scholarly journals Linaclotide for The Treatment of Refractory Lower Bowel Manifestations of Systemic Sclerosis

2020 ◽  
Author(s):  
Eric Dein ◽  
Fredrick M. Wigley ◽  
Zsuzsanna H. McMahan
Keyword(s):  
Side Effects ◽  
Low Dose ◽  
Artificial Nutrition ◽  
High Dose ◽  
Lower Gastrointestinal Tract ◽  
High Dose Therapy ◽  
Selective Agonist ◽  
Guanylate Cyclase C ◽  
Effective Option ◽  
Tract Involvement

Abstract Objective: Lower gastrointestinal tract involvement can affect up to 50% of SSc patients, and may result in malabsorption, pseudo-obstruction, hospitalization, and death. We report our experience with linaclotide, a selective agonist of guanylate cyclase C, for SSc patients with refractory lower GI disease.Methods: We performed a analysis of patients seen at the Johns Hopkins Scleroderma Center and identified patients prescribed linaclotide for refractory lower GI manifestations. Patients had clinical data prospectively collected in our longitudinal database. Linaclotide responders were on medication for at least 12 months with documented effectiveness by the treating physician. Results: Thirty-one patients with SSc were treated with linaclotide. Twenty-three of these patients (74%) had severe GI disease on initiation of linaclotide (Medsger GI score ≥3), as defined by recurrent pseudo-obstruction, malabsorption, and/or need for artificial nutrition. The majority of patients (90.3%; 28/31) had a treatment response, while only three patients (9.7%) reported ineffectiveness or intolerable side effects. Low-dose linaclotide (≤ 145 mcg daily) was used in 18 patients and was effective in 94%. High-dose therapy (>145 mcg daily) was effective in 11 of 13 patients (85%). Common side effects were diarrhea, cramping, or bloating (11/31, 35%). Ineffectiveness, cost, and abdominal pain were complaints cited among those who discontinued therapy. Conclusion: Linaclotide is a well-tolerated and efficacious pro-secretory and pro-motility agent that can be used to manage refractory lower GI manifestations in SSc. We found that low-dose linaclotide is an effective option and may be better tolerated, though a subset of patients may require high dose regimens.

scholarly journals Linaclotide for the treatment of refractory lower bowel manifestations of systemic sclerosis

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Eric J. Dein ◽  
Fredrick M. Wigley ◽  
Zsuzsanna H. McMahan
Keyword(s):  
Systemic Sclerosis ◽  
Side Effects ◽  
Low Dose ◽  
Artificial Nutrition ◽  
High Dose ◽  
Gi Tract ◽  
Selective Agonist ◽  
Guanylate Cyclase C ◽  
Effective Option ◽  
Tract Involvement

Abstract Background Lower gastrointestinal (GI) tract involvement can affect up to 50% of systemic sclerosis (SSc) patients, and may result in malabsorption, pseudo-obstruction, hospitalization, and death. We report our experience with linaclotide, a selective agonist of guanylate cyclase C (GC-C), for SSc patients with refractory lower GI disease. Methods We performed an analysis of patients seen at the Johns Hopkins Scleroderma Center and identified patients prescribed linaclotide for refractory lower GI manifestations. Patients had clinical data collected in our longitudinal database. Linaclotide responders were on medication for at least 12 months with documented effectiveness by the treating physician. Results Thirty-one patients with SSc were treated with linaclotide. At the time of linaclotide initiation, 23 of these patients (74%) were classified as having severe GI disease, as defined by recurrent pseudo-obstruction, malabsorption, and/or need for artificial nutrition (Medsger GI severity score ≥ 3). The majority of patients (90.3%; 28/31) had a treatment response, while only three patients (9.7%) reported ineffectiveness or intolerable side effects. Low-dose linaclotide (≤ 145 mcg daily) was used in 18 patients and was effective in 94%. High-dose therapy (> 145 mcg daily) was effective in 11 of 13 patients (85%). Common side effects were diarrhea, cramping, or bloating (11/31, 35%). Ineffectiveness, cost, and abdominal pain were complaints cited among those who discontinued therapy. Conclusion Linaclotide is a well-tolerated and efficacious pro-secretory and pro-motility agent that can be used to manage refractory lower GI manifestations in SSc. We found that low-dose linaclotide is an effective option and may be better tolerated, though a subset of patients may require high dose regimens.

scholarly journals Rapid Recovery and Short Duration Anesthesia after Low Dose Ketamine and High Dose Dexmedetomidine in Rhesus Macaques (Macaca mulatta)

2021 ◽  
Author(s):  
Kristin E Killoran ◽  
Courtney A Walsh ◽  
Jennifer L Asher ◽  
Molly B Tarleton ◽  
Steven R Wilson
Keyword(s):  
Macaca Mulatta ◽  
Recovery Time ◽  
Low Dose ◽  
Rhesus Macaques ◽  
High Dose ◽  
Selective Agonist ◽  
Female Rhesus ◽  
Recovery From Anesthesia ◽  
Higher Doses ◽  
Female Rhesus Macaques

Anesthesia in rhesus macaques is required for many procedures. Although ketamine is the backbone of most anestheticprotocols, tolerance to the drug can develop, resulting in the need for higher doses to provide sufficient restraint. Combination with other drugs, such as α-agonists, can be ketamine-sparing, providing for sufficient restraint at lower ketamine doses. In addition, because α-agonists are reversible, recovery from anesthesia has the potential to be much shorter. We hypothesized that use of a low dose of ketamine with a high dose of dexmedetomidine, an α2 receptor selective agonist, in male and female rhesus macaques less than 15 y of age would provide adequate anesthesia for short procedures and that recovery would be faster than in macaques given a higher dose of ketamine (10 mg/kg) alone. We found that the combination, in conjunction with atipamezole for reversal, provided smooth induction of anesthesia and significantly shorter recovery time than did ketamine alone, with no significant effects of sex. The combination of low dose ketamine and high dose dexmedetomidine also provided a 30-min window of anesthesia with analgesia sufficient for mild to moderately painful procedures.

6081Efficacy and limitations of quinidine therapy in patients with Brugada Syndrome

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
A Mazzanti ◽  
E Tenuta ◽  
M Marino ◽  
E Pagan ◽  
M Morini ◽  
...  
Keyword(s):  
Cardiac Arrest ◽  
Side Effects ◽  
High Risk ◽  
Brugada Syndrome ◽  
Low Dose ◽  
Clinical Course ◽  
High Risk Group ◽  
High Dose ◽  
Life Threatening ◽  
Patients Experience

Abstract Background Quinidine at high-dose is used in patients with Brugada Syndrome (BrS), but its efficacy to prevent life-threatening arrhythmic events (LAE) in BrS is unproven and its use is limited by side effects. Objective We assessed whether low-dose quinidine in BrS patients reduces: 1) the occurrence of a first LAE; 2) the arrhythmic burden in the high-risk group of cardiac arrest survivors. Methods We first compared the clinical course of 53 BrS patients treated with quinidine to that of 441 untreated controls, matched by sex, age, and symptoms. Furthermore, we calculated the annual incidence of LAEs off- and on-quinidine in 123 BrS patients who had survived a cardiac arrest. Results First, we compared the clinical course of 53 BrS patients treated with quinidine (i.e. “cases”: 89% males, median age 40 years) to that of 441 untreated, clinically-matched BrS patients (i.e. “controls”: 91% males, median age 41 years) present in our database of patients with inherited arrhythmias. Cases received quinidine (median dose of 450 mg per day) for 5.0±3.7 years. Quinidine was interrupted in only 3/53 cases (6%) for side effects and it conferred a nonsignificant reduction of the risk of a first LAE in cases versus controls (HR 0.74, 95% CI 0.22–2.48, P=0.62). Secondly, we calculated the annual recurrence of LAE off- and on-quinidine in 123 BrS cardiac arrest survivors, 27 of whom were treated with quinidine for 7.0±3.5 years. The annual rate of recurrent LAEs decreased significantly from 14.7% while off-quinidine to 3.9% while on-quinidine (P=0.03). Notably, recurrent life-threatening arrhythmic events were recorded in 4/27 (15%) symptomatic patients while on-quinidine. Conclusion We demonstrated for the first time in the long-term that low-dose quinidine reduces the recurrence of life-threatening arrhythmias in symptomatic BrS patients, with few side effects. Remarkably, about one-fifth of symptomatic patients experience life-threatening arrhythmias while on-treatment, suggesting that quinidine cannot replace implantable defibrillators in high-risk subjects.

scholarly journals Efficacy of NS-718, a Novel Lipid Nanosphere-Encapsulated Amphotericin B, againstCryptococcus neoformans

1998 ◽  
Vol 42 (7) ◽  
pp. 1722-1725 ◽  
Author(s):  
Mohammad Ashraf Hossain ◽  
Shigefumi Maesaki ◽  
Hiroshi Kakeya ◽  
Tetsuhiro Noda ◽  
Katsunori Yanagihara ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Antifungal Agent ◽  
Low Dose ◽  
Yeast Cells ◽  
High Dose ◽  
Pulmonary Cryptococcosis ◽  
High Dose Therapy ◽  
Dose Therapy

ABSTRACT In vitro and in vivo efficacies of NS-718, a lipid nanosphere-encapsulated amphotericin B (AMPH-B), have been studied. Of the tested AMPH-B formulations, NS-718 had the lowest MIC forCryptococcus neoformans. In a murine model, low-dose therapy (0.8 mg/kg of body weight) with NS-718 showed higher efficacy than that with AmBisome. High-dose therapy (2.0 mg/kg) with NS-718 was much more effective than those with Fungizone and AmBisome. In mice treated with a high dose of NS-718, only a few yeast cells had grown in lung by 7 days after inoculation. A pharmacokinetic study showed higher concentrations of AMPH-B in lung following administration of NS-718 than after administration of AmBisome. Our results indicated that NS-718, a new AMPH-B formulation, is a promising antifungal agent for treatment of pulmonary cryptococcosis and could be the most effective antifungal agent against C. neoformans infections.

Low-dose versus high-dose therapy for Gaucher disease: goals and markers

Blood ◽  
2007 ◽  
Vol 109 (1) ◽  
pp. 387-387 ◽  
Author(s):  
Carla E. M. Hollak ◽  
Maaike de Fost ◽  
Johannes M. F. G. Aerts ◽  
Stephan vom Dahl
Keyword(s):  
Gaucher Disease ◽  
Low Dose ◽  
High Dose ◽  
High Dose Therapy ◽  
Dose Therapy

Cyproterone acetate as initial treatment and maintenance therapy for hirsutism

1985 ◽  
Vol 109 (4) ◽  
pp. 522-529 ◽  
Author(s):  
I. M. Holdaway ◽  
M. S. Croxson ◽  
H. K. Ibbertson ◽  
A. Sheehan ◽  
B. Knox ◽  
...  
Keyword(s):  
Growth Rate ◽  
Side Effects ◽  
Maintenance Therapy ◽  
Cyproterone Acetate ◽  
Hair Growth ◽  
Low Dose ◽  
Sex Hormone Binding Globulin ◽  
Plasma Testosterone ◽  
High Dose ◽  
Dose Therapy

Abstract. Thirty-four patients with hirsutism were treated for 9 months with 100 mg cyproterone acetate (CA) given on days 5–15 of the menstrual cycle together with a combination oral contraceptive containing 2 mg CA and 50 μg ethinyloestradiol (Diane®) given on days 5–25 of the cycle. After 9 months treatment patients were randomised to a 12 month double-blind cross-over trial comparing Diane® plus 25 mg CA with Diane® plus placebo, to test the efficacy of low-dose CA as maintenance therapy. Thirty-one patients (92%) experienced moderate or good subjective improvement in hirsutism on high-dose CA, associated with a 40% mean overall improvement in objective hirsutism grade and 13% overall reduction in hair growth rate measured by a photographic technique. Minor or moderate side effects were experienced by 64% of patients and severe side effects by 11% at this dosage. There was a mean subjective relapse rate of 33% when patients were changed to low dose CA, and relapse rates were not significantly different between the two regimens with 28% relapsing on 25 mg CA + Diane® and 48% on placebo and Diane® (P < 0.05). Despite significant subjective relapse with low-dose treatment there was no significant deterioration in objective hirsutism grade or hair growth rate determined photographically. Levels of plasma testosterone, sex hormone binding globulin, free testosterone (derived) and androstenedione fell significantly on high dose CA and this reduction was maintained during low dose therapy. Cyproterone acetate at high dosage thus appeared an effective agent in the treatment of hirsutism, but 33% of patients considered they deteriorated when changed to low-dose therapy despite maintenance of androgen suppression and lack of change in objective measurements. Maintenance therapy after remission with high-dose CA appears justified since 60% of patients underwent subjective relapse when all treatment was stopped.

Maintenance Low Dose 13 Cis-Retinoic Acid and Alpha Tocopherol Improves Survival Compared to High Dose Therapy for 6 Months In LOW and INT-1/2 Stage MDS: Role for Prevention Trial

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 5053-5053
Author(s):  
Emmanuel C. Besa ◽  
Joseph Vadakara
Keyword(s):  
Retinoic Acid ◽  
Retrospective Study ◽  
Side Effects ◽  
Low Dose ◽  
Low Risk ◽  
Alpha Tocopherol ◽  
High Dose ◽  
Off Label ◽  
Stage Disease

Abstract Abstract 5053 There are no current therapies or preventative strategies other than transfusion support and possibly growth factor support for the management of low risk and INT 1 Myelodysplasia. There have been a few studies that looked into the effect of 13 cis-retinoic acid (13CRA) by itself and in combination with other drugs that showed some benefits to the use of 13CRA in MDS. A randomized blinded study failed to show any benefit of 13CRA over placebo; however in this study many of the patients discontinued therapy due to side effects of the 13CRA and significant number of the patients had advanced stage disease and either had CMML, RAEB, and RAEB-t based on the classification in use then. Other studies have suggested that the beneficial effect of 13CRA is possibly seen in early stage disease and in low risk Refractory Anemia patients. To look into the benefit that 13CRA might have on IPSS low risk, INT-1 and INT-2 MDS patients we conducted a retrospective study that looked at the effect of 13CRA given in two different doses and durations. Methods: This was a retrospective study that looked at patients with IPSS low risk and INT-1 and INT-2. The patients were divided into two groups. One group was treated with a dose of 13CRA at a dose of 100mg/m2/day for 6 months. The second cohort was treated with a dose of 40mg of 13CRA until disease progression. Disease progression was then compared in the two groups to see if there was any statistical difference in the treatment arms. One of the patients did not seem to have any side effects of 13CRA and it was later found that that patient was on alpha tocopherol, once this was realized then all the patients were given Alpha tocopherol (AT) at a dose 800mg per day along with 13CRA. Results: Twenty patients were identified in the high dose short term arm, and 29 patients in the low dose long term arm. Both groups were similar in age (mean, range) in years, male/female ratio, duration from diagnosis to treatment. IPSS scores and transfusion requirements were comparable. Responses were observed in both groups with an overall response rate of 44.8% in HDST and 75% in LDLT with similar, low AML transformation in INT-1-2 patients of 15% in LDLT and 13.7% in HDST. A better median survival was observed with 5 patients still alive at 72 months in LDLT compared to 30 months in HDST group with a difference of 42 months (3.5 years) (Log-rank p value= 0.0099). The patients who were on the LDLT arm with alpha tocopherol had a much better toxicity profile with only 5% developing skin toxicity compared to as high as 27% in HDST arm and 100% in patients who only received 13CRA, similarly triglyceride changes were seen in 5%, 20%, and 52% respectively, AST elevations were seen in 0%, 2% and 19 % respectively. This suggest that lack of toxicity and good tolerance using 13 CRA at 40 mg/d with 800 mg of AT for long term preventive measure in early phase MDS may result in prolonged survival and may be used as basis for a prospective prevention trial. Disclosures: Off Label Use: 13 cis retinoic acid is used off label.

Comparison of Blood Graft Cellular Content in Myeloma (MM) Patients and Non-Hodgkin Lymphoma (NHL) Patients Mobilized with Chemotherapy Plus G-CSF with or without Plerixafor

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4414-4414
Author(s):  
Esa Jantunen ◽  
Ville Varmavuo ◽  
Raija Silvennoinen ◽  
Piia Valonen ◽  
Taru Kuittinen ◽  
...  
Keyword(s):  
B Lymphocytes ◽  
Low Dose ◽  
Lymphoid Cells ◽  
High Dose ◽  
Cellular Composition ◽  
High Dose Therapy ◽  
Dose Therapy ◽  
Non Hodgkin Lymphoma ◽  
Previous Therapy ◽  
Cd34 Cells

Abstract Abstract 4414 Background: Cellular composition of blood graft collected to support high-dose therapy may have important implications in regard to hematopoietic and immune reconstitution after high-dose therapy. Mobilization method used may have effect on graft composition as well as previous therapy given to the patients. Methods: We have retrospective analyzed by flow cytometry cellular composition of freezed blood grafts in 34 patients with NHL (chemotherapy + G-CSF mobilization 15, add-on plerixafor 19 patients) and compared the observations with those of 17 MM patients mobilized either with low-dose cyclophosphamide + G-CSF (n=12) or with add-on plerixafor (n=5). The analyses were performed from the first graft collected from the chemomobilized patients or from the first draft collected after the plerixafor injection, respectively. Antibodies used included CD34, CD38, CD133 in regard to CD34+ subclasses and CD3, CD4, CD8, CD19 and CD3CD16/CD56 to analyze lymphocyte subsets. In addition, 7-aminoactinomycin D staining was used to assess the amount of nonviable CD34+ and lymphoid cells. Results: In regard to the patients mobilized without plerixafor, MM patients had higher content of CD34+ cells (4.9 vs. 2.0 × 106/kg, p=0.009) as well as lower proportion of more primitive stem cells (0.8 vs. 1.9 % of all CD34+ cells, p=0.075) when compared to NHL patients. The amount of B-lymphocytes was also significantly higher in MM patients (0.5 × 106/kg vs. 0.0, p< 0.001). No differences were observed in the total amount of T (CD3+) cells, NK cells or in the proportion of nonviable CD34+ or lymphoid cells. Of the plerixafor treated patients, the amount of B-lymphocytes was higher in MM patients (1.8 × 106/kg vs. 0.0, p<0.001) as well as CD4/CD8 ratio (2.56 vs. 1.0, p=0.004) when compared to NHL patients. Conclusion: As there appears to be differences between MM and NHL patients mobilized with or without plerixafor, it might be advisable to analyze separately effects of mobilization therapy to graft content and post-transplant outcomes in these diseases. Apparently the type and intensity of previous therapy given to the patients (e.g. rituximab) has important effects on graft cellular composition. Disclosures: Jantunen: Genzyme: Has participated in EU Leadership meeting organized by Genzyme as well as Medical Advisory Board meeting organized by Genzyme Other, Honoraria. Silvennoinen:Genzyme: Consultancy.

scholarly journals Assessing whether disinfectants against the fungus Batrachochytrium dendrobatidis have negative effects on tadpoles and zooplankton

2009 ◽  
Vol 30 (3) ◽  
pp. 313-319 ◽  
Author(s):  
Mirjam von Rütte ◽  
Niklaus Peyer ◽  
Benedikt Schmidt ◽  
Nina Keller ◽  
Céline Geiser
Keyword(s):  
Side Effects ◽  
Low Dose ◽  
Batrachochytrium Dendrobatidis ◽  
High Dose ◽  
Zooplankton Abundance ◽  
Population Declines ◽  
Negative Effects ◽  
Negative Side ◽  
Negative Side Effects ◽  
Global Population

AbstractChytridiomycosis is an emerging disease of amphibians that has led to global population declines and possible extinctions. Vectoring of the pathogen, Batrachochytrium dendrobatidis (Bd) by anthropogenic means is thought to be important in its spread. To limit further increase in the distribution of Bd, field biologists and amateur naturalists ought to disinfect their boots and materials. However, imprudent use of potentially harmful disinfectants may have unwanted negative side effects on amphibians. We used a factorial experiment to test whether commonly used disinfectants (bleach and Virkon S) affect tadpole performance and zooplankton abundance. At the high dose of bleach, all tadpoles and zooplankton died. Tadpole performance and zooplankton abundance in the low dose of bleach and Virkon S treatments were undistinguishable from the control. Therefore, when bleach is used as a disinfectant, it must not get in contact with amphibians. Virkon S appears to be a disinfectant that can be used against Bd with no detectable negative effects on tadpoles and zooplankton.

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