Risk Factors for Thromboembolic Events in Patients With Dialysis-Dependent CKD: Pooled Analysis of Four Global Roxadustat Phase 3 Trials.

INTRODUCTION: Risk factors for thromboembolic events in patients with dialysis-dependent chronic kidney disease (CKD) receiving roxadustat are unknown. Iron deficiency has been reported as a risk factor for thrombosis in the general population. METHODS: Thromboembolic events with onset before and after week 12 in patients receiving roxadustat were evaluated in this pooled analysis of four global phase 3 trials, PYRENEES, SIERRAS, HIMALAYAS, and ROCKIES. Baseline risk factors for thromboembolic events were investigated by Cox regression analyses. Nested case-control analyses with matched pairs of case-control data explored the relationship between thromboembolic events and last known laboratory parameters before event onset. RESULTS: Of 2354 patients, 1026 thromboembolic events were observed in 568 patients. Baseline risk factors found included hemodialysis (vs peritoneal dialysis), advanced age (≥ 65 years), Black race, high high-sensitivity C-reactive protein, and history of thromboembolism, cardiovascular disease, or diabetes. Univariate case-control analyses revealed that high hemoglobin rate of rise (≥ 0.5 g/dL/week; odds ratio [OR] 2.09; 95% confidence interval [CI] 0.98-4.46) showed a trend towards increased risk of thromboembolic events before week 12, and high rate of hemoglobin decline was associated with events after week 12 (< - 0.5 g/dL/week; OR 3.73; 95% CI 1.68-8.27) as compared to stable hemoglobin levels (≥ - 0.1 to < 0.1 g/dL/week). Multivariate case-control analyses showed that low last known hemoglobin level (< 10 g/dL: adjusted OR 1.91; 95% CI 1.04-3.50; vs ≥ 12 g/dL) and low last known transferrin saturation (TSAT < 10%: adjusted OR 3.78; 95% CI 1.71-8.39; vs ≥ 30%) before event onset were associated with events after week 12. In patients with last known TSAT < 30%, higher roxadustat dose was associated with thromboembolic events; however, no association was observed in those with TSAT ≥ 30%. CONCLUSIONS: Among various risk factors for thromboembolic events, it is reasonable to avoid a rapid increase and decline in hemoglobin levels as well as ensure TSAT ≥ 30%, rather than increasing the roxadustat dose. Graphical Abstract available for this article. TRIAL REGISTRATION: NCT02278341, NCT02273726, NCT02052310, NCT02174731.

Roxadustat is an oral treatment for patients with anemia, or low hemoglobin levels, due to chronic kidney disease. Thromboembolic events are caused by a blood clot blocking blood vessels, and they have occurred in clinical trials of roxadustat. This analysis evaluated risk factors for thromboembolic events in patients receiving roxadustat to treat anemia of chronic kidney disease who are on dialysis. Two different statistical approaches were used to investigate risk factors for thromboembolic events that occurred before and after 12 weeks of roxadustat treatment. We found that rapid improvement of anemia after starting roxadustat treatment may be associated with an increased risk of thromboembolic events occurring in the first 12 weeks of treatment. In contrast, severe anemia or worsening of anemia was associated with an increased risk of thromboembolic events after week 12. Low iron levels in the blood or greater decline of available iron in the blood from baseline were also detected as risk factors for the events after week 12, suggesting that iron supplementation is important in patients who are iron-deficient. Moreover, thromboembolic events were also associated with older age (≥ 65 years), Black race, high levels of inflammation, and having had a previous thromboembolic event or having a history of cardiovascular disease or diabetes. Some risk factors, such as iron status and hemoglobin levels, can be changed after beginning roxadustat treatment and should be monitored and modified, as needed.

Clinical development of IDH1 inhibitors for cancer therapy.

Isocitrate dehydrogenase 1 (IDH1) has been investigated as a promising therapeutic target in select cancers with a mutated version of the enzyme (mtIDH1). With only one phase III trial published to date and two indications approved for routine clinical use by the FDA, we reviewed the entire clinical trial portfolio to broadly understand mtIDH1 inhibitor activity in patients. We queried PubMed.gov and ClinicalTrials.gov to identify published and ongoing clinical trials related to IDH1 and cancer. Progression-free survival (PFS), overall survival (OS), 2-hydroxyglutarate levels, and adverse events were summarized. To date, ten clinical trials investigating mtIDH1 inhibitors among patients with diverse malignancies (cholangiocarcinoma, acute myeloid leukemia, chondrosarcoma, glioma) have been published. Almost every trial (80%) has investigated ivosidenib. In multiple phase I trials, ivosidenib treatment resulted in promising radiographic and biochemical responses with improved survival outcomes (relative to historic data) among patients with both solid and hematologic mtIDH1 malignancies. Among patients enrolled in a phase III trial with advanced cholangiocarcinoma, ivosidenib resulted in a PFS rate of 32% at 6 months, as compared to 0% with placebo. There was a 5.2 month increase in OS with ivosidenib relative to placebo, after considering crossover. The treatment-specific grade ≥3 adverse event rate of ivosidenib was 2%-26% among all patients, and was just 3.6% among 284 patients who had a solid tumor across four trials. Although <1% of malignancies harbor IDH1 mutations, small molecule mtIDH1 inhibitors, namely ivosidenib, appear to be biologically active and well tolerated in patients with solid and hematologic mtIDH1 malignancies.

The efficacy and safety of roxadustat treatment for anemia in patients with kidney disease: a meta-analysis and systematic review.

BACKGROUND: Anemia is a common complication for patients with kidney disease. Roxadustat is an oral hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor (PHI), which is a newly approved oral drug for anemia. We performed this study to build evidence regarding efficacy and safety of roxadustat in kidney disease patients with or without dialysis. METHODS: We searched the databases of PubMed, Embase, Cochrane library and clinicaltrials.gov from the inception to July 20, 2020. The randomized controlled trials (RCTs) which compared roxadustat with placebo or other therapies in the treatment of anemia in kidney disease patients were included. Data were extracted from eligible studies and pooled in a meta-analysis model using RevMan5.3 and stata13.0 software. RESULTS: Eight RCTs with 1010 patients were included in our analysis. We found that roxadustat significantly increased hemoglobin (Hb) level (1.10 g/dL, 95% CI [0.52 g/dL, 1.67 g/dL], p = 0.0002), total iron-binding capacity (TIBC) (58.71 µg/dL, 95% CI [44.10 µg/dL, 73.32 µg/dL], p < 0.00001), iron level (9.28 µg/dL, 95% CI [0.11 µg/dL, 18.45 µg/dL], p = 0.05) compared with control group in kidney disease patients. In addition, our result showed that a significant reduction in hepcidin level (- 31.96 ng/mL, 95% CI [- 35.05 ng/mL, - 28.87 ng/mL], p < 0.00001), ferritin (- 44.82 ng/mL, 95% CI [- 64.42 ng/mL, - 25.23 ng/mL], p < 0.00001) was associated with roxadustat. No difference was found between roxadustat and control group in terms of oral iron supplementation, adverse events (AEs), serious adverse events (SAEs), infection, myocardial infraction, stroke, heart failure and death. CONCLUSIONS: Roxadustat has higher mean Hb level than placebo or EPO. Due to the short follow-up period and the lack of critical data, more RCTs are needed to prove long-term safety and effectiveness of roxadustat in the future.

Safety of Dietary Guanidinoacetic Acid: A Villain of a Good Guy?

Guanidinoacetic acid (GAA) is a natural amino acid derivative that is well-recognized for its central role in the biosynthesis of creatine, an essential compound involved in cellular energy metabolism. GAA (also known as glycocyamine or betacyamine) has been investigated as an energy-boosting dietary supplement in humans for more than 70 years. GAA is suggested to effectively increase low levels of tissue creatine and improve clinical features of cardiometabolic and neurological diseases, with GAA often outcompeting traditional bioenergetics agents in maintaining ATP status during stress. This perhaps happens due to a favorable delivery of GAA through specific membrane transporters (such as SLC6A6 and SLC6A13), previously dismissed as un-targetable carriers by other therapeutics, including creatine. The promising effects of dietary GAA might be countered by side-effects and possible toxicity. Animal studies reported neurotoxic and pro-oxidant effects of GAA accumulation, with exogenous GAA also appearing to increase methylation demand and circulating homocysteine, implying a possible metabolic burden of GAA intervention. This mini-review summarizes GAA toxicity evidence in human nutrition and outlines functional GAA safety through benefit-risk assessment and multi-criteria decision analysis.

Ixazomib maintenance therapy in newly diagnosed multiple myeloma: An integrated analysis of four phase I/II studies.

OBJECTIVES: To evaluate the safety and efficacy of maintenance therapy with the oral proteasome inhibitor ixazomib in patients with newly diagnosed multiple myeloma (NDMM) not undergoing transplantation. METHODS: Data were pooled from four NDMM phase I/II studies; patients received induction therapy with once- or twice-weekly ixazomib plus lenalidomide-dexamethasone (IRd), melphalan-prednisone (IMP), or cyclophosphamide-dexamethasone (ICd), followed by single-agent ixazomib maintenance, given at the last tolerated dose during induction, until disease progression, death, or unacceptable toxicity. RESULTS: A total of 121 patients achieved stable disease or better after induction (weekly IRd, n = 25; twice-weekly IRd, n = 18; weekly or twice-weekly IMP, n = 35; weekly ICd, n = 43) and received ≥ 1 dose of ixazomib maintenance. Grade ≥ 3 drug-related adverse events occurred in 24% of patients during maintenance; each event was reported in ≤2% of patients. Rates of complete response were 22% after induction and 35% after maintenance. A total of 28 patients (23%) improved their response during maintenance. CONCLUSIONS: Ixazomib maintenance following ixazomib-based induction is associated with deepening of responses and a positive safety profile with no cumulative toxicity in patients with NDMM not undergoing transplantation, suggesting that ixazomib is feasible for long-term administration. Phase III investigation of ixazomib maintenance is ongoing.

Ochrobactrum cytisi IPA7.2 promotes growth of potato microplants and is resistant to abiotic stress.

Bacteria in natural associations with agricultural crops are promising for use in the improvement of clonal micropropagation of plants. We clarified the taxonomic position of Ochrobactrum cytisi strain IPA7.2 and investigated its tolerance for salinity, high temperature, and glyphosate pollution. We also tested the strain's potential to promote the growth of potato (Solanum tuberosum L.) microplants. Using the IPA7.2 draft genome (no. NZ_MOEC00000000), we searched for housekeeping genes and also for the target genes encoding glyphosate tolerance and plant-growth-promoting ability. A multilocus sequence analysis of the gap, rpoB, dnaK, trpE, aroC, and recA housekeeping genes led us to identify isolate IPA7.2 as O. cytisi. The strain tolerated temperatures up to 50 °C and NaCl concentrations up to 3-4%, and it produced 8 µg ml-1 of indole-3-acetic acid. It also tolerated 6 mM glyphosate owing to the presence of type II 5-enolpyruvylshikimate-3-phosphate synthase. Finally, it was able to colonize the roots and tissues of potato microplants, an ability preserved by several generations after subculturing. We identified the development phase of potato microplants that was optimal for inoculation with O. cytisi IPA7.2. Inoculation of in vitro-grown 15-day-old microplants increased the mitotic index of root meristem cells (by 50%), the length of shoots (by 34%), the number of leaves (by 7%), and the number of roots (by 16%). Under ex vitro conditions, the inoculated plants had a greater leaf area (by 77%) and greater shoot and root dry weight (by 84 and 61%, respectively) than did the control plants. We recommend O. cytisi IPA 7.2 for use in the growing of potato microplants to improve the production of elite seed material.

Oral ixazomib maintenance following autologous stem cell transplantation (TOURMALINE-MM3): a double-blind, randomised, placebo-controlled phase 3 trial.

BACKGROUND: Maintenance therapy following autologous stem cell transplantation (ASCT) can delay disease progression and prolong survival in patients with multiple myeloma. Ixazomib is ideally suited for maintenance therapy given its convenient once-weekly oral dosing and low toxicity profile. In this study, we aimed to determine the safety and efficacy of ixazomib as maintenance therapy following ASCT. METHODS: The phase 3, double-blind, placebo-controlled TOURMALINE-MM3 study took place in 167 clinical or hospital sites in 30 countries in Europe, the Middle East, Africa, Asia, and North and South America. Eligible participants were adults with a confirmed diagnosis of symptomatic multiple myeloma according to International Myeloma Working Group criteria who had achieved at least a partial response after undergoing standard-of-care induction therapy followed by high-dose melphalan (200 mg/m2) conditioning and single ASCT within 12 months of diagnosis. Patients were randomly assigned in a 3:2 ratio to oral ixazomib or matching placebo on days 1, 8, and 15 in 28-day cycles for 2 years following induction, high-dose therapy, and transplantation. The initial 3 mg dose was increased to 4 mg from cycle 5 if tolerated during cycles 1-4. Randomisation was stratified by induction regimen, pre-induction disease stage, and response post-transplantation. The primary endpoint was progression-free survival (PFS) by intention-to-treat analysis. Safety was assessed in all patients who received at least one dose of ixazomib or placebo, according to treatment actually received. This trial is registered with ClinicalTrials.gov, number NCT02181413, and follow-up is ongoing. FINDINGS: Between July 31, 2014, and March 14, 2016, 656 patients were enrolled and randomly assigned to receive ixazomib maintenance therapy (n=395) or placebo (n=261). With a median follow-up of 31 months (IQR 27·3-35·7), we observed a 28% reduction in the risk of progression or death with ixazomib versus placebo (median PFS 26·5 months [95% CI 23·7-33·8] vs 21·3 months [18·0-24·7]; hazard ratio 0·72, 95% CI 0·58-0·89; p=0·0023). No increase in second malignancies was noted with ixazomib therapy (12 [3%] patients) compared with placebo (eight [3%] patients) at the time of this analysis. 108 (27%) of 394 patients in the ixazomib group and 51 (20%) of 259 patients in the placebo group experienced serious adverse events. During the treatment period, one patient died in the ixazomib group and none died in the placebo group. INTERPRETATION: Ixazomib maintenance prolongs PFS and represents an additional option for post-transplant maintenance therapy in patients with newly diagnosed multiple myeloma. FUNDING: Millennium Pharmaceuticals, a wholly owned subsidiary of Takeda Pharmaceutical Company.

Pancreatic function and histoarchitecture in Wistar rats following chronic exposure to Bushfire®: the mitigating role of zinc.

Objectives To assess the toxicopathologic effects of chronic exposure to the glyphosate-based herbicide Bushfire® on the pancreas of Wistar rats and the protective role of zinc. Methods We exposed the rats to daily doses of 14.4 to 750 mg/kg body weight of the glyphosate-based herbicide Bushfire® and to 50 or 100 mg/kg zinc, and measured blood glucose levels and serum insulin levels. Tissue samples were evaluated for histopathological alterations. Results Levels of both blood glucose and serum insulin increased in glyphosate-exposed rats, and moderate to severe degenerative changes were observed in both glandular pancreatic acinar cells and islets of Langerhans in all rats exposed to glyphosate. These effects were prevented by pretreatment with zinc. Conclusion Chronic exposure to glyphosate can alter pancreatic function and histoarchitecture, but zinc supplementation can mitigate these toxicopathologic effects.

Blue Vision (Cyanopsia) Associated With TURP Syndrome: A Case Report.

There have been many complications associated with transurethral resection of the prostate (TURP), known as TURP syndrome. Of the various irrigation fluids used for TURP, glycine irrigant has been historically popular given its relatively low cost. It is also a nonconductive solution and only slightly hypoosmolar, reducing the risk of burn injury or significant hemolysis. However, there have been many case reports of central nervous system toxicity such as transient blindness and encephalopathy related to glycine toxicity. Here, we report blue vision (cyanopsia), which has never been reported as a symptom of TURP syndrome.

The role of ixazomib as an augmented conditioning therapy in salvage autologous stem cell transplant (ASCT) and as a post-ASCT consolidation and maintenance strategy in patients with relapsed multiple myeloma (ACCoRd [UK-MRA Myeloma XII] trial): study protocol for a Phase III randomised controlled trial.

BACKGROUND: Multiple myeloma (MM) is a plasma cell tumour with an approximate annual incidence of 4500 in the UK. Therapeutic options for patients with MM have changed in the last decade with the arrival of proteasome inhibitors and immunomodulatory drugs. Despite these options, almost all patients will relapse post first-line autologous stem cell transplantation (ASCT). First relapse management (second-line treatment) has evolved in recent years with an expanding portfolio of novel agents, driving response rates influencing the durability of response. A second ASCT, as part of relapsed disease management (salvage ASCT), has been shown to prolong the progression-free survival and overall survival following a proteasome inhibitor-containing re-induction regimen, in the Cancer Research UK-funded National Cancer Research Institute Myeloma X (Intensive) study. It is now recommended that salvage ASCT be considered for suitable patients by the International Myeloma Working Group and the National Institute for Health and Care Excellence NG35 guidance. METHODS/DESIGN: ACCoRd (Myeloma XII) is a UK-nationwide, individually randomised, multi-centre, multiple randomisation, open-label phase III trial with an initial single intervention registration phase aimed at relapsing MM patients who have received ASCT in first-line treatment. We will register 406 participants into the trial to allow 284 and 248 participants to be randomised at the first and second randomisations, respectively. All participants will receive re-induction therapy until maximal response (four to six cycles of ixazomib, thalidomide and dexamethasone). Participants who achieve at least stable disease will be randomised (1:1) to receive either ASCTCon, using high-dose melphalan, or ASCTAug, using high-dose melphalan with ixazomib. All participants achieving or maintaining a minimal response or better, following salvage ASCT, will undergo a second randomisation (1:1) to consolidation and maintenance or observation. Participants randomised to consolidation and maintenance will receive consolidation with two cycles of ixazomib, thalidomide and dexamethasone, and maintenance with ixazomib until disease progression. DISCUSSION: The question of how best to maximise the durability of response to salvage ASCT warrants clinical investigation. Given the expanding scope of oral therapeutic agents, patient engagement with long-term maintenance strategies is a real opportunity. This study will provide evidence to better define post-relapse treatment in MM. TRIAL REGISTRATION: ISRCTN, ISRCTN10038996 . Registered on 15 December 2016.

Acute tubular necrosis following transurethral resection of the Prostate using Glycine as irrigating fluid.

Transurethral resection of the prostate is currently the gold standard for the surgical treatment of the benign prostatic hyperplasia. This surgery may lead transurethral resection of the prostate (TURP) syndrome and in some cases, acute tubular necrosis can develop. We report a patient who developed hyponatremia, hemolysis and oliguric acute renal failure as a major complication following TURP using glycine as irrigating fluid.A 64-year-old man was admitted for a prostate resection procedure. Physical examination revealed a healthy elderly man. Preoperative laboratory data showed serum sodium 140 mEq/L, blood urea nitrogen (BUN) 0.6 g/L, creatinine 0.7 mg/dL and hemoglobin 12.9 g/dL. Few hours after, the patient becomes incoherent and developed oliguria, nausea and vomiting. The laboratory data revealed rapidly elevating BUN and creatinine levels (BUN 2.4 g/L; creatinine 6.1 mg/dL), the serum sodium concentration decreased by 14 meq/L. A decreased hemoglobin level (7.4 g/dL) with an elevated lactate dehydrogenase level (665 U/L) was observed. Renal ultrasonography was normal. The diagnosis of acute tubular necrosis complicating TURP syndrome was retained. The hyponatremia was slowly corrected to 132 mmol/L by diuresis and fluid restriction. The renal function recovered after four hemodialysis sessions. Using glycine as an irrigant for TURP may cause hyponatremia, hemolysis and also acute renal failure, especially in patients with longer resection time. It is necessary to carry out every effort to shorten resection time and avoid extravasation during surgery.

Dietary guanidinoacetic acid increases brain creatine levels in healthy men.

OBJECTIVE: Guanidinoacetic acid (GAA) is an experimental dietary additive that might act as a creatine source in tissues with high-energy requirements. In this case study, we evaluated brain levels of creatine in white matter, gray matter, cerebellum, and thalamus during 8 wk oral GAA administration in five healthy men and monitored the prevalence and severity of side effects of the intervention. METHODS: Volunteers were supplemented daily with 36 mg/kg body weight (BW) of GAA for the first 4 wk of the intervention; afterward GAA dosage was titrated ≤60 mg/kg BW of GAA daily. At baseline, 4, and 8 wk, the participants underwent brain magnetic resonance spectroscopy, clinical chemistry studies, and open-ended questionnaire for side-effect prevalence and severity. RESULTS: Brain creatine levels increased in similar fashion in cerebellum, and white and gray matter after GAA supplementation, with an initial increase of 10.7% reported after 4 wk, and additional upsurge (7.7%) from the weeks 4 to 8 follow-up (P < 0.05). Thalamus creatine levels decreased after 4 wk for 6.5% (P = 0.02), and increased nonsignificantly after 8 wk for 8% (P = 0.09). GAA induced an increase in N-acetylaspartate levels at 8-wk follow-up in all brain areas evaluated (P < 0.05). No participants reported any neurologic adverse event (e.g., seizures, tingling, convulsions) during the intervention. CONCLUSIONS: Supplemental GAA led to a region-dependent increase of the creatine pool in the human brain. This might be relevant for restoring cellular bioenergetics in disorders characterized by low brain creatine and functional enzymatic machinery for creatine synthesis, including neurodegenerative diseases, brain tumors, or cerebrovascular disease.

Guanidinoacetic acid versus creatine for improved brain and muscle creatine levels: a superiority pilot trial in healthy men.

In this randomized, double-blind, crossover trial, we evaluated whether 4-week supplementation with guanidinoacetic acid (GAA) is superior to creatine in facilitating creatine levels in healthy men (n = 5). GAA (3.0 g/day) resulted in a more powerful rise (up to 16.2%) in tissue creatine levels in vastus medialis muscle, middle-cerebellar peduncle, and paracentral grey matter, as compared with creatine (P < 0.05). These results indicate that GAA as a preferred alternative to creatine for improved bioenergetics in energy-demanding tissues.

Potential harmful effects of dietary supplements in sports medicine.

PURPOSE OF REVIEW: The purpose of this article is to collect the most recent data regarding the safety of well-known or emerging dietary supplements used by athletes. RECENT FINDINGS: From January 2014 to April 2016, about 30 articles have been published in the field. New data show that 90% of sports supplements contain trace of estrogenic endocrine disruptors, with 25% of them having a higher estrogenic activity than acceptable. About 50% of the supplements are contaminated by melamine, a source of nonprotein nitrogen. Additional data accumulate toward the safety of nitrate ingestion. In the last 2 years, the safety of emerging supplements such as higenamine, potentially interesting to lose weight, creatine nitrate and guanidinoacetic acid has been evaluated but still needs further investigation. SUMMARY: The consumption of over-the-counter supplements is very popular in athletes. Although most supplements may be considered as safe when taking at the recommended doses, athletes should be aware of the potential risks linked to the consumption of supplements. In addition to the risks linked to overdosage and cross-effects when combining different supplements at the same time, inadvertent or deliberate contamination with stimulants, estrogenic compounds, diuretics or anabolic agents may occur.

Oral Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitor Roxadustat (FG-4592) for the Treatment of Anemia in Patients with CKD.

BACKGROUND AND OBJECTIVES: Roxadustat (FG-4592), an oral hypoxia-inducible factor prolyl hydroxylase inhibitor that stimulates erythropoiesis, regulates iron metabolism, and reduces hepcidin, was evaluated in this phase 2b study for safety, efficacy, optimal dose, and dose frequency in patients with nondialysis CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The 145 patients with nondialysis CKD and hemoglobin ≤10.5 g/dl were randomized into one of six cohorts of approximately 24 patients each with varying roxadustat starting doses (tiered weight and fixed amounts) and frequencies (two and three times weekly) followed by hemoglobin maintenance with roxadustat one to three times weekly. Treatment duration was 16 or 24 weeks. Intravenous iron was prohibited. The primary end point was the proportion of patients achieving hemoglobin increase of ≥1.0 g/dl from baseline and hemoglobin of ≥11.0 g/dl by week 17 (16 weeks of treatment). Secondary analyses included mean hemoglobin change from baseline, iron utilization, and serum lipids. Safety was evaluated by frequency/severity of adverse events. RESULTS: Of the 145 patients enrolled, 143 were evaluable for efficacy. Overall, 92% of patients achieved hemoglobin response. Higher compared with lower starting doses led to earlier achievement of hemoglobin response. Roxadustat-induced hemoglobin increases were independent of baseline C-reactive protein levels and iron repletion status. Overall, over the first 16 treatment weeks, hepcidin levels decreased by 16.9% (P=0.004), reticulocyte hemoglobin content was maintained, and hemoglobin increased by a mean (±SD) of 1.83 (±0.09) g/dl (P<0.001). Overall mean total cholesterol level was reduced by a mean (±SD) of 26 (±30) mg/dl (P<0.001) after 8 weeks of therapy, independent of the use of statins or other lipid-lowering agents. No drug-related serious adverse events were reported. CONCLUSIONS: In patients with nondialysis CKD who were anemic, various starting dose regimens of roxadustat were well tolerated and achieved anemia correction with reduced serum hepcidin levels. After anemia correction, hemoglobin was maintained by roxadustat at various dose frequencies without intravenous iron supplementation.

Ixazomib: First Global Approval.

Ixazomib (Ninlaro(®)) is an orally bioavailable, reversible proteasome inhibitor developed by Millennium Pharmaceuticals, Inc. (now Takeda Oncology). Ixazomib acts by binding to and inhibiting the ß5 subunit of the 20S proteasome. In November 2015, the US FDA approved ixazomib for use in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least one prior therapy. Ixazomib is under regulatory review for this indication in the EU. Phase III development of ixazomib is underway worldwide for newly-diagnosed multiple myeloma (in patients who are not eligible for stem cell transplant, or as maintenance therapy) and for relapsed or refractory systemic light chain (AL) amyloidosis. Ixazomib is also under phase I-II development for the treatment of several other haematological and non-haematological malignancies, graft-versus-host disease and lupus nephritis. This article summarizes the milestones in the development of ixazomib leading to this first approval for multiple myeloma.

Guanidinoacetic acid as a performance-enhancing agent.

Guanidinoacetic acid (GAA; also known as glycocyamine or guanidinoacetate) is the natural precursor of creatine, and under investigation as a novel dietary agent. It was first identified as a natural compound in humans ~80 years ago. In the 1950s, GAA's use as a therapeutic agent was explored, showing that supplemental GAA improved patient-reported outcomes and work capacity in clinical populations. Recently, a few studies have examined the safety and efficacy of GAA and suggest potential ergogenic benefits for physically active men and women. The purpose of this review is to examine possible applications of GAA supplementation for exercise performance enhancement, safety, and legislation issues.

POSTOPERATIVE COMPLICATIONS WITH GLYCINE AND STERILE DISTILLED WATER AFTER TRANSURETHRAL RESECTION OF PROSTATE.

BACKGROUND: Transurethral resection of prostate (TURP) is considered the gold standard for the surgical treatment of BPH. Irrigant fluid absorption by the patient is a potentially serious complication of TURP and can lead to dilutional hyponatremia and TURP syndrome. Other common complications of TURP include urinary tract infection and secondary haemorrhage. The objective of this study was to compare the frequency of postoperative complications (Urinary Tract infection and dilutional hyponatremia) between 1.5% glycine and sterile distilled water used as irrigant in BPH patients after TURP. METHODS: This randomized controlled trial was conducted in department of Urology, PIMS Islamabad, from August 2013 to February 2014. A total of 170 adult male patients between 50-80 years of age undergoing TURP with prostate volume more than 30cc on ultrasound. 85 patients each were randomly allocated to two groups. In group-A, glycine was used as irrigan,t solution during TURP while in group-B distilled water was used. Serum sodium levels were measured at 6th postoperative hour to look for dilutional hyponatremia. On the 15th postoperative day they were inquired about any clinical features of urinary tract infection. Also urine routine examination was performed to look for the presence of WBCs in the urine. RESULTS: Post-operative dilutional hyponatremia was observed in 13 (15.3%) patients in Group A and in 10 (11.8%) patients in group-B. The difference between both the groups being nonsignificant (p-value=0.501).Frequency of postoperative urinary tract infection on 15th postoperative day in group-A was 23(27.1%) while in group-B it was 16 (18.8%), the difference among both the groups being insignificant (p-value=0.202). CONCLUSION: Although the frequency of postoperative complications like UTI and dilutional hyponatremia was less with sterile distilled water, yet, the difference was statistically not significant.

Pharmacological screening of glycine amino acid prodrug of acetaminophen.

OBJECTIVE: To develop an amino acid prodrug of acetaminophen with comparable therapeutic profile and less hepatotoxicity than acetaminophen. MATERIALS AND METHODS: Acetaminophen prodrug was synthesized by esterification between the carboxyl group of amino acid glycine and hydroxyl group of acetaminophen. Analgesic, antipyretic, ulcer healing, and hepatotoxic activities were performed on Wistar rats in this study. RESULTS: Prodrug showed a 44% inhibition in writhings as compared to 53.3% of acetaminophen. Acetaminophen also offered highest antipyretic activity. Prodrug showed gastroprotective and hepatoprotective effects as it reduced the gastric lesions by 32.1% (P < 0.01) and significantly prevented the rise in liver enzymes (serum glutamic oxaloacetic transaminase, serum glutamic pyruvic transaminase and bilirubin). The most notable effect of prodrug was in preventing the depletion of hepatic glutathione (GSH), which is reduced by acetaminophen. CONCLUSION: Prodrug showed hepatoprotective and gastroprotective effects, although the therapeutic efficacy was compromised. Prodrug was successful in preventing a decrease in GSH, thereby exhibiting promising results in the field of prodrug designing to avoid the toxic effects of acetaminophen.