Loperamide and cardiac events: Is high-dose use still safe for chemotherapy-induced diarrhea?

2017 ◽  
Vol 24 (8) ◽  
pp. 634-636 ◽  
Author(s):  
Mário L de Lemos ◽  
Jolene Guenter ◽  
Victoria Kletas
Keyword(s):  
Daily Intake ◽  
Extended Period ◽  
Torsades De Pointes ◽  
Serum Levels ◽  
Cardiac Risk ◽  
High Dose ◽  
Cardiac Events ◽  
The Us ◽  
High Doses ◽  
Higher Doses

High-dose loperamide is often used for the acute management of chemotherapy-induced diarrhea, with a maximum daily dosing of up to 24 mg. Recently, the US Food and Drug Administration has issued a warning that loperamide can cause rare serious cardiac events, including QT prolongation, torsades de pointes, cardiac arrest and death. Most events were reported in patients taking very high doses for an extended period of time. Daily intake ranged from 64 mg to 1600 mg, often continuously for weeks or months. In addition, the reported serum levels of loperamide ranged from 22 ng/mL to 210 ng/mL, which is likely significantly higher than that expected from patients taking the recommended doses for chemotherapy-induced diarrhea. Overall, the incidence of serious cardiac events associated with loperamide remains low. In balance, the risk of uncontrolled complications from chemotherapy-induced diarrhea is likely greater than the rare cardiac risk associated with the chronic misuse of much higher doses of loperamide.

scholarly journals Low Doses of Ochratoxin-A Decrease IgY and IgA Production in Broiler Chicks

Toxins ◽  
2018 ◽  
Vol 10 (8) ◽  
pp. 316 ◽  
Author(s):  
Shahzad Khan ◽  
Emerson Venancio ◽  
Eduardo Fernandes ◽  
Elisa Hirooka ◽  
Alexandre Oba ◽  
...  
Keyword(s):  
Ochratoxin A ◽  
Dose Group ◽  
Daily Intake ◽  
Serum Levels ◽  
Bursa Of Fabricius ◽  
High Dose ◽  
Broiler Chicks ◽  
Immunological Parameters ◽  
Iga Production ◽  
Leukocyte Profiles

The mycotoxin, ochratoxin-A (OTA), produced by some fungi, and is a natural contaminant of many foods and animal feeds worldwide. Due to its toxic effects, the recommended maximum daily intake of OTA for poultry feeds is 0.1 mg OTA/kg (ECR2006/575/EC); this dose does not induce changes in hepatic/renal parameters, but decreases thymus size and serum globulin concentrations. Accordingly, in this study, we assessed quantitatively the total circulating IgY and IgA serum levels, in chicks consuming a 0.1 mg OTA/kg diet (limit) and higher doses (0.3–1.1 mg OTA/kg diet) for 14 or 21 days. We also evaluated other immunological parameters (thymus, bursa of Fabricius, and spleen weights and leukocyte profiles) at day 21. Decreased IgY serum levels were observed in all OTA-treated groups (p < 0.05). In the low-dose group, IgA levels were decreased on day 21, but not on day 14. The size of the thymus and the bursa of Fabricius was decreased in all OTA-treated groups (p < 0.05), whereas reduced spleen size and altered leukocyte profiles were detected only in the high-dose group (p < 0.05). We concluded that chronic exposure to OTA, even at the recommended highest dose, affected IgY and IgA production in chicks.

Azithromycin and the Risk of Cardiovascular Complications

2013 ◽  
Vol 27 (5) ◽  
pp. 496-500 ◽  
Author(s):  
Nicole M. Maisch ◽  
Jenny G. Kochupurackal ◽  
Jonathan Sin
Keyword(s):  
Cohort Study ◽  
Case Reports ◽  
Torsades De Pointes ◽  
Cardiac Risk ◽  
Cardiovascular Death ◽  
Cardiovascular Complications ◽  
Qt Prolongation ◽  
Baseline Risk ◽  
Cardiac Events ◽  
Increased Risk

The purpose of this review was to evaluate the literature to assess the incidence and true clinical relevance of recent Food and Drug Administration warnings regarding QT prolongation with azithromycin, given its widespread use, with over 40 million US outpatient prescriptions written in 2011. A literature search of MEDLINE (1946 to May 2013) and International Pharmaceutical Abstracts (1970 to May 2013) was conducted using the terms azithromycin, QT prolongation, torsades de pointes, arrhythmia, and cardiovascular death. A bibliographic search was also performed. Several relevant studies and case reports were identified and reviewed. One cohort study revealed an increased risk of cardiovascular death with azithromycin compared to no antibiotic, especially in those with higher cardiovascular risk. Another cohort study comparing azithromycin, penicillin V, and no antibiotic in a younger Danish population with less cardiac risk found no increased cardiovascular death associated with azithromycin use. The majority of case reports involved ill and/or elderly patients with multiple comorbidities and concomitant medications who were already at a higher risk of cardiovascular events. Although there is evidence that azithromycin may induce QT prolongation and adverse cardiac events, the incidence is fairly limited to patients with high baseline risk, including those with preexisting cardiovascular conditions and concomitant use of other QT-prolonging drugs.

Long-term treatment with finasteride induces apoptosis and pathological changes in female mice

2019 ◽  
Vol 38 (7) ◽  
pp. 762-774 ◽  
Author(s):  
AA Alkahtane ◽  
G Albasher ◽  
NK Al-Sultan ◽  
WS Alqahtani ◽  
S Alarifi ◽  
...  
Keyword(s):  
Serum Levels ◽  
Term Treatment ◽  
Androgenetic Alopecia ◽  
High Dose ◽  
Histopathological Analysis ◽  
Once Daily ◽  
Female Mice ◽  
Long Term Treatment ◽  
High Doses

Androgenetic alopecia is the most common type of alopecia, and it affects humans of both genders. Finasteride is a type II selective 5α-reductase inhibitor that is administered orally to treat androgenetic alopecia and benign prostatic hyperplasia in human males. However, its effect on the vital organs of females is unknown. This study was designed to investigate the effects of finasteride on the vital organs such as liver, kidney, and heart of female mice. To study the prospective effects of finasteride, female mice were orally administered two doses of finasteride (0.5 and 1.5 mg/kg) once daily for 35 days, and serum levels of various biochemical parameters and histopathology of various organs were examined. The results showed that serum levels of alkaline phosphatase were significantly increased by both high- and low-dose finasteride, whereas cholesterol was significantly increased by the high dose only. Creatine kinase was significantly increased by the high and low doses, whereas glucose was significantly decreased by both doses. Histopathological analysis and DNA damage assays showed that finasteride has adverse effects within both the short and the long periods in female mice. In addition, the proapoptotic genes Bax and caspase-3 were significantly increased by high dose finasteride, whereas the antiapoptotic gene Bcl-2 was significantly decreased by the low and high doses. In conclusion, finasteride is not currently approved for therapeutic use in females, and the findings in this study suggest caution in any future consideration of such use.

Effects of 4-hydroxyandrostenedione and hyperstimulation with pregnant mare serum gonadotrophin on early embryonic development in rats

2001 ◽  
Vol 79 (9) ◽  
pp. 744-753 ◽  
Author(s):  
Terry Y.Y Tong ◽  
Victor H.H Goh
Keyword(s):  
Embryonic Development ◽  
Early Embryonic Development ◽  
Female Rats ◽  
High Dose ◽  
Negative Effects ◽  
Embryo Survival ◽  
High Doses ◽  
Higher Doses ◽  
Pregnant Mare Serum Gonadotrophin

A possible role of high oestradiol levels in mediating the adverse effects of hyperstimulation with pregnant mare serum gonadotrophin (PMSG) on early embryonic development in the rat was investigated using an aromatase inhibitor, 4-hydroxyandrostenedione (4-OHA), to inhibit endogenous oestradiol production. Three experiments were conducted in this study. In the first, varying doses of 4-OHA were administered either concurrently with human chorionic gonadotropin (hCG) to pro-oestrus female rats hyperstimulated at early di-oestrus stage with 20 IU PMSG or alone into nonhyperstimulated pro-oestrus females. At high doses of 1000, 2000, or 5000 µg/rat, 4-OHA substantially improved the survival of embryos in hyperstimulated females, while low doses of 100 and 500 µg/rat were ineffective. The protective effect of 4-OHA on embryo count was optimum at 2000 µg. When administered alone, only the highest dose of 5000 µg/rat 4-OHA increased embryo count. In the second experiment, higher doses of PMSG were studied (30 or 40 IU), with or without 5000 µg/rat 4-OHA given at the time of hCG injection. PMSG proved to be more detrimental with increasing dose, and 5000 µg/rat 4-OHA was able to rescue embryos from death in the 30, but not 40, PMSG group. In the third experiment, the influence of the timing of 4-OHA treatment on its ability to improve the embryo count in hyperstimulated females was examined by introducing 4-OHA 24 h earlier, rather than at the time of hCG treatment. The results showed the importance of timing of 4-OHA administration, as 5000 µg/rat 4-OHA was able to restore embryo survival in the 40 PMSG hyperstimulated group only when it was administered 24 h before hCG injection. Together, these results highlighted that 4-OHA, when administered at the appropriate time and dose, could reverse the negative effects of hyperstimulation from PMSG on early embryonic development. This may be due to its potent aromatase inhibiting properties that lead to the suppression of oestrogen production, thereby alleviating the supraphysiological level of oestradiol, which is typically present in PMSG-treated females. Interestingly, 4-OHA treatment on its own was able to positively influence embryo count when given at a high dose of 5000 µg/rat, and this may be associated with its weak androgenic properties. In conclusion, this study supports the hypothesis that excessive oestradiol is responsible for the negative effects of hyperstimulation with PMSG on early embryonic development.Key words: 4-hydroxyandrostenedione, embryonic development, PMSG, rat.

Efficacy of AT in pre-eclampsia: a case-control prospective trial

2004 ◽  
Vol 91 (02) ◽  
pp. 283-289 ◽  
Author(s):  
Sara Fantinato ◽  
Francesca Manganelli ◽  
Massimo Milani ◽  
Umberto Nicolini ◽  
Antonio Girolami ◽  
...  
Keyword(s):  
Prospective Trial ◽  
Experimental Studies ◽  
High Dose ◽  
Granulocyte Elastase ◽  
Markers Of Inflammation ◽  
Significant Prolongation ◽  
Inflammatory State ◽  
High Doses ◽  
Higher Doses ◽  
D Dimer

SummaryPre-eclampsia is an extremely severe condition. It is associated with vasospasm, activation of the coagulation system and abnormal haemostasis. In pre-eclamptic patients increased plasmatic concentrations of fibronectin, laminin, von Willebrand factor (VWF) and endothelin are observed. Experimental studies on rats have also shown that the doses of antithrombin III (AT) needed to mediate anti-inflammatory processes are much higher than those required to obtain the anti-coagulant effect. The study aimed to evaluate the clinical efficacy of treatment with high AT doses (HD) in comparison with standard doses (SD). The primary endpoint was the prolongation of pregnancy defined as time (in days) from enrollment to delivery and to assess the maternal bleeding at and after delivery. The secondary endpoint was to demonstrate a role for AT in controlling haemostasis at conventional doses, and the inflammatory state at higher doses. The biochemical parameters assessed were: AT activity (%), Fibronectin (Fn), Fibrinogen, D-dimer, Uricemia, Proteinuria 24h, Protein C Reactive (PCR), Granulocyte Elastase and Endothelin. This study included 23 pre-eclamptic women. Patients were randomly subdivided into two groups: 10 patients (“cases”) were treated with high doses of AT (6 vials: 3000 units) once daily for 5 days, or until delivery, while 13 women (“controls”) were treated with doses of AT sufficient to maintain at least 80% of the activity. High-dose therapy was associated with prolongation of pregnancy by 2.5 days more when compared with controls (p = 0.03; Mann-Whitney test). The incidence of clinical significant bleeding was lower in cases than in controls (mean 550 mL vs. 650 mL, respectively). Preventiveand conservative-type treatment of moderatesevere pre-eclampsia, based on the administration high doses of AT, allows a significant prolongation of pregnancy, and thus a better neonatal outcome, as well as less maternal intra-and post-operative bleeding. Fn, PCR and elastase levels (markers of inflammation) decrease in the HD group in comparison with SD group. In the HD group, the AT plasma levels were obviously higher both at the end of the treatment (p < 0.0001) and after delivery (p = 0.03), in comparison with SD group. The fibrinogen and D-dimer levels were above the reference interval in both groups. TPA and PAI 1 were found to be significantly raised in the course of pre-eclampsia. In conclusion, the biochemical findings support a role for AT in controlling the haemostasis at conventional doses, and the inflammatory state at higher doses.

scholarly journals Cigarette smoke preparations, not moist snuff, impair expression of genes involved in immune signaling and cytolytic functions

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Gang Liu ◽  
Subhashini Arimilli ◽  
Evan Savage ◽  
G. L. Prasad
Keyword(s):  
Gene Expression ◽  
Immune Responses ◽  
Cigarette Smoke ◽  
Inflammatory Responses ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
High Dose ◽  
Pre Treatment ◽  
High Doses ◽  
Higher Doses

Abstract Cigarette smoke-induced chronic inflammation is associated with compromised immune responses. To understand how tobacco products impact immune responses, we assessed transcriptomic profiles in peripheral blood mononuclear cells (PBMCs) pretreated with Whole Smoke-Conditioned Medium (WS-CM) or Smokeless Tobacco Extracts (STE), and stimulated with lipopolysaccharide, phorbol myristate and ionomycin (agonists). Gene expression profiles from PBMCs treated with low equi-nicotine units (0.3 μg/mL) of WS-CM and one high dose of STE (100 μg/mL) were similar to those from untreated controls. Cells treated with medium and high doses of WS-CM (1.0 and 3.0 μg/mL) exhibited significantly different gene expression profiles compared to the low WS-CM dose and STE. Pre-treatment with higher doses of WS-CM inhibited the expression of several pro-inflammatory genes (IFNγ, TNFα, and IL-2), while CSF1-R and IL17RA were upregulated. Pre-treatment with high doses of WS-CM abolished agonist-stimulated secretion of IFNγ, TNF and IL-2 proteins. Pathway analyses revealed that higher doses of WS-CM inhibited NF-ĸB signaling, immune cell differentiation and inflammatory responses, and increased apoptotic pathways. Our results show that pre-treatment of PBMCs with higher doses of WS-CM inhibits immune activation and effector cytokine expression and secretion, resulting in a reduced immune response, whereas STE exerted minimal effects.

Effects of high doses of molybdenum and sulphate on the distribution of copper in plasma and in blood of sheep

1974 ◽  
Vol 25 (3) ◽  
pp. 467 ◽  
Author(s):  
JB Bingley
Keyword(s):  
Copper Concentration ◽  
Daily Intake ◽  
Clinical Signs ◽  
Haemoglobin Concentration ◽  
Red Cells ◽  
High Dose ◽  
Minimum Concentration ◽  
Total Copper ◽  
Total Plasma Concentration ◽  
High Doses

Sheep on a daily intake of 120 mg molybdenum and 7.4 g sulphate for 29 months maintained plasma total copper concentrations at twice (P < 0.05) and plasma direct-reacting copper concentrations at 10 times (P < 0.01) the pre-experimental level. Plasma ceruloplasmin levels in these sheep were not significantly increased, but the copper concentration in the red cells was reduced to one-tenth of the normal level (1.0 µg/ml). When the molybdenum dose was progressively diminished, plasma total copper and directreacting copper concentrations remained elevated above the normal until the molybdenum intake was reduced to 12 mg per day. The minimum concentration of copper in the red cells was induced when the molybdenum intake was 96 mg per day. Small amounts of copper detected in the ultrafiltrates of plasma from both treated and untreated sheep were independent of the total plasma concentration. The correlation between non-direct-reacting copper and ceruloplasmin in the plasma, whether determined spectrophotometrically or by its oxidase activity, was high (r = 0.89, P < 0.01). This allowed the use of a regression equation to calculate the non-direct-reacting copper concentration of the plasma. All the copper in the plasma from sheep on a high intake of molybdenum and sulphate could be accounted for in terms of direct-reacting copper, ceruloplasmin copper and ultrafiltrable copper. A significant decrease (P < 0.01) in the copper concentration of the wool was caused by treatment of the sheep with molybdenum and sulphate. At the end of the period the haemoglobin concentration in the blood of the sheep on the continuous high dose of molybdenum and sulphate had fallen 30%, but the weight of the sheep was maintained, and apart from the condition of the wool, no clinical signs of copper deficiency were observed.

Prevention of Anti-FVIII Inhibitor Formation Post Protein Infusion in Hemophilic Mice by Prior Feeding of the FVIII-C2 Domain.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 39-39 ◽  
Author(s):  
Fiona Rawle ◽  
Andrea Labelle ◽  
Earl Davie ◽  
Kathleen Pratt ◽  
David Lillicrap
Keyword(s):  
Neutralizing Antibodies ◽  
Expression System ◽  
Site Directed Mutagenesis ◽  
High Dose ◽  
C2 Domain ◽  
Clonal Deletion ◽  
Fviii Inhibitor ◽  
Immunogenic Epitope ◽  
High Doses ◽  
Higher Doses

Abstract The development of anti-factor VIII (FVIII) neutralizing antibodies (inhibitors) is a major obstacle to FVIII replacement therapy. Since the oral administration of an antigen may induce antigen-specific immune tolerance (oral tolerance, OT), we have investigated the effects of feeding human FVIII (hFVIII) or the purified C2 domain of the hFVIII protein (hFVIII-C2) to FVIII-deficient BALB/c (BAL-FVIIIKO) mice prior to hFVIII infusion. This project has two related components: (A) the induction of OT via feeding with hFVIII-C2 and (B) the identification of an immunogenic epitope within the C2 domain specific to BAL-FVIIIKO mice that could be used for peptide-specific OT. We have previously shown that multiple low dose (ug) feedings of hFVIII can induce transient tolerance to hFVIII in mice via active suppression. Other studies indicate that high dose (mg) feedings result in long lasting OT via clonal deletion or anergy. However, due to the high cost and limited availability of recombinant hFVIII, high dose feedings are not feasible. Immunogenic protein domains can also be used for OT, thus we used hFVIII-C2 allowing for the feeding of higher doses (0.1–1mg) than hFVIII (1–10ug). BAL-FVIIIKO mice were fed with a range of hFVIII-C2 and hFVIII doses, and injected subcutaneously (SC) with hFVIII (1ug) or hFVIII-C2 (10ug) with an incomplete adjuvant. Control mice were fed with PBS prior to protein infusion. Feeding with high doses of hFVIII-C2 prevented inhibitor development after hFVIII injection in 3/8 mice and decreased the inhibitor titer in 4/8 mice. This was accompanied by the production of cytokines IL-4 and IL-10 by splenocytes in vitro. 3/3 mice that were fed high doses of hFVIII-C2 and injected with hFVIII-C2 did not produce anti-FVIII inhibitors after hFVIII-C2 challenge, while control mice produced average inhibitors of 6.9 BU. Mice that were inhibitor negative after feeding with hFVIII or hFVIII-C2 and an injection of hFVIII, were injected with an additional dose of hFVIII four weeks post-feeding. Mice fed high hFVIII-C2 doses remained inhibitor negative, whereas mice fed low hFVIII-C2 or hFVIII doses developed inhibitors. Thus, feeding higher doses of hFVIII-C2 results in longer-term tolerance, compared to lower doses of hFVIII-C2 or hFVIII which results in short-term tolerance. These studies show that OT may be beneficial in preventing anti-FVIII inhibitor formation, and that high doses of fed protein will be required for long-term tolerance. Studies have shown that peptides spanning antibody epitopes can induce OT. To define strain-specific FVIII-C2 epitopes as targets for OT therapy, site-directed mutagenesis was used to create the mutants Q2311T/V2314A (MUT-hFVIII-C2) within the putative epitope 2311–2316. hFVIII-C2 and MUT-hFVIII-C2 were made using a Pichia pastoris yeast expression system, and were injected SC (10ug) with adjuvant into C57BL/6-FVIIIKO (C57-FVIIIKO) and BAL-FVIIIKO mice. hFVIIIC2 injection resulted in average anti-FVIII inhibitor titers of 5.13 BU and 6.90 BU in C57-FVIIIKO and BAL-FVIIIKO mice respectively. Injection of MUT-hFVIIIC2 resulted in 6.07 BU and 0.35 (0,0,0,1.4) BU in C57-FVIIIKO and BAL-FVIIIKO. These results illustrate that BAL-FVIIIKO mice recognize the region 2311–2316 as an immunogenic epitope, but the C57 strain does not. Thus, Q2311 and V2314 are important in the immunogenicity of this region and a peptide spanning 2311–316 could be used in OT induction in BAL-FVIIIKO mice.

scholarly journals Effect of Acrylamide Supplementation on the CART-, VAChT-, and nNOS-Immunoreactive Nervous Structures in the Porcine Stomach

Animals ◽  
2020 ◽  
Vol 10 (4) ◽  
pp. 555 ◽  
Author(s):  
Katarzyna Palus ◽  
Michał Bulc ◽  
Jarosław Całka
Keyword(s):  
Dose Group ◽  
Low Dose ◽  
Daily Intake ◽  
Food Products ◽  
Enteric Neurons ◽  
Control Group ◽  
High Dose ◽  
Double Immunofluorescence ◽  
High Temperature Processing ◽  
High Doses

Acrylamide is found in food products manufactured with high-temperature processing, and exposure to acrylamide contained in food products may cause a potential risk to human health. The aim of this investigation was to demonstrate the changes in the population of CART-, nNOS-, and VAChT-immunoreactive enteric neurons in the porcine stomach in response to supplementation of low and high acrylamide doses. The study was carried out with 15 Danish landrace gilts divided into three experimental groups: the control group—animals were administered empty gelatine capsules; the low-dose group—animals were administrated a tolerable daily intake (TDI) dose (0.5 µg/kg of body weight (b.w.)/day) of acrylamide capsules, and the high-dose group—animals were administrated high-dose (ten times higher than TDI: 5 µg/kg b.w./day) acrylamide capsules for 28 days. Using the double immunofluorescence staining method, it was established that supplementation with low and high doses of acrylamide resulted in alterations of the porcine stomach neuron phenotype, which was reflected in an increased number of CART-, VAChT-, and nNOS-immunoreactive neurons. These changes were accompanied by an increased density of CART-, VAChT-, and nNOS-positive fibres. The results suggest that the enteric nervous system plays an important role in protecting the gastrointestinal tract during acrylamide intoxication.

Effects of estrogen and growth hormone on skeleton in the ovariectomized rat with hypophysectomy

1997 ◽  
Vol 273 (4) ◽  
pp. E734-E742 ◽  
Author(s):  
James K. Yeh ◽  
Meng-Meng Chen ◽  
John F. Aloia
Keyword(s):  
Growth Hormone ◽  
Bone Formation ◽  
Cancellous Bone ◽  
Bone Growth ◽  
Combined Treatment ◽  
Serum Levels ◽  
Hormone Deficiency ◽  
High Dose ◽  
Sprague Dawley ◽  
High Doses

To investigate whether growth hormone (GH) and 17β-estradiol (E2) replacement can prevent osteopenia induced by pituitary and ovarian hormone deficiency [by hypophysectomy and ovariectomy (HX+OV)], we administered relatively low doses of GH (2.3 IU ⋅ kg−1 ⋅ day−1) and E2 (100 μg ⋅ kg−1 ⋅ wk−1) in experiment 1 and relatively high doses of GH (13.5 IU ⋅ kg−1 ⋅ day−1) and E2 (3,500 μg ⋅ kg−1 ⋅ wk−1) in experiment 2 to 2-mo-old HX+OV Sprague-Dawley rats for 6 wk. Our data show that the HX+OV of rats results in diminished periosteal bone formation, longitudinal bone growth, and decreased cancellous bone volume. Administration of either the low or high dose of GH to these rats increased their systemic growth, serum levels of osteocalcin, and cortical bone formation. Either low or high doses of GH or E2 alone only partially prevent cancellous bone loss. However, the combined treatment of GH plus E2 resulted in an additive increase in the cancellous bone mass. We conclude that the additive effect of GH plus E2 on cancellous bone is attributed to the suppressive effect of E2 on bone resorption and the anabolic effect of GH on bone formation.

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