Invasive Cryptococcosis and adalimumab treatment.
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ABSTRACT:
SUBMITTER: Horcajada JP
PROVIDER: S-EPMC2792838 | biostudies-literature | 2007 Jun
REPOSITORIES: biostudies-literature
Publications
Invasive Cryptococcosis and adalimumab treatment.
Horcajada Juan P JP Peña Jose L JL Martínez-Taboada Víctor M VM Pina Trinitario T Belaustegui Isabel I Cano María Eliecer ME García-Palomo Daniel D Fariñas M Carmen MC
Emerging infectious diseases 20070601 6
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Project description:Cryptococcosis is an important opportunistic infection and a leading cause of meningitis in patients with HIV infection. The antifungal pharmacological treatment is limited to amphotericin B, fluconazole and 5- flucytosine. In addition to the limited pharmacological options, the high toxicity, increased resistance rate and difficulty of the currently available antifungal molecules to cross the blood-brain barrier hamper the treatment. Thus, the search for new alternatives for the treatment of cryptococcal meningitis is extremely necessary. In this review, we describe the therapeutic strategies currently available, discuss new molecules with antifungal potential in different phases of clinical trials and in advanced pre-clinical phase, and examine drug nanocarriers to improve delivery to the central nervous system.
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Project description:BackgroundInvasive fungal diseases (IFD) caused by Cryptococcus and dimorphic fungi are associated with significant morbidity and mortality. Isavuconazole (ISAV) is a novel, broad-spectrum, triazole antifungal agent (IV and by mouth [PO]) developed for the treatment of IFD. It displays potent activity in vitro against these pathogens and in this report we examine outcomes of patients with cryptococcosis or dimorphic fungal infections treated with ISAV.MethodsThe VITAL study was an open-label nonrandomized phase 3 trial conducted to evaluate the efficacy and safety of ISAV treatment in management of rare IFD. Patients received ISAV 200 mg 3 times daily for 2 days followed by 200 mg once-daily (IV or PO). Proven IFD and overall response at end of treatment (EOT) were determined by an independent, data-review committee. Mortality and safety were also assessed.ResultsThirty-eight patients received ISAV for IFD caused by Cryptococcus spp. (n = 9), Paracoccidioides spp. (n = 10), Coccidioides spp. (n = 9), Histoplasma spp. (n = 7) and Blastomyces spp. (n = 3). The median length of therapy was 180 days (range 2-331 days). At EOT 24/38 (63%) patients exhibited a successful overall response. Furthermore, 8 of 38 (21%) had stable IFD at the end of therapy without progression of disease, and 6 (16%) patients had progressive IFD despite this antifungal therapy. Thirty-three (87%) patients experienced adverse events.ConclusionsISAV was well tolerated and demonstrated clinical activity against these endemic fungi with a safety profile similar to that observed in larger studies, validating its broad-spectrum in vitro activity and suggesting it may be a valuable alternative to currently available agents.Clinical trials registrationNCT00634049.
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Project description:Cryptococcosis has evolved into a major invasive fungal disease over the last century. Its primary epidemiology has been focused on three major outbreaks of disease that reflects both changing environmental exposures and growth of host risk factors. The molecular understandings of yeast pathobiology have been bolstered by identification of the yeast's dynamic genomic structures and functions. It is during these new insights into epidemiology and pathobiology that we have also improved our diagnosis of this infection with a new point-of-care, simple, cheap test which utilizes a lateral flow assay for antigen detection. With methods for effective identification of Cryptococcus in the host, the principles for management of this deadly infection include both use of old drugs and new insights into treatment strategies to improve outcome. In this review there are a series of recent insights, opinions, and facts which attempt to summarize our present knowledge base for this deadly fungal central nervous system infection with a particular emphasis on its diagnosis and management.
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Project description:BackgroundCryptococcosis is one of the most devastating fungal infections in humans. Despite the disease's clinical importance, current therapy is based on limited antifungals that are either toxic, inefficient, unavailable worldwide, or that quickly lead to resistance.ObjectivesThe goal of this study was to provide insight into the future of cryptococcosis treatment by describing the patent scenario in this field.MethodsWe identified and analysed patent documents revealing compounds with anti-cryptococcal activity supported by experimental evidence.FindingsPatenting in this field has been historically low, with an overall tendency of increase since 2012. Most applications are single filings, suggesting that they do not encompass strategic inventions requiring broad protection. Research and development essentially took place in China and the United States, which also represent the main countries of protection. Both academic and corporate institutions contributed to patenting in this field. Universities are the leading actors, with the highest patent family counts.ConclusionThe low number of patents in this field indicates that efforts to mitigate the unmet needs for cryptococcosis treatment remain insufficient. Without investment to drive research and innovation, patients will likely continue to face inadequate assistance. Given the current scenario characterised by poor funding and low interest for technological development, drug repurposing may be the best alternative for cryptococcosis treatment.
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Project description:Many infectious diseases disproportionately affect people in the developing world. Cryptococcal meningitis is one of the most common mycoses in HIV-AIDS patients, with the highest burden of disease in sub-Saharan Africa. Current best treatment regimens still result in unacceptably high mortality rates, and more effective antifungal agents are needed urgently. Drug development is hampered by the difficulty of developing effective antifungal agents that are not also toxic to human cells, and by a reluctance among pharmaceutical companies to invest in drugs that cannot guarantee a high financial return. Drug repurposing, where existing drugs are screened for alternative activities, is becoming an attractive approach in antimicrobial discovery programs, and various compound libraries are now commercially available. As these drugs have already undergone extensive optimisation and passed regulatory hurdles this can fast-track their progress to market for new uses. This study screened the Screen-Well Enzo library of 640 compounds for candidates that phenotypically inhibited the growth of Cryptococcus deuterogattii. The anthelminthic agent flubendazole, and L-type calcium channel blockers nifedipine, nisoldipine and felodipine, appeared particularly promising and were tested in additional strains and species. Flubendazole was very active against all pathogenic Cryptococcus species, with minimum inhibitory concentrations of 0.039-0.156 μg/mL, and was equally effective against isolates that were resistant to fluconazole. While nifedipine, nisoldipine and felodipine all inhibited Cryptococcus, nisoldipine was also effective against Candida, Saccharomyces and Aspergillus. This study validates repurposing as a rapid approach for finding new agents to treat neglected infectious diseases.
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Project description:A 45-year-old male with cardiac sarcoidosis verified by cardiac biopsy presented with multiple coexisting arrhythmias, including ventricular tachycardia of more than 1000 episodes per 24 h, paroxysmal atrial fibrillation, and third-degree atrioventricular block. He did not respond to corticosteroids dose of 20-60 mg once daily and mycophenolate mofetil dose of 1 g twice daily for 6 months. Cardiac magnetic resonance (CMR) demonstrated inflammation and late gadolinium enhancement on right ventricular wall and interventricular septum. Positron emission tomography-computed tomography (PET-CT) showed multifocal 18 F-fluorodeoxyglucose uptake in the heart. We replaced mycophenolate mofetil with adalimumab, a tumour necrosis factor-α inhibitor. After 3 months, his arrhythmias improved significantly, manifesting as premature ventricular contractions of only 500 beats per 24 h and first-degree atrioventricular block. CMR showed a significant reduction in inflammation and late gadolinium enhancement, and PET-CT showed a complete resolution of fluorodeoxyglucose uptake.
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Project description:Cryptococcosis is an invasive fungal disease with increased morbidity in China over the past two decades. Cryptococci can infect immunocompromised hosts as well as immunocompetent ones. In this study, we reviewed data of 71 inpatients with cryptococcosis at Ningbo First Hospital from May 2010 to May 2020 and compared the clinical profiles of pulmonary cryptococcosis (PC) and extrapulmonary cryptococcosis (EPC). Of 71 patients (38 males, 33 females), 70 were non-HIV. The annual inpatient population increased dramatically, especially in the PC group. PC was confirmed in 77.46% (55/71) of cases by pathology. The rest were EPC including intracranial infection (15.49%, 11/71) and cryptococcemia (7.04%, 5/71). Compared with PC, a larger proportion of EPC patients were found to have immunocompromised conditions judged by predisposing factors (p < 0.01), or detectable humoral or cellular immunodeficiency. Fever and headache were more common in EPC patients (p < 0.001). Patients with EPC had lower serum sodium level (p = 0.041), lower monocyte counts (p = 0.025) and higher C-reactive protein (p = 0.012). In our study, the sensitivity of cryptococcus antigen detection for EPC was 100% regardless of sample type, while serum lateral flow assay (LFA) tested negative in 25% (5/20) of PC. Immunocompromised hosts are more likely to suffer from EPC than PC.
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Project description:ObjectiveTo evaluate the efficacy of adalimumab in the healing of draining fistulas in patients with active Crohn's disease (CD).DesignA phase III, multicentre, randomised, double-blind, placebo controlled study with an open-label extension was conducted in 92 sites.PatientsA subgroup of adults with moderate to severely active CD (CD activity index 220-450) for >or=4 months who had draining fistulas at baseline.InterventionsAll patients received initial open-label adalimumab induction therapy (80 mg/40 mg at weeks 0/2). At week 4, all patients were randomly assigned to receive double-blind placebo or adalimumab 40 mg every other week or weekly to week 56 (irrespective of fistula status). Patients completing week 56 of therapy were then eligible to enroll in an open-label extension.Main outcome measuresComplete fistula healing/closure (assessed at every visit) was defined as no drainage, either spontaneous or with gentle compression.ResultsOf 854 patients enrolled, 117 had draining fistulas at both screening and baseline (70 randomly assigned to adalimumab and 47 to placebo). The mean number of draining fistulas per day was significantly decreased in adalimumab-treated patients compared with placebo-treated patients during the double-blind treatment period. Of all patients with healed fistulas at week 56 (both adalimumab and placebo groups), 90% (28/31) maintained healing following 1 year of open-label adalimumab therapy (observed analysis).ConclusionsIn patients with active CD, adalimumab therapy was more effective than placebo for inducing fistula healing. Complete fistula healing was sustained for up to 2 years by most patients in an open-label extension trial.
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