Severe Gastrointestinal Adverse Events Research Articles

Treatment-related gastrointestinal adverse events of nivolumab plus ipilimumab in randomized clinical trials: a systematic review and meta-analysis.

The authors used a meta-analysis to evaluate the risks of gastrointestinal adverse events in the cotreatment of malignant tumors with nivolumab and ipilimumab. The meta-analysis revealed that the most common gastrointestinal adverse event at all grades was diarrhea, followed by nausea, decreased appetite, vomiting, constipation, colitis and abdominal pain. The most common severe gastrointestinal adverse events were colitis and diarrhea. Different administration schemes differ in the risk of such events, and thus these events may be minimized by modulating the administration scheme of the cotreatment.

Isolation of alkaloidal and glycosidal fractions from leaves of Trigonella foenum-graecum L. cv. Desi indigenous to Pakistan for antiprostaglandin evaluation as substitute of nonsteroidal anti-inflammatory drugs

Ethnopharmacological relevanceTrigonella foenum graecum (fenugreek) has been in use for a long time as a traditional medicine and natural food additive. The reported gastro-protective property makes it unique among other herbs. Seeds and leaves have been shown to exert significant antiatherogenic, antidiabetic, antianorexic, antioxidant, anticarcinogenic, antihyperlipidemic, galactogogue and anti-inflammatory effects in several animal and human models. But its use as a substitute for ulcerative nonsteroidal anti-inflammatory drugs needs to be confirmed. Aim of the studyNonsteroidal anti-inflammatory drugs (NSAIDs) are in common use in treating inflammation associated with a variety of ailments, fever and pain such as menstrual cramps, back pain, arthritic pain and headaches. Their toxicity profile includes the risk of severe gastro-intestinal adverse events like increased bleeding tendency, ulceration, perforation, etc. Conventional NSAIDs have also been reported to reduce the glomerular filtration rate (GFR) by affecting afferent arterioles in nephrons. Exacerbated potassium levels were noted in patients using NSAIDs concomitantly with antihypertensive drugs belonging to the angiotensin converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) classes. In this context, the need of the hour is to discover and isolate new compounds from the reported medicinal plants for evaluation of antiprostaglandin potential and safety profile in terms of the hepato-renal system. These compounds may be used as substitutes for NSAIDs in the future management of inflammation and pain with therapeutic equivalency and organ safety. In this scenario, the present study aimed to assess the antiprostaglandin potential of alkaloidal and glycosidal fractions from the leaves of Trigonella foenum-graecum L. cv. Desi variety, indigenous to Pakistan, in albino mice along with safety profile. The herb has been used as folk medicine since ancient times for treating inflammation and pain. Material and methodsAlkaloidal and glycosidal fractions were separated from a methanol extract of leaves of the fenugreek Desi variety. After separation of fractions, their subsiding effects on carrageenan-induced inflammation, air pouch exudate prostaglandin-E2 levels, Brewer's yeast induced pyrexia and acetic acid induced abdominal constrictions were assessed in adult male albino mice. The safety profile of fractions was assessed by measuring their effects on mice sera hepato-renal biomarkers. ResultAlkaloidal fraction of T. foenum Desi variety was found to be significantly effective in reducing inflammation, air pouch exudate PGE2 levels, fever (≤37 °C) and pain by inhibiting writhes (up to 96.58%) Gradual inhibition of paw edema was observed 1–6 h post-dose, with maximum reduction percentages of 62.82% and 62.57% for 100 mg and 200 mg, respectively. Both fractions did not disturb the normal physiology of the hepato-renal system by showing normal biomarker values. ConclusionIn summary, the results demonstrate the potent antiprostaglandin potential of the alkaloidal fraction of gastroprotective fenugreek “Desi” leaves with hepato-renal system safety and hence justify its use as a substitute for ulcerative nonsteroidal anti-inflammatory drugs.

Benefits and harms of drug treatment for type 2 diabetes: systematic review and network meta-analysis of randomised controlled trials

ObjectiveTo compare the benefits and harms of drug treatments for adults with type 2 diabetes, adding non-steroidal mineralocorticoid receptor antagonists (including finerenone) and tirzepatide (a dual glucose dependent insulinotropic polypeptide...

Risk of Intestinal Necrosis With Sodium Polystyrene Sulfonate: A Systematic Review and Meta-analysis.

Reports of severe gastrointestinal side effects associated with sodium polystyrene sulfonate (SPS), particularly intestinal necrosis, have led some to recommend costlier alternative medications. No prior systematic review has included studies with controls reporting intestinal necrosis rates associated with SPS. A systematic literature search was conducted using Cochrane Library, Embase, Medline, Google Scholar, PubMed, Scopus, and Web of Science Core Collection from database inception through October 4, 2020. We included any clinical trial, cohort, or case-control study reporting an association between SPS and intestinal necrosis or severe gastrointestinal side effects. Six studies including 26,716 patients treated with SPS with controls met inclusion criteria. The pooled odds ratio (OR) of intestinal necrosis was 1.43 (95% CI, 0.39-5.20). The pooled hazard ratio (HR) for intestinal necrosis from the two studies that performed survival analysis was 2.00 (95% CI, 0.45-8.78). The pooled HR for the composite outcome of severe gastrointestinal adverse events was 1.46 (95% CI, 1.01-2.11). Based on our review of six studies, the risk of intestinal necrosis with SPS is not statistically greater than controls, although there was a statistically significantly increased risk for the composite outcome of severe gastrointestinal side effects based on two studies. Because of the risk of bias from potential confounding and selective reporting, the overall strength of evidence to support an association between SPS and intestinal necrosis or other severe gastrointestinal side effects is low. PROSPERO registration CRD42020213119.

Oral Treatment With Bisphosphonates of Osteoporosis Does Not Increase the Risk of Severe Gastrointestinal Side Effects: A Meta-Analysis of Randomized Controlled Trials.

IntroductionBisphosphonates (BPs) are first-line therapy for osteoporosis. Adherence is usually low in chronic, asymptomatic diseases, but gastrointestinal (GI) side-effects can also contribute to low adherence in BP therapy and may necessitate a review by a gastroenterologist with or without gastroscopy.AimsOur meta-analysis aims to determine the risk of severe GI adverse events due to oral BP therapy in osteoporotic patients.MethodsA systematic search was conducted in three databases up to September 2020 for randomized controlled trials (RCTs) detailing GI adverse events in adults with osteoporosis on BP compared to placebo. Risk ratios (RRs) with 95% confidence intervals (CI) were calculated for non-severe and severe adverse events indicating endoscopic procedure with the random-effects model. Statistical heterogeneity was assessed using chi2 and I2 statistics.ResultsForty-two RCTs with 39,047 patients with 9,999 non-severe and 1,503 severe GI adverse events were included. The incidence of non-severe and severe adverse events ranged between 0.3–54.9 and 0–10.3%, respectively. There was no difference between BP and control groups in terms of the risk of non-severe or severe side effects: RR=1.05 (CI: 0.98–1.12), I2 = 48.1%, and RR=1.01 (CI: 0.92–1.12), I2 = 0.0%, respectively. Subgroup analysis of the most commonly used BP, once-weekly alendronate 70 mg, revealed an association between bisphosphonates and the risk of non-severe GI adverse events, RR=1.16 (CI: 1.00–1.36), I2 = 40.7%, while the risk of severe GI side effects was not increased in this subgroup, RR=1.20 (CI: 0.83–1.74), I2 = 0.0%.ConclusionOur results show that bisphosphonates do not increase the risk of severe GI adverse events. However, the marked variability of the screening for side effects in the included studies, and the fact that in most of the studies GI diseases were exclusion criteria limits the strenght of evidence of our results. The conclusions drawn from the meta-analysis are therefore restricted to selected populations, and the results must be interpreted with caution.

Metformin versus the combined oral contraceptive pill for hirsutism, acne, and menstrual pattern in polycystic ovary syndrome.

Metformin versus the combined oral contraceptive pill for hirsutism, acne, and menstrual pattern in polycystic ovary syndrome.

775 Immune Checkpoint Inhibitor Therapy in Patients With Preexisting Inflammatory Bowel Disease

INTRODUCTION: We characterized gastrointestinal adverse events in patients with underlying inflammatory bowel disease (IBD) who received immune checkpoint inhibitors. METHODS: We performed a fourteen-center, retrospective study of patients with documented IBD who received immune checkpoint inhibitor therapy between January 2010 and February 2019. Backward selection and multivariate logistic regression were conducted to assess risk of gastrointestinal adverse events. RESULTS: Of the 102 included patients, 17 received therapy targeting cytotoxic T-lymphocyte antigen-4 and 85 received monotherapy targeting programmed death-1 or its ligand. Half the patients had Crohn's disease and half had ulcerative colitis. The median time from last active IBD episode to immunotherapy initiation was 5 years (interquartile range, 3-12). Forty-three patients were not receiving treatment for IBD (Table 1). Gastrointestinal adverse events occurred in 42 patients (41%) after a median of 62 days (interquartile range, 33-123), a rate higher than that among similar patients without underlying IBD who were treated at centers participating in the study (11%; P < 0.001). Gastrointestinal events among patients with IBD included grade 3 or 4 diarrhea in 21 patients. Four patients experienced colonic perforation, 2 of whom required surgery. No gastrointestinal adverse event-related deaths were recorded (Table 2). Anti-cytotoxic T-lymphocyte antign-4 therapy was associated with increased risk of gastrointestinal adverse events on univariate but not multivariate analysis (respectively, odds ratio, 3.19; 95%confidence interval, 1.8-9.48; P = 0.037 and odds ratio, 4.72; 95% confidence interval, 0.95-23.53; P = 0.058). CONCLUSION: Preexisting IBD increases the risk of severe gastrointestinal adverse events in patients treated with immune checkpoint inhibitors.

Achieving glycaemic control without weight gain, hypoglycaemia, or gastrointestinal adverse events in type 2 diabetes in the SUSTAIN clinical trial programme.

AimTo evaluate the potential for semaglutide to help people with type 2 diabetes (T2D) achieve glycated haemoglobin (HbA1c) targets while avoiding unwanted outcomes, such as weight gain, hypoglycaemia and gastrointestinal (GI) side effects.Materials and methodsData from the phase IIIa SUSTAIN 1 to 5 clinical trials were analysed. Participants had inadequately controlled T2D and were drug‐naïve (SUSTAIN 1) or on a range of background treatments (SUSTAIN 2 to 5). The main protocol‐specified composite endpoint was the proportion of participants achieving HbA1c <53 mmol/mol (7.0%) at end of treatment (30 or 56 weeks) without weight gain and with no severe or blood glucose (BG)‐confirmed symptomatic hypoglycaemia. A post hoc composite endpoint was the proportion of participants achieving the primary composite endpoint without moderate or severe GI adverse events (AEs).ResultsAcross the SUSTAIN trials 1 to 5, 3918 participants with T2D were randomized to once‐weekly subcutaneous semaglutide 0.5 mg, 1.0 mg, or comparators (placebo, sitagliptin 100 mg, exenatide extended release 2.0 mg or insulin glargine). The proportion of participants achieving HbA1c <53 mmol/mol (7.0%) with no weight gain and no severe/BG‐confirmed symptomatic hypoglycaemia was 47% to 66% (semaglutide 0.5 mg) and 57% to 74% (semaglutide 1.0 mg) vs 7% to 19% (placebo) and 16% to 29% (active comparators; all P < .0001). More participants achieved the primary composite endpoint with no moderate or severe GI AEs with semaglutide vs comparators (all P < .0001).ConclusionSemaglutide helped more people with T2D achieve HbA1c targets than did comparators in the SUSTAIN 1 to 5 trials, while avoiding unwanted outcomes such as weight gain, hypoglycaemia and GI side effects.

Safety of ibuprofen in infants younger than six months: A retrospective cohort study

ObjectiveWe hypothesized (1) that gastrointestinal (GI) and renal adverse events (AE) would occur more often in infants first prescribed ibuprofen before rather than after six months of age and (2) that ibuprofen would be associated with more adverse effects than acetaminophen in infants younger than six months.MethodsWe created two partly overlapping retrospective cohorts of infants aged less than six months when California Medicaid first paid for ibuprofen or acetaminophen between 2004 and 2010. In the first cohort we compared the incidence rate ratio (RR) of GI and renal AE between those infants first prescribed ibuprofen before six months of age with those first prescribed ibuprofen after six months of age. In the second cohort we compared the RR of GI and renal AE between infants younger than six months prescribed ibuprofen (+/-acetaminophen) with those prescribed only acetaminophen.ResultsWe identified 41,669 prescriptions for ibuprofen and 176,991 prescriptions for acetaminophen in 180,333 eligible infants (median age 2.1 months). We did not observe higher RR of any AE in infants first prescribed ibuprofen before rather than after six months of age. Most infants prescribed ibuprofen were also prescribed acetaminophen. Any GI (adjusted (a)RR 1.25, 95% CI 1.13–1.38) and moderate or severe GI AE (aRR 1.24, 95% CI 1.09–1.40) were more common in infants younger than six months who were prescribed ibuprofen versus acetaminophen alone. Severe GI (aRR 0.63, 95% CI 0.27–1.45) and renal AE (aRR 1.84 95% CI 0.66–5.19) were not different between the ibuprofen (+/-acetaminophen) and acetaminophen-only groups.ConclusionsGI and renal AEs were not higher in infants younger than six months who were prescribed ibuprofen compared with those aged six to 12 months. AEs were increased in infants younger than six months who were prescribed ibuprofen compared with infants who were prescribed acetaminophen alone.

Antacid Therapy and Disease Progression in Patients with Idiopathic Pulmonary Fibrosis Who Received Pirfenidone

Background: Gastroesophageal reflux disease is a potential risk factor for idiopathic pulmonary fibrosis (IPF) progression; however, the impact of antacid therapy (AAT) is under debate. Objective: To evaluate the effect of AAT on IPF progression in pirfenidone-treated patients. Methods: This post hoc analysis included patients with IPF who received pirfenidone in 3 trials (CAPACITY [PIPF-004/PIPF-006] and ASCEND [PIPF-016]). Pulmonary function, exercise tolerance, survival, hospitalizations, and adverse events (AEs) over 52 weeks were analyzed by baseline AAT use. Disease progression was defined as a decrease in forced vital capacity (FVC) of ≥10%, a decrease in 6-min walking distance of ≥50 m, or death over 1 year. Results: Of 623 patients, 44% received AAT. No significant differences were found at 52 weeks (AAT versus non-AAT, respectively) in disease progression (24.9 vs. 30.6%; p = 0.12), all-cause mortality rate (2.9 vs. 4.0%; p = 0.47), IPF-related mortality rate (1.1 vs. 2.0%; p = 0.37), all-cause hospitalization rate (16.1 vs. 18.3%; p = 0.48), or mean change in percent FVC (-2.7 vs. -3.1%; p = 0.44). A relative, but not absolute, FVC decline of ≥10% favored AAT (15 vs. 22%; p = 0.03). Severe gastrointestinal AEs (3.7 vs. 0.9%; p = 0.015) and severe pulmonary infections (3.7 vs. 1.1%; p = 0.035) were more frequent with AAT. Conclusions: AAT and pirfenidone had outcomes comparable to those of pirfenidone alone in patients with IPF, underscoring the need for prospective trials to elucidate the role of AAT with or without antifibrotic drugs as a treatment for IPF.

Anti-EGFR monoclonal Antibodies increase the risk of severe Gastrointestinal adverse events in Cancer Patients: a systematic review and meta-analysis

Anti-EGFR monoclonal Antibodies increase the risk of severe Gastrointestinal adverse events in Cancer Patients: a systematic review and meta-analysis

Comparison of the Efficacy and Safety of Dual-Opioid Treatment With Morphine Plus Oxycodone Versus Oxycodone/Acetaminophen for Moderate to Severe Acute Pain After Total Knee Arthroplasty

BackgroundIn acute pain models, coadministration of low doses of morphine and oxycodone markedly enhanced analgesia relative to either opioid given alone. Enhanced analgesia with coadministration of morphine and oxycodone has also been reported in acute and chronic moderate to severe pain conditions during double-blind studies. ObjectiveThe goal of this study was to compare the efficacy and tolerability of a flexible dose regimen of the morphine/oxycodone combination versus oxycodone/acetaminophen and fixed low-dose morphine/oxycodone. MethodsThis was a 5-center, randomized, open-label study of hospitalized patients (n = 44) with acute moderate to severe postoperative pain after total knee arthroplasty. Inpatients were randomized to a flexible dose regimen of morphine/oxycodone (3 mg/2 mg to 24 mg/16 mg), fixed low-dose morphine/oxycodone regimen (3 mg/2 mg), or oxycodone/acetaminophen (5 mg/325 mg). Treatment was initiated following surgery after intravenous (IV) morphine patient-controlled analgesia. An algorithm was evaluated for converting the patient-controlled analgesia morphine dose to an initial oral dose of morphine/oxycodone. The primary efficacy variable was the time-weighted sum of pain intensity difference from 0 to 48 hours. ResultsThe median values for the sum of the pain intensity difference from 0 to 48 hours for the morphine/oxycodone flexible dose and oxycodone/acetaminophen were similar and approximately twice that of fixed morphine/oxycodone 3 mg/2 mg (148.0, 139.5, and 71.3, respectively). Moderate to severe gastrointestinal adverse events occurred in 50% of patients in the oxycodone/acetaminophen group compared with 15% of the equianalgesic morphine/oxycodone group. On several items of the Brief Pain Inventory (general activity, walking ability, and sleep), the morphine/oxycodone flexible dose produced greater benefit than oxycodone/acetaminophen. ConclusionsFlexible dose morphine/oxycodone was superior to low-dose morphine/oxycodone and comparable to oxycodone/acetaminophen. Flexible dose morphine/oxycodone-treated patients had a lower rate of moderate to severe nausea or vomiting than equianalgesic oxycodone/acetaminophen-treated patients. Thus, morphine/oxycodone offers an attractive alternative to oxycodone/acetaminophen for the management of moderate to severe postoperative pain. ClinicalTrials.gov: identifier: NCT00818493.

Etoricoxib and the treatment of ankylosing spondylitis

Introduction: Nonsteroidal anti-inflammatory drugs (NSAIDs) are first-line therapies in the management of patients with ankylosing spondylitis. This chronic inflammatory skeletal disorder, a subtype of spondyloarthritis, is characterized by inflammatory back pain and affects young adults causing important suffering and disability. Long-term use of conventional NSAIDs is associated with a risk of gastrointestinal complications. Etoricoxib is a specific cyclooxygenase 2 inhibitor with strong anti-inflammatory effects and a favorable pharmacokinetic profile for the management of inflammatory disorders. The drug has been associated with reduced severe gastrointestinal adverse events. However, the cardiovascular safety of cyclooxygenase 2 inhibitors has been debated.Areas covered: This review discusses etoricoxib in the treatment of ankylosing spondylitis. Literature searches were performed in PubMed, Web of Science, and the Cochrane library based on the terms “etoricoxib” and “ankylosing spondylitis” or “spondyloarthritis” as well as “safety” and “side-effects.”Expert opinion: Etoricoxib is useful in the first-line management of ankylosing spondylitis patients. Its anti-inflammatory effects and relative protection against severe gastrointestinal side effects should be balanced with negative effects on the cardiovascular system and an overall subjective tolerance not better than that of conventional NSAIDs. Whether etoricoxib will also become a mainstay in the prevention of structural damage in ankylosing spondylitis is not yet clear.

Angiogenesis inhibitors for the treatment of ovarian cancer.

Many women with ovarian cancer eventually develop resistance to conventional chemotherapy drugs, and so novel agents are being developed to target specific molecular pathways. One such class of drugs inhibits angiogenesis (the development of new blood vessels), which is essential for tumour growth. It is important to establish whether the addition of these new drugs to conventional chemotherapy regimens improves survival, and what the side-effects may be. To compare the effectiveness and toxicities of angiogenesis inhibitors in the treatment of ovarian cancer. We sought to identify completed randomised controlled trials (RCTs) by searching The Cochrane Gynaecological Cancer Review Group's Trial Register, The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2010, Issue 10), MEDLINE and EMBASE (1990 to October 2010). We also searched registers of clinical trials, and contacted investigators of completed and ongoing trials for further information. Randomised controlled studies comparing angiogenesis inhibitors with either standard chemotherapy or no treatment, in women with ovarian cancer. Two independent authors carried out data collection and extraction. We used a random-effects model for pooling data. We did not find any fully-published, completed RCTs of angiogenesis inhibitors that met our inclusion criteria. We identified five abstracts of completed RCTs of four different angiogenesis-inhibiting agents, with a total of 3701 participants.Meta-analysis of two trials found no statistically significant difference in overall survival (OS) between women with newly-diagnosed advanced ovarian cancer who received concurrent and maintenance bevacizumab compared to those who received chemotherapy (carboplatin and paclitaxel) alone. However, women who received concurrent and maintenance bevacizumab had their risk of disease progression reduced by a quarter (hazard ratio (HR) 0.75, 95% confidence interval (CI) 0.68 to 0.83; P < 0.001); they also had a significantly increased risk of severe gastrointestinal adverse events, moderate or severe hypertension and severe bleeding.One trial also compared chemotherapy to concurrent (but not maintenance bevacizumab), and found no statistically significant difference in OS or progression-free survival (PFS). However, the women who received bevacizumab had a significantly higher risk of moderate or severe hypertension.A three-armed RCT, of paclitaxel alone or with low- or high-dose AMG 386, in women with recurrent ovarian cancer, found no statistically significant difference in OS. However, women who received low-dose AMG 386 had a third less risk of disease progression than those who received placebo (HR 0.57, 95% CI 0.36 to 0.91; P = 0.02). The trial found no evidence of increased adverse events in the intervention arms.Two relatively small RCTs (one of VEGF-Trap, the other of BIBF 1120) found no evidence of either significant survival benefit or increased severe adverse events, compared to placebo, but they both lacked statistical power.All five trials had unclear risk of bias, largely because they have only been published in abstract form, and thus many methodological details are unclear. We identified twelve suitable ongoing trials. There is, as yet, no fully-published RCT evidence for the efficacy or safety of angiogenesis inhibitors for the treatment of ovarian cancer, but some preliminary results are available from five trials. There is some evidence from a meta-analysis of two trials that the addition of concurrent and maintenance bevacizumab to standard chemotherapy may reduce the risk of disease progression, in women with newly-diagnosed advanced ovarian cancer. There is also some evidence from a single trial that low-dose AMG 386 may reduce the risk of disease progression in women with recurrent ovarian cancer. However, there is currently no evidence that angiogenesis inhibitors improve OS, nor is there enough evidence to justify the routine use of angiogenesis inhibitors in treating women with ovarian cancer. We eagerly await both the more detailed results of these five completed trials, and the preliminary results of the several ongoing trials.

Evaluation of the safety and tolerability of a short higher-dose primaquine regimen for presumptive anti-relapse therapy in healthy subjects

The safety and tolerability of primaquine (PQ) administered as a short higher-dose (30 mg twice daily for 7 days) regimen in 203 Australian Defence Force personnel was evaluated in an open-label presumptive anti-relapse therapy study. No clinically significant differences were measured in the subjects’ haematological and biochemical indices before and after PQ treatment. The most common adverse events were nausea, abdominal pain, headache and insomnia, many of which were mild in severity (30%; 60/203) and transient; 19% of subjects (39/203) experienced moderate (with some interference with daily duties requiring no or minimal medical therapy) adverse events. Two subjects (1%) had severe gastrointestinal adverse events requiring cessation of medication, but neither was seriously ill. Ten subjects (5%) had peripheral cyanosis (blueness of the lips), but none reported any respiratory compromise. These findings suggest that the short higher-dose PQ regimen is safe and well tolerated, which could improve PQ compliance and effectiveness.

Combined oral prolonged-release oxycodone and naloxone in opioid-induced bowel dysfunction: review of efficacy and safety data in the treatment of patients experiencing chronic pain

Importance of the field: Despite proven analgesic efficacy, opioid use is associated with frequently dose-limiting bowel dysfunction that seriously impacts patients' quality of life (QoL). Agents used at present to manage opioid-induced constipation do not address the underlying opioid receptor-mediated cause of bowel dysfunction and are often ineffective. There is, therefore, a significant need for more effective treatment options. The combination of the strong opioid oxycodone and the opioid antagonist naloxone has the potential to prevent opioid-induced bowel dysfunction (OIBD) while maintaining analgesic efficacy.Objective: To review the safety and efficacy of oral prolonged-release (PR) oxycodone/naloxone in the treatment of patients experiencing chronic pain.Areas covered in this review: A MEDLINE search was done (January 2002 – July 2009) for available literature for prolonged release oxycodone and naloxone in different patient groups. Results were limited to English-language and clinical trials. Data were also obtained from congress materials.What knowledge the reader will gain: Unmet needs of opioid pain treatment in terms of OIBD, reduced QoL and low treatment compliance, leading to reduced efficacy. A data overview demonstrates the efficacy and tolerability of PR oxycodone/naloxone in the management of severe chronic pain without the burden of severe gastrointestinal adverse events. The combined formulation of a highly effective opioid and an antagonist that acts locally to reduce gastrointestinal side effects is expected to simplify pain management.Take home message: The combination of PR oxycodone/naloxone offers the potential of maintaining normal bowel function in patients requiring opioid therapy – it is a strong analgesic that is well tolerated.

Four Drugs Induction Therapy (fludarabine, cytarabine, idarubicin and gemtuzumab ozogamycin) for the Treatment of Elderly Acute Myeloid Leukemia Patients.

Abstract 1027Poster Board I-49 Background:Current therapeutic strategies for the treatment of elderly acute myeloid leukemia (AML) patients are still unsatisfactory. Induction regimens relying on anthracycline and cytarabine combination (3+7) still represent the standard reference therapy, with complete remission (CR) rate of 35-60% but no more than 10-20% of patients living more than three years from diagnosis.The addition of other drugs to overcome resistance and prevent subsequent relapse, has often shown greater toxicity without improving results. AimWe designed a phase II study aiming to assess toxicity and efficacy of My-FLAI regimen in patients with newly diagnosed AML aged more than 60 years. Fifty-one patients were enrolled with a median age of 68 years (range 60-76). The median leukocyte count was 10.2 ×109/L (range 0.7-222.7). Twenty-five patients had a secondary AML and 31% had a complex kariotype. Fludarabine, cytarabine and idarubicin were administered for three consecutive days at the daily dose of 25 mg/m2, 1 g/ m2 and 5 mg/ m2 respectively. Gemtuzumab ozogamycin (Mylotarg, My) was infused at day four at the dose of 5 mg. Patients achieving a CR after the induction course were planned to receive a second identical course of My-FLAI. Granulocyte colony-stimulating factor (G-CSF) was administered at physician's discretion to promote granulocytic recovery if clinically indicated. Results:Twenty-seven patients achieved a CR (one of these with an incomplete platelet recovery) and 4 obtained a partial response (marrow blast 5-19%) for an overall response rate (ORR) of 61%. Seventeen patients (33%) showed a resistant disease and three (6%) died during induction (DDI). Seventeen patients received an identical consolidation course. Seven patients were treated with cytarabine-based consolidation and the remaining 27 patients were not treated furthermore. The disease-free survival (DFS) and overall survival (OS) were 6 months (range 2.4-48.0) and 13 months (range 1.1-61.5) respectively. DFS appear to be more favorable in patients receiving additional therapy after two My-FLAI cycles (IDAC n=3; ASCT n= 4; experimental drugs n= 1; My n=4) in comparison to patients no further treated, being 12.8 (range 4.7-18.0) and 5.9 (range 2.4-48.0) months respectively. The median duration of G-CSF administration was 6 days (range 0-35) in induction and 8 days (range 0-15) in consolidation cycle. All patients developed a grade IV hematological toxicity. Median time to ANC recovery (>1 ×109/L) was 21 days (range 10-52) after induction course and 18 days (range 12-20) after consolidation course. Median time to PLT recovery (PLT>20 ×109/L and PLT>100 ×109/L) was 18 days (range 9-54) and 23 days (range 15-78) after induction and 18 days (range 12-20) and 32 days (range 21-110) after the consolidation course. Thirty-six patients had infectious complication; 33 experienced a microbiologically documented infection (n=20 gram+, n=12 gram- n=1 candidemia). Eighteen patients had a fever of unknown origin (FUO) and 12 patients suffered from pulmonary infection (n=2 bacterial; n=8 probable fungal; n=2 aspergillosis). One patient developed a maxillary sinus aspergillosis. Grade III/IV haemorrhagic complications were observed in 5 patients. No severe gastro-intestinal adverse events were observed. With a median follow-up of 8.8 months (range 0.5-61.5) 41 patients died. Five patients died in first CR for cardiac failure (n=2) and for infective complication (n=3). The remaining died for disease. Nine patients are alive, four of them in first CR. Conclusions:The four drug regimen My-FLAI is overall well tolerated in an elderly AML population. However, the efficacy did not appear to be superior to that of standard “3+7” regimen. Acknowledgments:Supported by BolognAIL, AIRC, European LeukemiaNET, COFIN, FIRB 2006, Fondazione del Monte di Bologna e Ravenna Disclosures:No relevant conflicts of interest to declare.

Effect of food on the pharmacokinetics of lonafarnib (SCH 66336) following single and multiple doses

The objective was to determine whether food affects the pharmacokinetics and safety of lonafanib, an orally bioavailable farnesyl transferase inhibitor that is under clinical evaluation for the treatment of various hematologic malignancies and solid tumors. Two Phase 1 studies were conducted in separate patient populations. A single-dose study was performed in 12 healthy subjects who received lonafarnib 100 mg under fasted and fed conditions. Additionally, a multiple-dose study was performed in 19 patients with advanced cancer who received lonafarnib 200 mg Q 12 H for 28 days under fasted and fed conditions. Nine of the 19 patients completed both treatment cycles and were used for pharmacokinetic assessment. A 2-week washout period separated treatments in each study. Single-dose pharmacokinetics were assessed at various time points up to 48 hours postdose and multiple-dose pharmacokinetics were assessed at Day 15 for 24 hours postdose. The pharmacokinetics of lonafarnib were affected by food during single-dose but not multiple-dose administration. Relative oral bioavailabilities (fed vs. fasted) based on log-transformed maximum plasma concentration (C(max)) and area under the concentration-time curve (AUC) were 48% and 77%, respectively, following single-dose administration, and 87% and 96%, respectively, following multiple-dose administration. Intrasubject variability in the pharmacokinetic parameters was less pronounced after multiple dosing (17%) than that after single dosing (33%) of lonafarnib. Intersubject variability was unaffected by food in either study. In the single-dose study, 7 of the 12 subjects (58%) reported treatment emergent adverse events, the most common being headache. No clinically significant differences in adverse events were seen between fasting and fed states after a single dose administration. Thus, single dose 100 mg lonafarnib was safe and generally well tolerated. In the multiple-dose study, all 19 subjects reported at least one treatment-emergent adverse event. General disorders including fatigue and anorexia, and gastrointestinal disorders including diarrhea, vomiting and nausea, were the most commonly reported adverse events after multiple doses. While gastrointestinal adverse events were reported with equal frequency under both fasting (82%, 14/17) and fed states (83%, 15/18), the incidence of severe gastrointestinal adverse events was higher in fasted (47%, 8/17) vs. fed subjects (22%, 4/18) after multiple-dose administration. The administration of food does not affect the pharmacokinetics of lonafanib following multiple-dose administration. We recommend that multiple-dose lonafarnib should be administered with food to enhance tolerability.

Nitric Oxide, Aspirin-Triggered Lipoxins and NO-Aspirin in Gastric Protection

The use of nonsteroidal anti-inflammatory drugs is associated with an incidence of severe gastrointestinal adverse events of 2-4%, the most common of which is bleeding. These events are largely attributable to the ability of these drugs to suppress prostaglandin and thromboxane synthesis. Prostaglandins perform a number of important functions in the gastrointestinal tract, particularly with respect to resistance of the mucosa to injury. Nitric oxide also appears to be a key mediator of gastrointestinal mucosal defence, and this has been exploited in the development of a novel class of anti-inflammatory drugs, called "NO-NSAIDs", which exhibit little if any gastrointestinal toxicity. NO-NSAIDs are more effective than traditional NSAIDs in reducing pain and inflammation. Another class of inflammatory mediators that contribute to gastrointestinal mucosal defence are the lipoxins. These products of arachidonic acid metabolism can increase the resistance of the stomach to the damaging effects of aspirin. Indeed, aspirin can trigger the formation of a lipoxin by the stomach which acts to diminish the damaging effects of this drug. Lipoxins and nitric oxide are important mediators of mucosal defence in the stomach (and elsewhere in the gastrointestinal tract) and represent attractive therapeutic targets for reducing the incidence of gastric ulceration.

Colesevelam.

Colesevelam, a bile acid sequestrant used in the treatment of patients with hypercholesterolemia, is a lipid-lowering polymer that has high affinity for bile acids. In animals colesevelam was not systemically absorbed after oral administration and was rapidly eliminated via the gastrointestinal tract. Colesevelam did not alter the serum concentrations or pharmacokinetic properties of drugs from several different classes in healthy volunteers. Colesevelam administered orally in patients with primary hypercholesterolemia significantly reduced serum levels of low density lipoprotein (LDL)-cholesterol and total cholesterol. This lipid-lowering activity was sustained during short (6 weeks) and longer term (24 weeks) treatment. Combination therapy with colesevelam plus hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (lovastatin, simvastatin or atorvastatin) was associated with additive reductions in serum levels of LDL-cholesterol and total cholesterol, relative to either agent alone. Colesevelam treatment was well tolerated and lacked severe gastrointestinal adverse events typical of other bile acid sequestrants (bloating, flatulence, heartburn and nausea). The most frequently reported adverse events were constipation and dyspepsia. In humans colesevelam did not induce clinically significant changes in serum levels of vitamins, coagulation parameters or liver enzymes.