis (HAT), single-agent eflornithine was still the treatment of choice when this trial commenced. This study intended to provide supportive evidence to complement previous trials. METHODS: A multi-centre randomised, open-label, non-inferiority trial was carried out in the Trypanosoma brucei gambiense endemic districts of North-Western Uganda to compare the efficacy and safety of NECT (200 mg/kg eflornithine infusions every 12 h for 7 days and 8 hourly oral nifurtimox at 5 mg/kg for 10 days) to the standard eflornithine regimen (6 hourly at 100 mg/kg for 14 days). The primary endpoint was the cure rate, determined as the proportion of patients alive and without laboratory signs of infection at 18 months post-treatment, with no demonstrated trypanosomes in the cerebrospinal fluid (CSF), blood or lymph node aspirates, and CSF white blood cell count < 20 /µl. The non-inferiority margin was set at 10%. RESULTS: One hundred and nine patients were enrolled; all contributed to the intent-to-treat (ITT), modified intent-to-treat (mITT) and safety populations, while 105 constituted the per-protocol population (PP). The cure rate was 90.9% for NECT and 88.9% for eflornithine in the ITT and mITT populations; the same was 90.6 and 88.5%, respectively in the PP population. Non-inferiority was demonstrated for NECT in all populations: differences in cure rates were 0.02 (95% CI: -0.07-0.11) and 0.02 (95% CI: -0.08-0.12) respectively. Two patients died while on treatment (1 in each arm), and 3 more during follow-up in the NECT arm. No difference was found between the two arms for the secondary efficacy and safety parameters. A meta-analysis involving several studies demonstrated non-inferiority of NECT to eflornithine monotherapy. CONCLUSIONS: These results confirm findings of earlier trials and support implementation of NECT as first-line treatment for late stage T. b. gambiense HAT. The overall risk difference for cure between NECT and eflornithine between this and two previous randomised controlled trials is 0.03 (95% CI: -0.02-0.08). The NECT regimen is simpler, safer, shorter and less expensive than single-agent DFMO. TRIAL REGISTRATION: ISRCTN ISRCTN03148609 (registered 18 April 2008).
Subject(s)
Eflornithine/administration & dosage , Nifurtimox/administration & dosage , Trypanocidal Agents/administration & dosage , Trypanosoma brucei gambiense , Trypanosomiasis, African/drug therapy , Adolescent , Adult , Drug Therapy, Combination , Eflornithine/adverse effects , Female , Follow-Up Studies , Humans , Male , Nifurtimox/adverse effects , Safety , Treatment Outcome , Trypanocidal Agents/adverse effects , Trypanosomiasis, African/epidemiology , Uganda/epidemiology , Young AdultABSTRACT
Human African trypanosomiasis is endemic to parts of sub-Saharan Africa and should be considered in the differential diagnosis of patients who have visited or lived in Africa. We report a 2017 case of stage 2 Trypanosoma brucei gambiense disease in an emigrant who returned to China from Gabon.
Subject(s)
Emigrants and Immigrants , Trypanosomiasis, African/epidemiology , Trypanosomiasis, African/parasitology , China/epidemiology , Drug Therapy, Combination , Eflornithine/administration & dosage , Eflornithine/therapeutic use , Gabon/epidemiology , Humans , Nifurtimox/administration & dosage , Nifurtimox/therapeutic use , Trypanocidal Agents/administration & dosage , Trypanocidal Agents/therapeutic use , Trypanosoma brucei gambienseABSTRACT
Different chemotherapy drugs are generally introduced in clinical practices combining with therapy for glioma treatment. However, these chemotherapy drugs have rarely been compared with each other and the optimum drug still remains to be proved. In this research, medical databases were consulted, PubMed, Embase and Cochrane Library included. As primary outcomes, hazard ratio (HR) of overall survival (OS) and progression-free survival (PFS) with their corresponding 95% credential intervals (CrI) were reported. A network meta-analysis was conducted; the surface under the cumulative ranking curve (SUCRA) was utilized for treatment rank and a cluster analysis based on SUCRA values was performed. This research includes 14 trials with 3,681 subjects and eight interventions. In terms of network meta-analysis, placebo was proved to be inferior to the combination of temozolomide (TMZ), nimustine (ACNU) and cisplatin (CDDP). Also, bevacizumab (BEV) in conjunction with TMZ were significantly more effective than placebo with an HR of 0.40. The estimated probabilities from SUCRA verified the above outcomes, confirming that the combination of TMZ, ACNU and CDDP exhibited the highest ranking probability of 0.889 with respect to OS, while BEV in combination with TMZ - with a probability of 0.772 - ranked the first place with respect to PFS. According to the results of this network meta-analysis, the combination of (1) TMZ, ACNU and CDDP; (2) BEV in combination with TMZ and (3) cilengitide in combination with TMZ, are considered as the preferable choices of chemotherapy drugs for glioma treatment.
Subject(s)
Antineoplastic Agents/therapeutic use , Brain Neoplasms/therapy , Chemoradiotherapy , Glioma/therapy , Antibodies, Monoclonal, Humanized , Antineoplastic Agents/administration & dosage , Bayes Theorem , Bevacizumab/administration & dosage , Brain Neoplasms/mortality , Cisplatin/administration & dosage , Dacarbazine/administration & dosage , Dacarbazine/analogs & derivatives , Disease-Free Survival , Eflornithine/administration & dosage , Glioma/mortality , Humans , Mitolactol/administration & dosage , Network Meta-Analysis , Nimustine/administration & dosage , Probability , Randomized Controlled Trials as Topic , Snake Venoms/administration & dosage , Temozolomide , Treatment Outcome , Vincristine/administration & dosageABSTRACT
BACKGROUND AND AIM: Although Non-steroidal anti-inflammatory drugs reduce colorectal adenoma burden in familial adenomatous polyposis (FAP), the utility of combining chemopreventive agents in FAP is not known. We conducted a randomised trial of celecoxib (CXB) versus CXB+diflouromethylornithine (DFMO) to determine the synergistic effect, if any. METHODS: The primary endpoint was % change in adenoma count in a defined field. Secondary endpoints were adenoma burden (weighted by adenoma diameter) and video review of entire colon/rectal segments. Adverse event (AEs) were monitored by National Cancer Institution toxicity criteria. RESULTS: 112 subjects were randomised: 60 men and 52 women at a mean age of 38â years. For the 89 patients who had landmark-matched polyp counts available at baseline and 6â months, the mean % change in adenoma count over the 6â months of trial was -13.0% for CXB+DFMO and -1.0% for CXB (p=0.69). Mean % change in adenoma burden was -40% (CXB+DFMO) vs -27% (CXB) (p=0.13). Video-based global polyp change was -0.80 for CXB+DFMO vs -0.33 for CXB (p=0.03). Fatigue was the only significant AE, worse on the CXB arm (p=0.02). CONCLUSIONS: CXB combined with DFMO yielded moderate synergy according to a video-based global assessment. No significant difference in adenoma count, the primary endpoint, was seen between the two study arms. No evidence of DFMO-related ototoxicity was seen. There were no adverse cardiovascular outcomes in either trial arm and no significant increase in AEs in the CXB+DFMO arm of the trial. Differences in outcomes between primary and secondary endpoints may relate to sensitivity of the endpoint measures themselves. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov number N01-CN95040.