Solid dispersion systems for enhanced dissolution of poorly water-soluble candesartan cilexetil: In vitro evaluation and simulated pharmacokinetics studies.

BACKGROUND: Candesartan cilexetil (CC) is a selective angiotensin II receptor antagonist widely used to treat hypertension. CC is a substrate of P-glycoprotein (P-gp), causing its efflux to the intestinal lumen. It is also practically insoluble in water and has low oral bioavailability (14%). Thus, the current study aims to improve the in vitro dissolution of CC by developing solid dispersion systems (SDSs) and corroborating the in vitro results using a simulated pharmacokinetics study. METHODS: The SDSs were prepared using polyvinyl pyrrolidone (PVP) as a water-soluble polymer, Eudragit E100 (EE100) as a pH-dependent soluble carrier, and a combination of these two polymers. The saturation solubility and the dissolution rate studies of the prepared systems in three dissolution media were performed. The optimized system SE-EE5 was selected for further investigations, including DSC, XRD, FTIR, FESEM, DLS, TSEM, IVIVC convolution study, and stability studies. RESULTS: The solubility of CC significantly increased by a factor of 27,037.344 when formulated as a solid dispersion matrix using EE100 at a ratio of 1:5 (w/w) drug to polymer (SE-EE5 SD), compared to the solubility of the pure drug. The mechanism of solubility and dissolution rate enhancement of CC by the optimized SDS was found to be via the conversion of the crystalline CC into the amorphous form as well as nanoparticles formation upon dissolution at a pH below 5. The instrumental analysis tests showed good compatibility between CC and EE100 and there was no chemical interaction between the drug and the polymer. Moreover, the stability tests confirmed that the optimized system was stable after three months of storage at 25°C. CONCLUSION: The utilization of the solid dispersion technique employing EE 100 polymer as a matrix demonstrates significant success in enhancing the solubility, dissolution, and subsequently, the bioavailability of water-insoluble drugs like CC.

Clinical Characteristics and Etiological Spectrum of Pancytopenia in Pediatric Age Group: A Cross-Sectional Outlook From a Developing Country.

Background The etiologies of pancytopenia in the pediatric age group remain exceedingly ubiquitous and warrant extensive hematological and interventional investigations like bone marrow biopsy. It varies widely from benign nutritional disorders to fatal malignancies. The present study aims to delineate the prevalence of various causes of pancytopenia in the pediatric population. Methods The present cross-sectional study included 96 patients between the age of one month till 15 years with pancytopenia. Study participants were evaluated for various parameters including their demographical details, clinical features, immunization history, and nature of the disorder. The prevalence of various etiologies (nutritional, neoplastic, infectious, autoimmune, and others) of pancytopenia was ascertained. Results Of the 96 patients, 42 (43.75%) were males with a mean age of 69.47 ± 7.12 months. Fever was present in 71.87%, arthralgias in 56.25%, weight loss in 35.41%, and failure to thrive in 18.75% of patients. The bone marrow examination revealed aplastic changes in 36 (37.50%), hyperplastic changes in 21 (21.87%), and normal cellularity in 40.62% of patients. Megaloblastic anemia was the most common nutritional cause of pancytopenia present in 21.85% of cases. Acute lymphoblastic leukemia (ALL) was the most prevalent neoplastic etiology present in 19.79% of patients. Aplastic anemia, miliary tuberculosis, parvovirus B19, and hemolytic anemia were other notable etiologies. Conclusion Megaloblastic anemia and infections like tuberculosis were common treatable etiologies of pancytopenia among the pediatric age group. ALL was the most common neoplastic etiology. Bone marrow biopsy remains crucial in elucidating the various neoplastic and nutritional etiologies of pancytopenia in children.

Performance of Salivary Extracellular RNA Biomarker Panels for Gastric Cancer Differs between Distinct Populations.

Gastric cancer (GC) has the fifth highest incidence among cancers and is the fourth leading cause of cancer-related death GC has predominantly a higher number of cases in certain ethnic groups such as the Korean population. GC found at an early stage is more treatable and has a higher survival rate as compared with GC found at a late stage. However, a diagnosis of GC is often delayed due to the lack of early symptoms and available screening programs in United States. Extracellular RNA (exRNA) is an emerging paradigm; exRNAs have the potential to serve as biomarkers in panels aimed at early detection of cancer. We previously reported the successful use of a panel of salivary exRNA for detecting GC in a high-prevalence Korean cohort, and that genetic changes reflected cancer-associated salivary exRNA changes. The current study is a case-control study of salivary exRNA biomarkers for detecting GC in an ethnically distinct U.S. cohort. A model constructed for the U.S. cohort combined demographic characteristics and salivary miRNA and mRNA biomarkers for GC and yielded an area under the receiver operating characteristic (ROC) curve (AUC) of 0.78. However, the constituents of this model differed from that constructed for the Korean cohort, thus, emphasizing the importance of population-specific biomarker development and validation.

A rare presentation of blastomycosis as a multi-focal infection involving the spine, pleura, lungs, and psoas muscles in a Saudi male patient: a case report.

BACKGROUND: Blastomycosis is a disease caused by the fungus Blastomyces-a thermally dimorphic fungus that can cause granulomatous and/or purulent infection. CASE PRESENTATION: We report here a case of chronic blastomycosis infection in a 24-year-old male patient from Saudi Arabia who presented with recurrent skin abscesses associated with deep-seated and multilevel paraspinal (dorsal and lumbar) collections and bilateral empyema with pulmonary involvement and bilateral psoas abscesses. The diagnosis was made after a CT-guided pleural biopsy revealed the characteristic histopathological findings of blastomycosis. The patient underwent several drainage procedures and was successfully treated with a long-term course of oral itraconazole. CONCLUSIONS: Chronic blastomycosis may have clinical and radiologic features similar to thoracic tuberculosis or malignant disease. There is no definite clinical symptom of blastomycosis, and thus a high degree of suspicion is required for early diagnosis. This case is a rare form of blastomycosis with chronic multifocal purulent infection and is the second case of blastomycosis reported in Saudi Arabia.

Chronic Pulmonary Aspergillosis and Type 2 Diabetes Mellitus Complicating Granulomatosis with Polyangiitis in an Adult Saudi Male: A Case Report.

BACKGROUND: Granulomatosis with polyangiitis (GPA) is an extremely rare autoimmune, necrotizing granulomatous disease of unknown etiology affecting small and medium-sized blood vessels. Chronic pulmonary aspergillosis (CPA) is a rare fungal infection with high morbidity and mortality that usually affects immunocompetent or mildly immunosuppressed patients with underlying respiratory disease. Antifungal agents (voriconazole, itraconazole) are the mainstay of therapy. Intravenous drug therapy (amphotericin B or an echinocandin), alone or in combination with azoles, is the last resort in special situations such as azole failure, resistance, or severe disease. Sometimes CPA and GPA coexist and are difficult to distinguish due to the nonspecific symptoms and similarity of clinical and radiological features, so a high degree of suspicion is required to make the correct diagnosis. CASE PRESENTATION: We reported that a 28-year-old man from Saudi Arabia was diagnosed with GPA. The patient had been complaining of cough, fatigue, polyarthralgia and red eyes for 40 days before he was admitted to our hospital. The diagnosis of GPA was confirmed by clinical and radiological examinations and a pathological report of a lung biopsy, and he was treated with immunosuppressive drugs. The patient's condition was complicated by chronic pulmonary aspergillosis and type 2 diabetes mellitus. Initial treatments included systemic glucocorticoids, methotrexate, followed by rituximab and voriconazole, finally intravenous cyclophosphamide and amphotericin B, with no complete remission. The thoracic surgical team postponed surgical debridement of the significant cavitary lung lesions until the active fungal infection could be brought under control. CONCLUSION: The clinical and radiological features of GPA are similar to those of pulmonary tuberculosis, chronic pulmonary aspergillosis, and lung cancer. The lack of clear clinical symptoms of GPA requires a high degree of suspicion for early diagnosis. This case illustrates the dilemma of diagnosis and treatment of GPA and superimposed fungal infection. Secondary infection, particularly fungal infection, must be considered when GPA cannot be controlled with an immunosuppressant.

Disseminated Mycobacterium bovis Infection Complicating Intravesical BCG Instillation for the Treatment of Superficial Transitional Cell Carcinoma of the Bladder.

BACKGROUND: Intravesical instillation of Bacillus Calmette-Guérin (BCG) remains a first-line treatment for superficial transitional cell carcinoma of the bladder. Although its use is relatively safe, severe complications such as granulomatous hepatitis, osteomyelitis, pneumonitis, and sepsis occur in few patients. Complications of intravesical instillation of BCG can be local or systemic, with early or late presentation. CASE PRESENTATION: Here, we report an 88-year-old man who developed fever, rigors, and episodes of syncope following fourth intravesical BCG instillation for the treatment of superficial transitional cell carcinoma of the bladder. Pancytopenia, disseminated intravascular coagulation, ground glass appearance on computerized tomography of the chest scan in addition to multiple bone marrow granulomas, suggested the diagnosis of disseminated BCG infection. All these features recovered on antituberculosis treatment. CONCLUSION: Our case study highlights the importance of early recognition and prompt treatment of patients with disseminated BCG infection following intravesical instillation. Although isolation of mycobacterium is desirable to make the diagnosis, it is not unusual to have negative smears and cultures and this should not be used to dismiss the possibility of BCG infection.

Cytomegalovirus Reactivation in Adult Recipients of Autologous Stem Cell Transplantation: a Single Center Experience.

INTRODUCTION: Cytomegalovirus (CMV) reactivation and infection are well-recognized complications after allogeneic stem cell transplantation (SCT). Only a few studies have addressed CMV reactivation after autologous SCT (ASCT). METHODS: We retrospectively reviewed medical records of 210 adult patients who underwent ASCT for lymphoma or multiple myeloma (MM) at a single center from January 1(st), 2007 until December 31(st), 2012. All patients were monitored weekly with CMV antigenemia test till day 42 after transplantation, and for 2 months after last positive test in those who had any positive CMV antigenemia test before day 42. RESULTS: Thirty-seven (17.6%) patients had CMV reactivation; 23 patients had lymphoma while 14 had MM as the underlying disease. There was no difference in the rate of CMV reactivation between lymphoma and MM patients (20% versus 14.7%, P = 0.32). The majority of the patients were treated with ganciclovir/valganciclovir, all patients had their reactivation resolved with therapy, and none developed symptomatic CMV infection. None of the patients who died within 100 days of transplantation had CMV reactivation. Log-rank test showed that CMV reactivation had no effect on the overall survival of patients (P values, 0.29). CONCLUSION: In our cohort, CMV reactivation rate after ASCT was 17.6%. There was no difference in reactivation rates between lymphoma and MM patients. With the use of preemptive therapy, symptomatic CMV infection was not documented in any patient in our cohort. CMV reactivation had no impact on patients' survival post ASCT.

Clinical presentations and outcomes of influenza infection among hematology/oncology patients from a single cancer center: pandemic and post-pandemic seasons.

BACKGROUND: Influenza can cause severe infection in hematology/oncology patients. The occurrence of the 2009 pandemic represented an opportunity to study the impact of influenza on such patients in pandemic and post-pandemic seasons. METHODS: We retrospectively reviewed medical records of hematology/oncology patients who had laboratory-confirmed influenza infection during the 2009 pandemic and the first post-pandemic seasons. We assessed influenza-related outcomes in both seasons with emphasis on the development of pneumonia and mortality. We also analyzed factors associated with poor outcomes. RESULTS: We included 350 patients; 207 were diagnosed in the pandemic and 143 in the post-pandemic seasons. Influenza severity was similar in both seasons with no significant differences in the development of pneumonia or death. Infection with the pH1N1 virus was associated with the development of pneumonia (24.7% vs 14.9%, p = 0.029) but did not affect mortality. A multivariate analysis showed that initiation of antiviral treatment after > 48 h, healthcare acquisition of influenza, and low albumin were independent risk factors for the development of pneumonia (p values 0.022, 0.003, and < 0.0001, respectively). A log-rank test showed increased mortality in patients who received therapy > 48 h after onset of symptoms (p = 0.001). CONCLUSIONS: In hematology/oncology patients, influenza was as severe in the post-pandemic as in the pandemic season. Pneumonia developed more commonly in patients infected with pH1N1 virus. Healthcare acquisition of infection and low albumin were associated with the development of pneumonia. Delayed initiation of antiviral treatment was associated with both pneumonia and mortality.

A multicenter study of pandemic influenza A (H1N1) infection in patients with solid tumors in 3 countries: early therapy improves outcomes.

BACKGROUND: Pandemic influenza A (hereafter 2009/H1N1) caused significant morbidity and mortality during the 2009 pandemia. Patients with chronic medical conditions and immunosuppressive diseases had a greater risk of complications. However, data regarding the characteristics and outcome of 2009/H1N1 infection in patients with solid tumors are nonexistent. Herein, the authors describe a series of influenza 2009/H1N1 in patients with solid malignancies at 3 major cancer hospitals worldwide. METHODS: The authors retrospectively reviewed the records of patients with solid organ malignancies and 2009/H1N1 from The University of Texas M. D. Anderson Cancer Center in Houston, Texas; the Mexican National Cancer Institute, Federal District of Mexico; and King Hussein Cancer Center in Amman, Jordan from the period of the 2009 H1N1 pandemia. Data on demographics, disease characteristics, and outcome were extracted. RESULTS: In total, 115 cases were identified during the pandemic influenza among the 3 institutions. High rates of hospitalization (50%), pneumonia (23%), and death (9.5%) were reported. Patients who developed pneumonia and those who died were moderately to severely immunocompromised (P = .001 and P = .006, respectively). A multivariate competing risk analysis demonstrated that a delay >48 hours in starting antiviral therapy was associated significantly with an increased risk of developing pneumonia (P = .013). CONCLUSIONS: The 2009/H1N1 pandemic caused severe illness in immunocompromised patients with cancer who had solid tumors, and heavily immunosuppressed patients were at greater risk of developing pneumonia and death. Early initiation of antiviral therapy is crucial in this patient population to decrease morbidity and probably mortality.

Hepatitis C virus and the lung: implications for therapy.

Hepatitis C virus (HCV) infection is a chronic blood-borne disease that affects > 4,000,000 individuals in the United States. The majority of individuals with HVC infection acquire a chronic hepatitis that predisposes them to the complications of cirrhosis and hepatoma. Chronic HCV infection is, however, associated with multiple extrahepatic manifestations as well, including recently recognized effects on the lung. These include primary effects on lung function, as well as secondary effects in the settings of progressive liver disease and drug treatment for HCV. In this article, we discuss the emerging clinical data that support a role for HCV infection in lung disease, describe the multiple pulmonary manifestations of this viral infection, and outline the therapies available for specific pulmonary complications of chronic HCV infection.

Multiple brain abscesses caused by Cladophialophora bantianum: a challenging case.

Cladophialophora bantianum, a dematiaceous fungus with dark pigmented hyphae, is a rare cause of central nervous system (CNS) infection. This aggressive mold has a high mortality rate, primarily related to its poor response to currently available antifungal therapy. In this article, we report a 74-year-old immunocompromised man who presented with left-sided weakness, sensory deficit, and an abnormal magnetic resonance imaging (MRI) of the brain, which showed multiple ring-enhancing cerebral lesions. The largest lesion measured 4.6 x 3.9 centimeters and was located within the parietal region. He underwent a stereotactic needle biopsy, revealing a pigmented fungus which subsequently grew Cladophialophora bantiana. The patient failed initial monotherapy with liposomal amphotericin B. Later in the patient's hospital course, Flucytosine and voriconazole were added but there was no significant change in the size of the lesions on a repeat brain MRI performed one month into therapy. Surgical resection of the largest lesion was performed. Nevertheless, he continued to deteriorate and therapy was withheld per family request.

Educational attainment and risk of stroke and myocardial infarction.

BACKGROUND: Prior reports have suggested that low educational attainment could be associated with higher incidence of some of the cardiovascular conditions. MATERIAL/METHODS: We evaluated the association of educational attainment (> or =12 years or <12 years) with the incidence of fatal strokes, ischemic stroke, intracerebral hemorrhage, and myocardial infarction in a cohort of 21,443 United States adults who participated in either the First National Health and Nutrition Examination Survey (NHANES-I) Epidemiologic Follow-up Study (NHEFS) or the Second National Health and Nutrition Examination Survey Mortality Follow-up Study (NHANES-II). Cox proportional hazards analyses were used to examine the relationships. RESULTS: During a mean follow-up period of 15.2+/-4.6 years, the risk for all fatal strokes was increased in persons who reported less than 12 years of education. The increased risk was more prominent in persons aged 50 years or less (relative risk [RR], 2.6; 95% confidence interval [CI], 1.1-6.0) compared with persons aged greater than 50 years (RR, 1.3, 95% CI, 1.0-1.6). A higher risk of myocardial infarction associated with less than 12 years of education was observed in both persons aged 50 years or less (RR 1.7, 95% CI 1.2-2.4) and those aged greater than 50 years (RR 1.3, 95% CI 1.1-1.5). The risk for fatal intracerebral hemorrhages (RR 2.0, 95% CI 1.1-3.5) was higher in persons with less than 12 years of education (no significant interaction demonstrated with age). CONCLUSIONS: Educational attainment has a significant effect on the risk for stroke and myocardial infarction, independent of socioeconomic status and other cardiovascular risk factors.

Aggressive mechanical clot disruption and low-dose intra-arterial third-generation thrombolytic agent for ischemic stroke: a prospective study.

OBJECTIVE: We prospectively evaluated the safety and effectiveness of aggressive mechanical disruption of clot in conjunction with intra-arterial administration of a low-dose third-generation thrombolytic agent (reteplase) to treat ischemic stroke in patients who were considered poor candidates for intravenous alteplase therapy or who failed to improve after intravenous thrombolysis. Mechanical clot disruption was used if low-dose pharmacological thrombolysis was ineffective. This strategy was adopted to increase the recanalization rate without increasing the risk of intracerebral hemorrhage. METHODS: Patients were considered poor candidates for intravenous therapy because of severity of neurological deficits, interval from symptom onset to presentation of at least 3 hours, or recent major surgery. We administered a maximum total dose of 4 U of reteplase intra-arterially in 1-U increments via superselective catheterization. After the initial doses were administered, we performed mechanical angioplasty (for proximal occlusion) or snare manipulation (for distal occlusion) at the occlusion site if recanalization had not occurred. The remaining doses of thrombolytics were subsequently administered if required for further recanalization. Angiographic responses were graded using modified Thrombolysis in Myocardial Infarction (TIMI) criteria. Clinical evaluations were performed before and 24 hours, 7 to 10 days, and 1 to 3 months after treatment. RESULTS: Nineteen consecutive patients were treated (mean age, 64.3 +/- 16.2 yr; 10 were men). Initial National Institutes of Health Stroke Scale scores ranged from 11 to 42. Time from onset to treatment ranged from 1 to 9 hours. Occlusion sites were in the following arteries: cervical internal carotid (n = 7), intracranial internal carotid (n = 1), middle cerebral (n = 9), and basilar (n = 2). Of the 19 patients, thrombolysis alone was used in 5 patients, angioplasty was performed in 11 patients, and snare maneuvers were used in 5 patients. Complete restoration of blood flow (modified TIMI Grade 4) was observed in 12 patients, near-complete restoration of flow (modified TIMI Grade 3) in 4 patients, minimal response (modified TIMI Grade 1) in 1 patient, and no response in 2 patients (modified TIMI Grade 0). Neurological improvement at 24 hours (decline of at least 4 points in National Institutes of Health Stroke Scale score) was observed in seven patients. Five other patients experienced further improvement in National Institutes of Health Stroke Scale score at 7 to 10 days. No vessel rupture, dissection, or symptomatic intracranial hemorrhages were observed. At the time of follow-up evaluation, 7 of 19 patients were functionally independent. CONCLUSION: A high rate of recanalization and clinical improvement can be observed in patients with ischemic stroke using low-dose thrombolytic agents with adjunctive mechanical disruption of clot. Moreover, this strategy may reduce the risk of intracerebral hemorrhage observed with thrombolytics.