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Neel Mehta,1,&ast; Neal E Slatkin,2,3,&ast; Robert J Israel,4,&ast; Nancy Stambler,5,&ast; Eric D Shah6,&ast; 1Department of Anesthesiology, Weill Cornell School of Medicine, New York, NY, USA; 2School of Medicine, University of California Riverside, Riverside, CA, USA; 3Medical Affairs, Salix Pharmaceuticals, Bridgewater, NJ, USA; 4Clinical and Medical Affairs, Bausch Health US LLC, Bridgewater, NJ, USA; 5Clinical Research, Progenics Pharmaceuticals, a Subsidiary of Lantheus Holdings Inc, North Billerica, MA, USA; 6Division of Gastroenterology and Hepatology, University of Michigan, Michigan Medicine, Ann Arbor, MI, USA&ast;These authors contributed equally to this workCorrespondence: Eric D Shah, Division of Gastroenterology and Hepatology, University of Michigan | Michigan Medicine, 300 N Ingalls Street, Ann Arbor, MI, 48109, USA, Tel +1 877 285-7788, Email ershah@umich.eduPurpose: We evaluated the impact of baseline patient characteristics on safety and efficacy of methylnaltrexone, a peripherally acting μ-opioid receptor antagonist, in patients with advanced illness with opioid-induced constipation (OIC).Patients and Methods: This analysis pooled data from 2 randomized, double-blind, placebo-controlled studies (study 302: NCT00402038; study 4000: NCT00672477) in patients with advanced illness, including cancer, and OIC. Patients were randomized to receive subcutaneous methylnaltrexone (study 302: 0.15 mg/kg; study 4000: 8 or 12 mg based on weight) or placebo every other day for 2 weeks. The proportions of patients achieving rescue-free laxation within 4 or 24 hours after the first dose of study drug were assessed in patient subgroups stratified by baseline age, Eastern Cooperative Oncology Group (ECOG) performance status, cancer status, laxative type, and opioid requirement. Treatment-emergent adverse events (TEAEs) were evaluated.Results: Overall, 363 patients were included in this analysis (methylnaltrexone, 178; placebo, 185). Mean (SD) age was 66.3 (13.7) years and 48.5% were men overall. A significantly greater proportion of patients receiving methylnaltrexone versus placebo achieved rescue-free laxation within 4 hours (111/178 [62.4%] vs 31/185 [16.8%]; P< 0.0001) and 24 hours (135/178 [75.8%] vs 81/185 [43.8%]; P< 0.0001) of the first dose. These trends were consistent across all subgroups. Most patients experienced ≥ 1 TEAE in the overall population (methylnaltrexone, 82.1%; placebo, 76.2%), which remained consistent when stratified by baseline characteristics. More than half of TEAEs were gastrointestinal in nature. Abdominal pain was more common in patients receiving methylnaltrexone than placebo across baseline characteristic subgroups.Conclusion: Methylnaltrexone treatment was superior to placebo in achieving rescue-free laxation within 4 and 24 hours after the first dose, irrespective of patients’ cancer status, baseline ECOG performance status, or baseline opioid or laxative use. The methylnaltrexone safety profile remained consistent across baseline characteristic subgroups.Keywords: methylnaltrexone, opioid-induced constipation, μ-opioid receptor antagonist

Bruce H Chamberlain,1 Michelle Rhiner,2 Neal E Slatkin,3,4 Nancy Stambler,5 Robert J Israel6 1Genesis Healthcare, Davenport, IA, USA; 2Department of Family Medicine, Loma Linda University Health, Loma Linda, CA, USA; 3University of California Riverside, School of Medicine, Riverside, CA, USA; 4Salix Pharmaceuticals, Medical Affairs, Bridgewater, NJ, USA; 5Progenics Pharmaceuticals, Inc, a subsidiary of Lantheus Holdings, Inc, Clinical Research, North Billerica, MA, USA; 6Bausch Health US, LLC, Clinical and Medical Affairs, Bridgewater, NJ, USACorrespondence: Robert J Israel, Bausch Health US, LLC, Clinical and Medical Affairs, 400 Somerset Corporate Boulevard, Room 6-1001, Bridgewater, NJ, 08807, USA, Tel +1 908 541-2288, Fax +1 585 338-0668, Email Robert.Israel@bauschhealth.comPurpose: Opioid-induced constipation (OIC) is a common side effect of opioid therapy. Methylnaltrexone (MNTX) is a selective, peripherally acting μ-opioid receptor antagonist, with demonstrated efficacy in treating OIC. We pooled results from MNTX clinical trials to compare responses to an initial dose in patients with chronic cancer and noncancer pain.Patients and Methods: This post hoc analysis used pooled data from 3 randomized, placebo-controlled studies of MNTX in patients with advanced illness with OIC. Assessments included the proportions of patients achieving rescue-free laxation (RFL) within 4 and 24 hours of the first study drug dose, time to RFL, current and worst pain intensity, and adverse events, stratified by the presence/absence of cancer.Results: A total of 355 patients with cancer (MNTX n = 198, placebo n = 157) and 163 without active cancer (MNTX n = 83; placebo n = 80) were included. More patients treated with MNTX compared with those who received placebo achieved an RFL within 4 (cancer: MNTX, 61.1% vs placebo,15.3%, p< 0.0001; noncancer: MNTX, 62.2% vs placebo, 17.5%, p< 0.0001) and 24 hours (cancer: MNTX, 71.2% vs placebo, 41.4%, p< 0.0001; noncancer: MNTX, 74.4% vs placebo, 37.5%, p< 0.0001) of the initial dose. Cumulative RFL response rates within 4 hours of the first, second, or third dose of study drug were also higher in MNTX-treated patients. The estimated time to RFL was shorter among those who received MNTX and similar in cancer and noncancer patients. Mean pain scores declined similarly in all groups. The most common adverse events in both cancer and noncancer patients were abdominal pain, flatulence, and nausea.Conclusion: After the first dose, MNTX rapidly induced a laxation response in the majority of both cancer and noncancer patients with advanced illness. Opioid-induced analgesia was not compromised, and adverse events were primarily gastrointestinal in nature. Methylnaltrexone is a well-tolerated and effective treatment for OIC in both cancer and noncancer patients.Keywords: peripheral mu-opioid receptor antagonist, PAMORA, chronic pain, opioid

Eric D Shah,1 Bruce H Chamberlain,2 Michelle Rhiner,3 Neil E Slatkin,4,5 Nancy Stambler,6 Robert J Israel7 1Section of Gastroenterology and Hepatology, Dartmouth-Hitchcock Medical Center, Lebanon, NH, USA; 2Genesis Healthcare, Davenport, IA, USA; 3Department of Family Medicine, Loma Linda University Health, Loma Linda, CA, USA; 4School of Medicine, University of California Riverside, Riverside, CA, USA; 5Medical Affairs, Salix Pharmaceuticals, Bridgewater, NJ, USA; 6Clinical Research, Progenics Pharmaceuticals, Inc., A Subsidiary of Lantheus Holdings, Inc, New York, NY, USA; 7Clinical and Medical Affairs, Bausch Health US, LLC, Bridgewater, NJ, USACorrespondence: Eric D Shah, Section of Gastroenterology and Hepatology, Dartmouth-Hitchcock Medical Center, 1 Medical Center Drive, Lebanon, NH, 03766, USA, Tel +1 603-650-5261, Email eric.d.shah@hitchcock.orgPurpose: To evaluate the efficacy and safety of subcutaneous (SC) methylnaltrexone for opioid-induced constipation (OIC) in patients with and without active cancer.Patients and Methods: We analyzed two randomized, double-blind, placebo-controlled, Phase 3/4 trials (NCT00402038, NCT00672477). Patients received SC methylnaltrexone (study 302, 0.15 mg/kg; study 4000, 8 mg or 12 mg based on body weight) or placebo every other day for 2 weeks. Patients were stratified by cancer status. Primary efficacy endpoints included proportion of patients achieving rescue-free laxation (RFL); secondary endpoints included time to RFL, pain intensity scores, and safety/tolerability. Trial results were evaluated separately.Results: The safety population (patients receiving ≥ 1 study drug dose) included 364 patients (study 302, n=134; study 4000, n=230). Study 302 had 78 patients with active cancer (methylnaltrexone, n=37; placebo, n=41) and 56 without cancer (methylnaltrexone, n=26; placebo, n=30); study 4000 had 152 patients with active cancer (methylnaltrexone, n=79; placebo, n=73) and 78 without cancer (methylnaltrexone, n=37; placebo, n=41). A significantly greater proportion of patients treated with methylnaltrexone achieved a laxation response within 4 hours after at least 2 of the first 4 doses versus placebo, dosed by body weight (cancer, 54.1% [methylnaltrexone] vs 7.3% [placebo], P< 0.0001; noncancer, 48.0% vs 10.0%; P< 0.005) or given as a weight-adjusted fixed dose (cancer, 59.5% vs 6.8%; noncancer, 70.3% vs 14.6%; P< 0.0001 each). With fixed-dose methylnaltrexone, average time to RFL for patients with and without cancer was < 1 hour of the first dose; with methylnaltrexone dosed by body weight, the first RFL occurred in < 4 and < 7 hours of treatment in patients with and without cancer, respectively. No significant differences were found in pain scores. SC methylnaltrexone was well tolerated at all doses in all patient cohorts.Conclusion: SC methylnaltrexone was efficacious in inducing rapid RFL and safe among patients with and without active cancer suffering from OIC.Keywords: methylnaltrexone, opioid-induced constipation, μ-opioid receptor antagonist, cancer, chronic pain

Bruce H Chamberlain,1 Michelle Rhiner,2 Neal E Slatkin,3,4 Nancy Stambler,5 Robert J Israel6 1Genesis Healthcare, Davenport, IA, USA; 2Loma Linda University Health, Department of Family Medicine, Loma Linda, CA, USA; 3University of California Riverside, School of Medicine, Riverside, CA, USA; 4Salix Pharmaceuticals, Medical Affairs, Bridgewater, NJ, USA; 5Progenics Pharmaceuticals, Inc., a subsidiary of Lantheus Holdings Inc., Clinical Research, New York, NY, USA; 6Bausch Health US, LLC, Clinical and Medical Affairs, Bridgewater, NJ, USACorrespondence: Robert J IsraelBausch Health US, LLC, Clinical and Medical Affairs, 400 Somerset Corporate Boulevard, Room 6-1001, Bridgewater, NJ, 08807, USATel +1 908 541-2288Fax +1 585 338-0668Email Robert.Israel@bauschhealth.comPurpose: Methylnaltrexone inhibits opioid-induced constipation (OIC) by binding to peripheral μ-opioid receptors without impacting central opioid receptor mediated analgesia. This analysis compared methylnaltrexone efficacy and safety among advanced illness patients with and without active cancer and OIC.Patients and Methods: This post hoc analysis included two multicenter, randomized, double-blind, placebo-controlled studies in adults with advanced illness and OIC who received subcutaneous methylnaltrexone. Efficacy endpoints included the proportion of patients achieving rescue-free laxation (RFL), time to RFL, weekly laxations within 24 hours after dosing, rescue laxative use, and pain scores. Adverse events were monitored for safety.Results: After pooling, 178 patients received methylnaltrexone (n = 116 with cancer) and 185 received placebo (n = 114 with cancer). Median baseline daily opioid morphine equivalents (mg/d) were higher in cancer (methylnaltrexone: 180; placebo: 188) versus noncancer patients (methylnaltrexone: 120; placebo: 80). The proportions of patients achieving RFL within 4 hours after ≥ 2 of the first 4 doses were significantly greater with methylnaltrexone (cancer: 56.9%; noncancer: 58.1%) versus placebo (cancer: 5.3%; noncancer: 11.3%; P < 0.0001). The median time to laxation within 24 hours after the first methylnaltrexone dose was significantly shorter in cancer and noncancer patients versus placebo (cancer: 0.96 vs 22.53 hours, P < 0.0001; noncancer: 1.25 vs > 24 hours, P = 0.0002). The mean number of weekly laxations within 24 hours after dosing by week 2 was significantly higher in methylnaltrexone- vs placebo-treated cancer and noncancer patients (cancer: 7.9 vs 4.9, P < 0.0001; noncancer: 8.4 vs 5.0, P < 0.0001). Methylnaltrexone reduced rescue laxative use without impacting pain scores. Consistent with previous data, methylnaltrexone was well tolerated in cancer and noncancer patients, and the AE profile did not suggest symptoms of opioid withdrawal.Conclusion: Methylnaltrexone reduced RFL time in advanced-illness patients with and without active cancer, while maintaining pain control with opioid treatment despite higher baseline opioid use among cancer patients.Keywords: methylnaltrexone, opioid-induced constipation, μ-opioid receptor antagonist, cancer, chronic pain

Richard L Rauck,1 Neal E Slatkin,2,3 Nancy Stambler,4 Robert J Israel3 1Carolinas Pain Institute, Winston-Salem, NC, USA; 2School of Medicine, University of California Riverside, Riverside, CA, USA; 3Medical Affairs, Salix Pharmaceuticals, Bridgewater, NJ, USA; 4Clinical Research, Progenics Pharmaceuticals, New York, NY, USA Purpose: Oral methylnaltrexone was shown to be effective in treating opioid-induced constipation (OIC) in patients with chronic noncancer pain in a Phase III randomized controlled trial. This report provides a detailed safety analysis from that study. Methods: Adults (n=803) with chronic noncancer pain for ≥2 months and confirmed OIC while receiving opioid doses ≥50 mg morphine equivalent per day for ≥14 days were randomized 1:1:1:1 to oral methylnaltrexone (150, 300, or 450 mg) or placebo once daily for 4 weeks, followed by as-needed use for 8 weeks. Safety was evaluated by examining treatment-emergent adverse events (TEAEs), clinical laboratory parameters, vital signs, electrocardiography, rescue-laxative and opioid use, Objective Opioid Withdrawal Scale (OOWS) and Subjective Opioid Withdrawal Scale (SOWS), and pain-intensity scores. Results: TEAEs occurred at a similar incidence in the methylnaltrexone groups (59.0%) and placebo group (63.0%). The most common TEAEs with methylnaltrexone were abdominal pain (8.0% vs 8.5% with placebo), nausea (6.8% vs 9.0%), and diarrhea (6.0% vs 3.5%). Cardiac-related TEAEs occurred in 1.8% and 1.0% of patients, respectively, and no major adverse cardiovascular events were reported. No patient had a cluster of TEAEs associated with opioid withdrawal after excluding gastrointestinal TEAEs. Changes in laboratory parameters, vital signs, and electrocardiography were generally small and similar across treatment groups. Rescue-laxative use was more common with placebo than methylnaltrexone 450 mg (6.20% vs 4.27% of study days, P=0.024). Changes in opioid dose, OOWS and SOWS scores, and pain-intensity scores during treatment were minimal. Conclusion: Oral methylnaltrexone had a safety profile comparable with placebo in the treatment of OIC in patients with chronic noncancer pain, with no evidence of cardiac toxicity or opioid withdrawal. Keywords: analgesia, µ-opioid-receptor antagonist, nonmalignant, safety

Two alternative mechanisms are suggested for nitrite accumulation in the oxygenated oligotrophic water column: (1) excretion by phytoplankton or (2) microbial oxidation of ammonium (nitrification). This study assessed the role of these 2 mechanisms, based on seasonal and high-resolution diurnal depth profiles of the dissolved inorganic nitrogen (DIN) species (nitrite, ammonium, nitrate) and chlorophyll a in the Gulf of Aqaba, Red Sea. Both mechanisms operated in the water column, but in different seasons; nitrification was the prime process responsible for nitrite accumulation during the stratified summer season and phytoplankton nitrite excretion operated during winter mixing. At the onset of summer stratification two N peaks developed below the photic zone, an ammonium maximum (AM) and below it the primary nitrite maximum (PNM). Both peaks were located at a depth range where phytoplankton are thought to be inactive and not excreting nitrite. During summer stratification, the water column deep chlorophyll maximum (DCM), AM, PNM and the nitracline were ordered by a downward increase in N oxidation state similar to the temporal order of the N-species during nitrification. This similarity, together with the diurnal stability of the PNM and its co-existence with oscillating chlorophyll profiles above the DCM, is consistent with nitrification as the key process forming the PNM. We suggest that transport and reaction control the vertical order and separation of N-species in the water column. The ratios between the rate constants for ammonification, ammonium oxidation, nitrite oxidation and nitrate assimilation were estimated by a simple box model to be 1:3:1.5:0.15, respectively. These field estimates are similar to the ratios between the rate constants measured in laboratory experiments.

We investigated the implications of deep winter mixing for the nitrogen budget in two adjacent systems, the northern Red Sea proper, and the Gulf of Aqaba. Both are subtropical oligotrophic water bodies. The main difference is that in the gulf deep winter mixing takes place regularly, whereas the northern Red Sea proper is permanently stratified. In the Gulf of Aqaba, we observed significantly lower nitrate deficits, i.e. deviations from the Redfield ratio, than in the northern Red Sea proper. Assuming that other external inputs and losses in N or P are very similar in both systems, the higher nitrate deficit can be explained by either lower nitrogen fixation in the (stratified) northern Red Sea, which seems unlikely. An alternative explanation would be higher rates of benthic denitrification than in the gulf. By comparing the two systems we have indirect evidence that benthic denitrification was much lower in the Gulf of Aqaba due to higher oxygen concentrations. This we attributed to the occurrence of deep winter mixing, and as a consequence, the nitrate deficit was close to zero (i.e. N:P ratio close to "Redfield"). If both nitrogen fixation and benthic denitrification take place, as in the northern Red Sea proper, the result was a positive nitrate deficit (i.e. a deficit in nitrate) in the ambient water. The nitrate deficit in the northern Red Sea was observed in spite of high iron deposition from the surrounding desert. Our results strongly support the concept of nitrogen as the proximate, and phosphate as the ultimate limiting nutrient for primary production in the sea. This must not be neglected in efforts for protecting the adjacent reefs against eutrophication. [ABSTRACT FROM AUTHOR]

Hermatypic-zooxanthellate corals track the diel patterns of the main environmental parameters - temperature, UV and visible light - by acclimation processes that include biochemical responses. The diel course of solar radiation is followed by photosynthesis rates and thereby elicits simultaneous changes in tissue oxygen tension due to the shift in photosynthesis/respiration balance. The recurrent patterns of sunlight are reflected in fluorescence yields, photosynthetic pigment content and activity of the two protective enzymes superoxide dismutase (SOD) and catalase (CAT), enzymes that are among the universal defenses against free radical damage in living tissue. All of these were investigated in three scleractinian corals: Favia favus, Plerogyra sinuosa and Goniopora lobata. The activity of SOD and CAT in the animal host followed the course of solar radiation, increased with the rates of photosynthetic oxygen production and was correlated with a decrease in the maximum quantum yield of photochemistry in Photosystem II (PSII) (ΔF′/Fm′). SOD and CAT activity in the symbiotic algae also exhibited a light intensity correlated pattern, albeit a less pronounced one. The observed rise of the free-radical-scavenger enzymes, with a time scale of minutes to several hours, is an important protective mechanism for the existence and remarkable success of the unique cnidarian-dinoflagellate associations, in which photosynthetic oxygen production takes place within animal cells. This represents a facet of the precarious act of balancing the photosynthetic production of oxygen by the algal symbionts with their destructive action on all living cells, especially those of the animal host. [ABSTRACT FROM AUTHOR]

Bio-optical relationships between inherent and apparent optical properties, and between optical properties and phytoplankton pigment concentration ( C ) averaged in a discrete layer, were developed. These relationships were derived from analysis of data collected during the period 1996-1998 in the Gulf of Aqaba (Eilat), a 'Case 1' type water body. Parameterization of these relationships was accomplished by combining Gershun's equation, radiative transfer theory for average cosine of underwater light field, and a set of different bio-optical models. An analysis of the asymptotic light field was carried out. Semi-analytical single-wavelength (at λ =443 nm) algorithms for in situ and remote sensing (RS) estimation of mean pigment concentration were developed, and evaluated by sensitivity and error analysis. The advantages of RS single-wavelength algorithms in comparison with current two- and multi-wavelengths RS algorithms are discussed. [ABSTRACT FROM AUTHOR]