Oral mucositis (OM) is a common adverse effect resulting from cancer therapy. The OM it has implications that may compromise oncologic treatment and decrease the patient's quality of life. The ...therapeutic options to prevent or treat the symptoms of OM are scarce; there is no effective therapy that improves the symptoms. Based on the need for further research for the treatment of OM, the present study objective was to evaluate the effect of telmisartan (TELM) on the OM induced by 5-fluorouracil (5-FU), using as animal model Golden Syrian hamsters. 5-FU followed by mechanical trauma on day 4 was used to induce OM in hamsters. Euthanasia occurred on the day 10. The experiments were constituted by the groups saline, mechanical trauma, 5-FU, and TELM in three doses (1, 5, or 10 mg/kg). Macroscopic, histopathological, and immunohistochemical analyses as well as immunofluorescence experiments were performed on the oral mucosa of the animals. The samples also were used for analysis enzyme-linked immunosorbent assays and quantitative real-time polymerase chain reactions (qPCR). TELM (5 or 10 mg/kg) was able to reduce the inflammatory ulceration and infiltration in the oral mucosa of the animals, decreasing the levels of the cytokines TNF-α and IL-1β. These treatments was minimize the immunostaining for cyclooxygenase-2, matrix metalloproteinase-9, transforming growth factor-β, and smad 2/3. The nuclear transcription factor kappa B (NFκB) p65 and inducible nitric oxide synthase were reduced in the oral mucosa. Finally, TELM (10 mg/kg) increased the PPARγ gene expression and reduced STAT1 and NFκB p65 gene expression relative to the 5-FU group. Therefore, TELM prevents the OM produced by 5-FU on animal model.
Abstract
Background
Histoplasmosis is a major AIDS-defining illness in Latin America. Liposomal amphotericin B (L-AmB) is the drug of choice for treatment, but access is restricted due to the high ...drug and hospitalization costs of the conventional long regimens.
Methods
Prospective randomized multicenter open-label trial of 1- or 2-dose induction therapy with L-AmB versus control for disseminated histoplasmosis in AIDS, followed by oral itraconazole therapy. We randomized subjects to: (i) single dose 10 mg/kg of L-AmB; (ii) 10 mg/kg of L-AmB on D1, and 5 mg/kg of L-AmB on D3; (iii) 3 mg/kg of L-AmB daily for 2 weeks (control). The primary outcome was clinical response (resolution of fever and signs/symptoms attributable to histoplasmosis) at day 14.
Results
A total of 118 subjects were randomized, and median CD4+ counts, and clinical presentations were similar between arms. Infusion-related toxicity, kidney toxicity at multiple time-points, and frequency of anemia, hypokalemia, hypomagnesemia, and liver toxicity were similar. Day 14 clinical response was 84% for single-dose L-AmB, 69% 2-dose L-AmB, and 74% for control arm (P = .69). Overall survival on D14 was 89.0% (34/38) for single-dose L-AmB, 78.0% (29/37) for 2-dose L-AmB, and 92.1% (35/38) for control arm (P = .82).
Conclusions
One day induction therapy with 10 mg/kg of L-AmB in AIDS-related histoplasmosis was safe. Although clinical response may be non-inferior to standard L-AmB therapy, a confirmatory phase III clinical trial is needed. A single induction dose would markedly reduce drug-acquisition costs (>4-fold) and markedly shorten and simplify treatment, which are key points in terms of increased access.
This is the first trial to demonstrate that AIDS patients with disseminated histoplasmosis can be safely and effectively treated with a single high dose of liposomal amphotericin B (10 mg/kg).
Graphical Abstract
Graphical Abstract
This graphical abstract is also available at Tidbit https://tidbitapp.io/tidbits/single-high-dose-of-liposomal-amphotericin-b-in-hiv-aids-related-disseminated-histoplasmosisa-randomized-trial
Histoplasmosis is a major AIDS-defining illness in Latin America. Liposomal amphotericin B (L-AmB) is the drug of choice for treatment, but access is restricted due to the high drug and ...hospitalization costs of the conventional long regimens.
Prospective randomized multicenter open-label trial of one or two-dose induction therapy with L-AmB versus control for disseminated histoplasmosis in AIDS, followed by oral itraconazole therapy. We randomized subjects to: (i) Single dose 10 mg/kg of L-AmB; (ii) 10 mg/kg of L-AmB on D1, and 5 mg/kg of L-AmB on D3; (iii) 3 mg/kg of L-AmB daily for 2 weeks (control). The primary outcome was clinical response (resolution of fever and signs/symptoms attributable to histoplasmosis) at day 14.
A total of 118 subjects were randomizedMedian CD4+ counts and clinical presentations were similar between arms. Infusion-related toxicity, kidney toxicity at multiple time-points and frequency of anemia, hypokalemia, hypomagnesemia, and liver toxicity were similar. Day 14 clinical response was 84% for Single-dose L-AmB, 69% Two-dose L-AmB, and 74% Control arm (p=0.69). Overall survival on D14 was 89.0% (34/38) for Single-dose L-AmB, 78.0% (29/37) for Two-dose L-AmB, and 92.1% (35/38) for Control arm (p=0.82).
One day induction therapy with 10 mg/kg of L-AmB in AIDS-related histoplasmosis was safe. Although clinical response may be non-inferior to standard L-AmB therapy, a confirmatory phase III clinical trial is needed. A single induction dose would markedly reduce drug-acquisition costs (>4-fold) and markedly shorten and simplify treatment, which are key points in terms of increased access.
Neq135 is the first low micromolar trypanosomatidae inhibitor acting against Trypanosoma cruzi glyceraldehyde 3-phosphate dehydrogenase (TcGAPDH). It binds to the NAD+ site, being selective in vitro ...toward the parasite.
The 1,4-dihydro-4-oxoquinoline ribonucleoside, Neq135, is the first low micromolar trypanosomatidae inhibitor to show good ligand efficiency (0.28kcalmol−1atom−1) and good ligand lipophilicity efficiency (0.37kcalmol−1atom−1) when acting against Trypanosoma cruzi glyceraldehyde 3-phosphate dehydrogenase (TcGAPDH). This and other six ribonucleosides were synthesized using our in-house technology, and assayed against the GAPDH NAD+ site using isothermal titration calorimetry (ITC). Compound Neq135 had acceptable in vitro cytotoxicity, inhibited TcGAPDH with a Kiapp value of 16μM and killed the trypomastigote form of Trypanosoma cruzi Tulahuen strain with a concentration similar to that displayed by the control drug benznidazole. Neq135 is tenfold lower kinetic affinity against hGAPDH and does not kill Balb-c fibroblast nor spleen mouse cells. These results emphasize the possibility of integrating ligand- and target-based designs to uncover potent and selective TcGAPDH inhibitors that expands the opportunity for further medicinal chemistry endeavor towards NAD+ TcGAPDH site.
Purpose: Human Immunodefiency Virus (HIV) protease inhibitors (PI) remain a crucial component of highly active therapy (HAART) and recently have been demonstrated to have potent antitumor effect on a ...wide variety of tumor cell lines. However, discontinuation of therapy is an important issue, which may be related to various side-effects, especially diarrhea. The aim of this study was to evaluate the effects of nelfinavir (NFV), an HIV PI, and of alanyl-glutamine (AQ) supplementation, on intestinal cell migration, proliferation, apoptosis and necrosis, using IEC-6 cells and on intestinal crypt depth, villus length, villus area, mitotic index and apoptosis in Swiss mice. Methods: Migration was evaluated at 12 and 24 h after injury using a wound healing assay. Cellular proliferation was measured indirectly at 24 and 48 h using tetrazolium salt WST-1. Apoptosis and necrosis were measured by flow cytometry using the Annexin V assay. Intestinal morphometry and mitotic index in vivo were assessed following a seven-day treatment with 100 mg/kg of NFV, given orally. In vivo proliferation and apoptosis were evaluated by intestinal crypt mitotic index and immunohistochemistry, respectively. Results: In vitro, AQ supplementation enhanced IEC-6 cell migration and proliferation, following challenge with NFV. In vivo, AQ increased intestinal villus length, villus area, crypt depth and cell proliferation and cell migration, following treatment with NFV. AQ did not decrease cell death induced by NFV both in vivo and in vitro. Conclusions: AQ supplementation is potentially beneficial in preventing the effects of PIs, such as NFV, in the intestinal tract.
Abstract
Background
Histoplasmosis is a major AIDS-defining infection in Latin America. Liposomal amphotericin B (L-AmB) is the drug of choice for treatment, but access is limited.
Methods
...Prospective randomized open-label trial of induction therapy with L-AmB for disseminated histoplasmosis in AIDS, followed by oral itraconazole therapy (started on the day after L-AmB was finished). We conducted this trial at 6 centers in Brazil (2019-2022). We randomized subjects to 3 arms of: Single dose 10 mg/kg of L-AmB;10 mg/kg of L-AmB on D1, and 5 mg/kg of L-AmB on D3;3 mg/kg of L-AmB for 2 weeks (control).
As a non-inferiority trial, 80% power could detect > 20% non-inferiority margin for a one-sided alpha=0.05 with a sample size of 29 subjects per arm. Clinical response at day 14 was the primary outcome.
Results
Of 512 screened patients, 118 subjects were randomized (Arm 1, n=40; Arm 2, n=39; Arm 3, n=39). Median CD4 was 25 cells/µL. Subjects presented with weight loss (70%), pulmonary complaints (67%), fever (66%), abdominal findings (59%), skin lesions (38%), lymphadenopathy (38%), and oral lesions (36%). Clinical and lab findings did not differ among arms. Histoplasmosis diagnosis was predominantly via urine antigen (97%).
Infusion-related toxicity on D1 was similar in each arm (p=0.56). Kidney toxicity was similar on D3 (p=0.83), D7 (p=0.10), and D14 (p=0.17) as was frequency of anemia, hypokalemia, hypomagnesemia, and liver toxicity (all p >0.05). No subject withdrew due to drug toxicities.
D14 clinical response was 82% for Arm 1, 68% Arm 2, and 72% Arm 3 (p=0.69). Absolute risk difference for Arm 1 was 10.3% (95%CI, -8.3% to 28.8%) vs. Arm 3 controls; Arm 2 was -4.2% (95%CI, -24.9% to 16.4%) to controls. Overall survival on D14 was 89.5% (34/38) for Arm 1, 78.4% (29/37) for Arm 2, and 92.1% (35/38) for Arm 3 (p=0.82); 2 subjects were excluded from efficacy analysis due to meningitis and tuberculosis, and 3 were lost to follow up.
Conclusion
Induction therapy with 10 mg/kg of L-AmB in AIDS-related histoplasmosis was safe. Although efficacy is likely to be non-inferior to standard L-AmB therapy, a confirmatory phase III trial is needed. Such a strategy would markedly reduce drug-acquisition costs (> 4-fold), therefore improving access to L-AmB across the globe.
Disclosures
Alessandro C. Pasqualotto, FECMM, Gilead: Grant/Research Support|United Medical: Advisor/Consultant|United Medical: Honoraria Diego R. Falci, MD, United Medical: Advisor/Consultant|United Medical: Honoraria Andrej Spec, MD, MSCI, Astellas: Grant/Research Support Dennis Israelski, MD, Gilead Sciences: Empoyee.
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