Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0027947 (neutropenia)
 17,527 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Posaconazole is a triazole antifungal agent, administered as an oral suspension, with an extended spectrum of in vitro activity. Posaconazole 800 mg/day demonstrated clinically relevant activity against a range of fungi in patients with invasive fungal infections who were refractory to, or intolerant of, other antifungal therapy in an open-label, multicentre, phase III study (330 patients received posaconazole and 279 patients served as external controls). In aspergillosis, the global response success rate at the end-of-therapy visit (primary endpoint) was significantly higher in posaconazole recipients than in external controls (42% vs 26%). Posaconazole was also associated with overall success rates of 54% in zygomycosis, 46% in fusariosis, 43% in Pseudallescheria infection, 80% in phaeohyphomycosis and 100% in histoplasmosis. Success rates were 48% in refractory candidiasis, 69% in refractory coccidioidomycosis, 48% in refractory cryptococcal infection and 82% in refractory chromoblastomycosis or mycetoma. Posaconazole also demonstrated potential in febrile neutropenia in an open-label phase II study (success rate of 81% 7 days after the end of treatment). In a noncomparative, multicentre, phase III study in patients with advanced HIV infection who had azole-refractory oropharyngeal and/or oesophageal candidiasis, posaconazole 400 or 800 mg/day resulted in a clinical response in 132 of 176 patients (75%). Oral posaconazole suspension was generally well tolerated in patients with invasive fungal infections, including patients who received treatment for >or=1 year.
 ...
PMID:Posaconazole. 1603 92

The pharmacokinetic profiles, safety, and efficacies of different dosing schedules of posaconazole oral suspension in patients with possible, probable, and proven refractory invasive fungal infection (rIFI) or febrile neutropenia (FN) were evaluated in a multicenter, open-label, parallel-group study. Sixty-six patients with FN and 32 patients with rIFI were randomly assigned to one of three posaconazole regimens: 200 mg four times a day (q.i.d.) for nine doses, followed by 400 mg twice a day (b.i.d.); 400 mg q.i.d. for nine doses, followed by 600 mg b.i.d.; or 800 mg b.i.d. for five doses, followed by 800 mg once a day (q.d.). Therapy was continued for up to 6 months in patients with rIFI or until neutrophil recovery occurred in patients with FN. The 400-mg-b.i.d. dose provided the highest overall mean exposure, with 135% (P = 0.0004) and 182% (P < 0.0001) greater exposure than the 600-mg-b.i.d. and 800-mg-q.d. doses, respectively. However, exposure in allogeneic bone marrow transplant (BMT) recipients (n = 12) was 52% lower than in non-BMT patients. Treatment-related adverse events (occurring in 24% of patients) were mostly gastrointestinal in nature. Twenty-four percent of patients had adverse events leading to premature discontinuation (none were treatment related). In efficacy-evaluable patients, successful clinical response was observed in 43% with rIFI (56% of patients receiving 400 mg b.i.d., 17% receiving 600 mg b.i.d., and 50% receiving 800 mg q.d.) and 77% with FN (74% receiving 400 mg b.i.d., 78% receiving 600 mg b.i.d., and 81% receiving 800 mg q.d.). Posaconazole is well tolerated and absorbed. Divided doses of 800 mg (400 mg b.i.d.) provide the greatest posaconazole exposure.
 ...
PMID:Pharmacokinetics, safety, and efficacy of posaconazole in patients with persistent febrile neutropenia or refractory invasive fungal infection. 1643 24

The pharmacokinetics of posaconazole oral suspension in neutropenic patients undergoing high-dose chemotherapy and stem cell transplantation were evaluated, and the association of plasma posaconazole exposure with the presence and severity of oral mucositis was explored in this nonrandomized, open-label, parallel-group, multiple-dose pharmacokinetic study. Thirty patients were enrolled and received one of three regimens (group I, 200 mg once daily; group II, 400 mg once daily; group III, 200 mg four times daily) for the duration of neutropenia. The mean total exposure for day 1, as shown by the area under the concentration-time curve from 0 to 24 h (AUC(0-24)), was 1.96 mg . h/liter in group I and was 51% higher in group II and in group III. Increases in AUC(0-24) and maximum plasma concentration (C(max)) in groups II and III were dose related. The AUC(0-24) and C(max) values on day 1 were similar between groups II and III. There was interpatient variability of up to 68% in the pharmacokinetic values for our study population. Steady state was attained by days 5 to 6. Average steady-state plasma posaconazole trough values were 192, 219, and 414 ng/ml in groups I, II, and III, respectively. The AUC(0-24) and apparent oral clearance increased by increasing dose and dosing frequency. Mucositis appeared to reduce exposure but did not significantly affect mean total posaconazole exposure (AUC and C(max)) at steady state (P = 0.1483). Moreover, this reduction could be overcome by increasing the total dose and dosing frequency. Posaconazole was safe and well tolerated.
 ...
PMID:Pharmacokinetics and safety of oral posaconazole in neutropenic stem cell transplant recipients. 1672 57

Posaconazole is a lipophilic triazole antifungal agent that is structurally similar to itraconazole but has an expended spectrum of activity including yeast, molds, and dimorphic fungi. Posaconazole was licensed by the European Commission for the treatment of invasive aspergillosis, fusariosis, mycetoma, chromoblastomycosis, and coccidioidomycosis in adults who are refractory, or intolerant to other antifungal agents. Posaconazole was recently indicated for prophylaxis of invasive fungal infections in the following patients: patients receiving remission-induction chemotherapy for acute myelogenous leukemia (AML) or myelodysplastic syndromes (MDS) expected to result in prolonged neutropenia and hematopoietic stem cell transplant (HSCT) recipients who are undergoing high-dose immunosuppressive therapy for versus host disease. The spectacular activity of posaconazole against refractory infections due to zygomycetes is encouraging and suggests using posaconazole in this case. Posaconazole is only available in oral suspension formulation. Posaconazole was well tolerated in clinical trials and has lower drug interaction profile compared to other available azoles.
 ...
PMID:[The latest data on posaconazole]. 1726 54

Posaconazole is a new drug in the triazole class that has recently been investigated in pivotal Phase III clinical trials. Its antifungal activity is based on the inhibition of the fungal ergosterol synthesis. As demonstrated in vitro, posaconazole exhibits fungicidal activity against Aspergillus spp., Candida spp. and zygomycetes. Currently, posaconazole is only available as an oral suspension. Food consumption affects the bioavailability of posaconazole, while the exposure to posaconazole increases in a dose-proportional manner with a saturation of absorption occurring with a daily dose over 800 mg. Posaconazole is well tolerated without an increase in risk of any treatment-related adverse events during prolonged treatment for 6 or more months (n = 108). Posaconazole has been recently approved by the US FDA and other regulatory bodies for the treatment of oropharyngeal candidiasis, and the prophylaxis of invasive Aspergillus and Candida infections in severely immunocompromised patients. As demonstrated in two pivotal Phase III trials, posaconazole prophylaxis of invasive fungal infection in patients severely immunocompromised by graft-versus-host disease (n = 600) or neutropenia (n = 602) is superior to fluconazole and/or itraconazole prophylaxis. Significantly more patients who received posaconazole, instead of fluconazole, as treatment for oropharyngeal candidiasis sustained clinical success after the treatment was stopped. Preliminary data from a subgroup analysis (n = 24) of two salvage therapy trials for invasive fungal infections, as well as single case reports and series and in vitro studies, suggest that posaconazole might be an attractive oral treatment alternative for zygomycosis.
 ...
PMID:Posaconazole: a next-generation triazole antifungal. 1766 96

Posaconazole is a triazole antifungal agent with a spectrum of activity that includes Candida and Cryptococcus species, many molds, and some endemic fungi. Posaconazole has received US Food and Drug Administration approval for the treatment of oropharyngeal candidiasis, including infections refractory to itraconazole and/or fluconazole. It is also approved as prophylaxis for invasive Aspergillus and Candida infections in patients aged >or=13 years who are at high risk of developing these infections, in adult and adolescent hematopoietic stem cell transplant recipients with graft-versus-host disease, and in persons with hematologic malignancies and prolonged neutropenia due to chemotherapy, who are at high risk of developing these infections. Approval for additional indications is being sought. Limited clinical experience suggests efficacy for the treatment of infections due to Zygomycetes and as salvage therapy for patients with invasive aspergillosis and coccidioidomycosis. Currently available only as an oral suspension, posaconazole, which has been well tolerated, requires administration with food or a nutritional supplement to assure adequate bioavailability. Posaconazole is predominantly eliminated in the feces, where it appears as unchanged drug. Metabolism, mostly glucuronidation, plays only a minor role in its elimination, as does renal clearance; as a consequence, dose adjustment is not required in the presence of renal or hepatic insufficiency. Although not a substrate of hepatic CYP450 3A4, posaconazole inhibits this enzyme and thus has the potential for significant pharmacokinetic interactions with drugs metabolized by this isoform. Its use in combination with CYP450 substrates that prolong the QTc interval is contraindicated, as is its use with ergot alkaloids; administration of posaconazole with other substrates and/or inducers of this enzyme system requires caution. Posaconazole is both a substrate and inhibitor of P-glycoprotein. Currently, the major roles for posaconazole in clinical practice are as prophylaxis for neutropenic patients with significant risk of infection with filamentous fungi and as therapy for zygomycoses. It may also have a role in the treatment of other filamentous fungal and some yeast infections, but assessment of its overall place in antifungal therapy awaits the availability of further clinical experience.
 ...
PMID:Reviews of anti-infective agents: posaconazole: a broad-spectrum triazole antifungal agent. 1841 3

Posaconazole is a second-generation triazole antifungal agent with a broad spectrum of activity that includes Aspergillus spp., Candida spp. and the Zygomycetes. In the US, posaconazole oral suspension administered three times daily is indicated for prophylaxis against invasive Aspergillus and Candida infections in patients aged > or =13 years who are at high risk of developing these infections because of immunosuppression, such as haematopoietic stem cell transplant (HSCT) recipients with graft-versus-host disease (GVHD), or those with haematological malignancies with prolonged neutropenia as a result of chemotherapy. EU-approved prophylactic indications for posaconazole are similar to those in the US. Posaconazole provided effective prophylaxis against invasive fungal infections and was generally well tolerated in two large, well designed trials in HSCT recipients with GVHD, or patients receiving induction-remission chemotherapy for acute myeloid leukaemia (AML) or myelodysplastic syndrome (MDS) that was expected to result in prolonged neutropenia. It offers coverage of clinically relevant pathogens and is potentially associated with fewer drug-drug interactions than other licensed triazole antifungal agents. Its usefulness in some patients may be limited by the lack of an intravenous formulation, although one is currently being developed. As with other antifungal agents, concerns remain regarding the potential emergence of resistance to broad-spectrum antifungal prophylaxis with posaconazole. Despite this, posaconazole is a valuable emerging option for use as prophylaxis against invasive fungal infections in immunocompromized patients who are at high risk of developing these infections.
 ...
PMID:Posaconazole : a review of its use in the prophylaxis of invasive fungal infections. 1845 64

There is no widely accepted standard for antifungal prophylaxis in patients with hematologic malignancies. The Infectious Diseases Working Party of the German Society for Haematology and Oncology assigned a committee of hematologists and infectious disease specialists to develop recommendations. Literature data bases were systematically searched for clinical trials on antifungal prophylaxis. The studies identified were shared within the committee. Data were extracted by two of the authors (OAC and MSi). The consensus process was conducted by email communication. Finally, a review committee discussed the proposed recommendations. After consensus was established the recommendations were finalized. A total of 86 trials were identified including 16,922 patients. Only a few trials yielded significant differences in efficacy. Fluconazole 400 mg/d improved the incidence rates of invasive fungal infections and attributable mortality in allogeneic stem cell recipients. Posaconazole 600 mg/d reduced the incidence of IFI and attributable mortality in allogeneic stem cell recipients with severe graft versus host disease, and in patients with acute myelogenous leukemia or myelodysplastic syndrome additionally reduced overall mortality. Aerosolized liposomal amphotericin B reduced the incidence rate of invasive pulmonary aspergillosis. Posaconazole 600 mg/d is recommended in patients with acute myelogenous leukemia/myelodysplastic syndrome or undergoing allogeneic stem cell recipients with graft versus host disease for the prevention of invasive fungal infections and attributable mortality (Level A I). Fluconazole 400 mg/d is recommended in allogeneic stem cell recipients until development of graft versus host disease only (Level A I). Aerosolized liposomal amphotericin B is recommended during prolonged neutropenia (Level B II).
 ...
PMID:Primary prophylaxis of invasive fungal infections in patients with hematologic malignancies. Recommendations of the Infectious Diseases Working Party of the German Society for Haematology and Oncology. 1906 34

Since 2001 five new systemically administered antifungal agents have been approved for clinical use. This represents a major advance for antifungal therapy in haematological malignancy patients undergoing chemotherapy or haematopoietic stem cell transplant (HSCT). The echinocandins are a new class of antifungals with a novel mode of action. Capsofungin has already established itself as a valuable therapy for candidaemia and salvage therapy of invasive aspergillosis. Although both anidulafungin and micafungin are approved for treatment of candidiasis, their role in invasive aspergillosis requires more clinical trial evaluation. Of the two newer triazoles, voriconazole has been recommended in international guidelines as primary therapy for acute invasive aspergillosis. Posaconazole has a broad spectrum of activity in vitro and a potentially key role in antifungal prophylaxis in high-risk HSCT recipients and during prolonged neutropenia. Although some of these drugs have important interactions with other medications, and potential toxicities, they are safer to use and more efficacious than amphotericin B deoxycholate. Their arrival gives more choices to treat rarer mycoses and will facilitate clinical trial assessment of combination therapy of aspergillosis where single agent therapy gives less than 50% success rates.
 ...
PMID:Newer antifungal agents for invasive fungal infections in patients with haematological malignancy. 1912 Mar 71

Invasive Zygomycetes infection complicating prolonged neutropenia is associated with high mortality in the absence of immune recovery. We report a patient who developed disseminated zygomycosis due to Rhizopus microsporus during induction chemotherapy for acute myeloid leukemia. Rescue allogeneic hematopoietic stem cell transplantation (allo-HSCT) was performed as her only chance of cure of this infection and to treat refractory leukemia. Posaconazole combined with liposomal amphotericin B contained the zygomycosis during prolonged neutropenia due to allo-HSCT followed by intense immunosuppression for grade IV acute graft-versus-host disease. Surgical removal of all infected sites after immune recovery, with prolonged posaconazole treatment, ultimately cured the infection. New combination antifungal therapies might sufficiently control disseminated zygomycosis to allow allo-HSCT to be performed, assuring life-saving immune recovery. Surgery appears to be necessary for definite cure of these infections.
 ...
PMID:Disseminated Rhizopus microsporus infection cured by salvage allogeneic hematopoietic stem cell transplantation, antifungal combination therapy, and surgical resection. 2016 67


1 2 3 4 Next >>