Pioglitazone as an adjuvant of amphotericin B for the treatment of cryptococcosis

Ribeiro, Noelly Queiroz; Santos, Anderson Philip Nonato; Emídio, Elúzia Castro Peres; Costa, Marliete Carvalho; Freitas, Gustavo José Cotta; Carmo, Paulo Henrique Fonseca do; Silva, Monique Ferreira; Brito, Camila Bernardo de; Souza, Daniele G.; Santos, Danielle Anjos dos

doi:10.1016/j.ijantimicag.2019.06.020

Cited by 16 publications

(13 citation statements)

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“…PC is confirmed mainly by pathological examination (3,4) of surgical specimens, percutaneous lung biopsy samples, or bronchoscopic biopsy samples. The treatment of PC includes surgery and medical treatment (5)(6)(7). Surgical treatment has the advantages of radical local resection and a short treatment period.…”

Section: Introductionmentioning

confidence: 99%

Clinical analysis of 16 cases of pulmonary cryptococcosis in patients with normal immune function

Zhang

Xue

et al. 2020

Ann Palliat Med

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Background: Pulmonary cryptococcosis (PC) is an invasive pulmonary fungal disease caused by Cryptococcus neoformans or Cryptococcus gattii. Cryptococcus is the opportunistic pathogen. Immune damage and chronic consumptive diseases are the high risk. The prevalence of cryptococcus infection is 5% to 10% in individuals with weakened immune function. In recent years, with the application of glucocorticoids, antitumor drugs, and broad-spectrum antibiotics, the prevalence of cryptococcal infection has increased yearly. Cryptococcus infection can also occur in normal people without underlying diseases. One in every 100,000 individuals with normal immune function is also affected, but these cases are often misdiagnosed due to inadequate understanding and low awareness of PC in individuals with normal immune function. In this study, we investigated the clinical characteristics of PC in patients with normal immune function to improve the diagnosis and treatment of these cases.Methods: We retrospectively analyzed the clinical, imaging and pathological data of 16 patients with pulmonary cryptococcosis treated at Beijing Shijitan Hospital between 2010 and 2017.Results: Of the 16 patients with disseminated cryptococcosis, 6 were men, and 10 were women; their ages were 35 to 76 years (median: 53 years). Initial symptoms were cough, sputum, chest pain, and fever. Thirteen patients had a history of chronic disease or tumor, including diabetes and bronchial asthma (n=2), simple hypertension (n=2), chronic bronchitis (n=2), diabetes and hypertension (n=5), previous tuberculosis (n=1), and previous lung cancer surgery (n=1). Chest computed tomography (CT) in these 16 patients showed single or multiple nodules and masses (n=14), lobar consolidation (n=1), and diffuse mixed lesions (n =1).Lung biopsy showed granulomatous lesions in these 16 patients. Cryptococcus neoformans was identified with Grocott's methenamine silver and Grocott's methenamine silver (GMS) stains. Fourteen patients received fluconazole alone; two patients with intracranial infection received fluconazole combined with amphotericin B. Five patients improved significantly, and nine patients improved with significant lesion absorption. Conclusions:The clinical manifestations of PC are nonspecific in patients with normal immune function.Lung biopsy and cryptococcus antigen tests of cerebrospinal fluid are valuable diagnostic aids. Fluconazole is an effective treatment for disseminated cryptococcal infection.

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Section: Introductionmentioning

confidence: 99%

Clinical analysis of 16 cases of pulmonary cryptococcosis in patients with normal immune function

Zhang

Xue

et al. 2020

Ann Palliat Med

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“…PIO has been shown to be a promising adjuvant for the treatment of cryptococcosis in murine model, since its association with AMB reduced toxicity, allowing an increased mice survival and decreased fungal burden in lungs and brain [ 11 ]. Despite the promising results, no clinical trial has been performed so far in cryptococcosis patients.…”

Section: Discussionmentioning

confidence: 99%

“…According to previous data [ 25 ], the mortality rate of patients 10 weeks after the beginning of treatment is 41.2%. In our pre-clinical study for PIO repositioning, the survival after 10 wees of the protocol was about 100% [ 11 ]. The current mortality rate of cryptococcosis patients at the EMH is 29.8%, which corresponds to a success rate of 70.2%.…”

Section: Methodsmentioning

confidence: 99%

“…We used the concept of drug repurposing, which is based on the use of an established drug (with known pharmacology and toxicology) for a new useful indication [ 10 ]. In this context, several studies demonstrated that the antidiabetic PPARγ agonist pioglitazone (PIO) has anti-inflammatory effects [ 11 ], and increases host tolerance in malaria by activation of pathways that leads to neuroprotective and neuroregenerative effects. These effects are also useful for central nervous system (CNS) injury, stroke and ischemia [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

“…PIO reduced AMB toxicity by decreasing creatinine and liver transaminase levels, improving mice's physiology. Overall, PIO + AMB had additional benefits than AMB alone, with increased mice survival, decreased morbidity and reduced fungal burden, without altering blood glucose levels [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

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Randomized, phase 1/2, double-blind pioglitazone repositioning trial combined with antifungals for the treatment of cryptococcal meningitis – PIO study

Gouveia-Eufrásio

Ribeiro

Santos

et al. 2021

Contemporary Clinical Trials Communications

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Background Cryptococcosis affects more than 220,000 patients/year, with high mortality even when the standard treatment [amphotericin B (AMB), 5-flucytosin (5-FC) and fluconazole] is used. AMB presents high toxicity and 5-FC is not currently available in Brazil. In a pre-clinical study, pioglitazone (PIO - an antidiabetic drug) decreased AMB toxicity and lead to an increased mice survival, reduced morbidity and fungal burden in brain and lungs. The aim of this trial is to evaluate the efficacy and safety of PIO combined with standard antifungal treatment for human cryptococcosis. Methods A phase 1/2, randomized, double blind, placebo-controlled trial will be performed with patients from Belo Horizonte, Brazil. They will be divided into three groups (placebo, PIO 15 mg/day or PIO 45 mg/day) and will receive an additional pill during the induction phase of cryptococcosis’ treatment. Our hypothesis is that treated patients will have increased survival, so the primary outcome will be the mortality rate. Patients will be monitored for survival, side effects, fungal burden and inflammatory mediators in blood and cerebrospinal fluid. The follow up will occur for up 60 days. Conclusions We expect that PIO will be an adequate adjuvant to the standard cryptococcosis’ treatment. Trial registration ICTRP/WHO (and International Clinical Trial Registry Plataform (ICTRP/WHO) ( http://apps.who.int/trialsearch/Trial2.aspx?TrialID=RBR-9fv3f4 ), RBR-9fv3f4 ( http://www.ensaiosclinicos.gov.br/rg/RBR-9fv3f4 ). UTN Number: U1111-1226-1535. Ethical approvement number: CAAE 17377019.0.0000.5149.

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Drug repositioning of benzimidazole anthelmintics in the treatment of cryptococcosis: a review

2021

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Pioglitazone as an adjuvant of amphotericin B for the treatment of cryptococcosis

Cited by 16 publications

References 28 publications

Clinical analysis of 16 cases of pulmonary cryptococcosis in patients with normal immune function

Clinical analysis of 16 cases of pulmonary cryptococcosis in patients with normal immune function

Randomized, phase 1/2, double-blind pioglitazone repositioning trial combined with antifungals for the treatment of cryptococcal meningitis – PIO study

Drug repositioning of benzimidazole anthelmintics in the treatment of cryptococcosis: a review

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