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.

Comparison Between Physiological Scores SIPF, CURB-65, and APACHE II as Predictors of Prognosis and Mortality in Hospitalized Patients with COVID-19 Pneumonia: A Multicenter Study, Saudi Arabia.

Background: A coronavirus pandemic (COVID-19) is associated with catastrophic effects on the world with high morbidity and mortality. We aimed to evaluate the accuracy of physiological shock index (SIPF) (shock index and hypoxemia), CURB -65, acute physiology, and chronic health assessment II (APACHE II) as predictors of prognosis and in-hospital mortality in patients with COVID-19 pneumonia. Methods: In Saudi Arabia, a multicenter retrospective study was conducted on hospitalized adult patients confirmed to have COVID-19 pneumonia. Information needed to calculate SIPF, CURB-65, and APACHE II scores were obtained from medical records within 24 hours of admission. Results: The study included 1131 COVID-19 patients who met the inclusion criteria. They were divided into two groups: (A) the ICU group (n=340; 30.1%) and (B) the ward group (n=791; 69.9%). The most common concomitant diseases of patients at initial ICU admission were hypertension (71.5%) and diabetes (62.4%), and most of them were men (63.8%). The overall mortality was 18.7%, and the mortality rate was higher in the ICU group than in the ward group (39.4% vs 9.6%; p < 0.001). The SIPF score showed a significantly higher ability to predict both ICU admission and mortality in patients with COVID-19 pneumonia compared with APACHE II and CURB -65; (AUC 0.89 vs 0.87; p < 0.001) and (AUC 0.89 vs 0.84; p < 0.001) for ICU admission and (AUC 0.90 vs 0.65; p < 0.001) and (AUC 0.90 vs 0.80; p < 0.001) for mortality, respectively. Conclusion: The ability of the SIPF score to predict ICU admission and mortality in COVID-19 pneumonia is higher than that of APACHE II and CURB-65. The overall mortality was 18.7%, and the mortality rate was higher in the ICU group than in the ward group (39.4% vs 9.6%; p < 0.001).

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.

Clustering of Covid-19 infections among healthcare workers: Experience from a tertiary care center in Saudi Arabia.

INTRODUCTION: Coronavirus infectious disease 2019 (COVID-19) had a significant impact on healthcare workers (HCWs) worldwide. Understanding the dynamics of infection transmission is important to develop strategies to prevent its spread. METHODS: A retrospective study of a cohort of HCWs with COVID-19 from a single tertiary care hospital during the first wave of the pandemic. Epidemiological investigations and identification of clusters of infection were done prospectively. RESULTS: A total of 326 HCWs had COVID-19 based on positive polymerase chain reaction tests for SARS-CoV-2. Ten clusters of infection were identified; nine clusters had HCWs as the index cases while one cluster had a patient as the index case. The largest cluster involved 15 transmissions, and one cluster included a secondary transmission. Sharing accommodation and social gatherings were the commonest epidemiological links. The majority of infected HCWs had mild infections, 23 (6%) required hospital admission and 3 (1%) required intensive care; all fully recovered. Majority of infections (80%) were community-acquired. Living in shared accommodation was associated with COVID-19 (120/690 versus 206/1610, P value = .01) while working in COVID-19 designated wards/units was not associated with COVID-19 (52/297 vs 274/2003, P value = .13). CONCLUSIONS: Clustering of COVID-19 was common among HCWs and related to shared accommodation and social gatherings, infection was of mild severity, and was not associated with caring for COVID-19 patients.

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.

Favipiravir versus standard of care in patients with severe COVID-19 infections: A retrospective comparative study.

OBJECTIVE: To assess the efficacy of Favipiravir compared to the standard therapy in treating patients with severe COVID-19 infection. METHODS: This is a retrospective cohort of patients with COVID-19 pneumonia who were treated with favipiravir, versus comparison group that received the standard of care. RESULTS: A total of 226 patients were included; 110 patients received favipiravir and 116 patients received standard of care. Patients who received favipiravir had longer time to recovery (14.2 ± 8.8 versus 12.8 ± 5.2, p = 0.17). Favipiravir was associated with an improved early day 14 mortality (4 [3.6%] versus 11 [9.5%]), p = 0.008), but was associated with a higher day 28 mortality (26 [23.6%] versus 11 [9.5%], p = 0.02). The overall mortality was higher in the favipiravir versus the standard of care group but difference was not statistically significant (33 [30.0%] versus 24 [20.7%], p = 0.10). CONCLUSION: The addition of favipiravir to standard of care was not associated with any improvement in clinical outcomes or mortality. Larger randomized controlled clinical trials are needed to further assess the efficacy of favipiravir.

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.

Revisited Chaos in a Diffusion-Precipitation-Redissolution Liesegang System.

Co(OH)2 Liesegang periodic precipitation systems exhibit oscillations in the number of bands due to band redissolution in high NH4OH concentration. We revisit the problem previously considered (Nasreddine and Sultan, J. Phys. Chem. A 1999, 103, 2934-2940) by rigorously refining the experiments and the Chaos analysis. Chaos is established in this diffusion-precipitation-redissolution system, as is evident from the refined outputs of the Chaos analysis tools. A brief account of possible applications of Chaos in Liesegang systems is presented.

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.

Mycobacterium riyadhense infections.

Mycobacterium riyadhense is a newly described slowly growing, non-tuberculous mycobacterium species. We describe 2 new cases of Mycobacterium riyadhense infections presenting with extra-pulmonary involvement, and reviewed all previously reported cases in the literature. We also describe the spectrum of the disease and explore treatment options based on the experience with the current and previously reported cases.

Clinical aspects and outcomes of 70 patients with Middle East respiratory syndrome coronavirus infection: a single-center experience in Saudi Arabia.

OBJECTIVES: To report the experience with Middle East respiratory syndrome coronavirus (MERS-CoV) infection at a single center in Saudi Arabia. METHODS: Cases of laboratory-confirmed MERS-CoV occurring from October 1, 2012 to May 31, 2014 were reviewed retrospectively. Information sources included medical files, infection control outbreak investigations, and the preventive medicine database of MERS-CoV-infected patients. Data were collected on clinical and epidemiological aspects and outcomes. RESULTS: Seventy consecutive patients were included. Patients were mostly of older age (median 62 years), male (46, 65.7%), and had healthcare acquisition of infection (39, 55.7%). Fever (43, 61.4%), dyspnea (42, 60%), and cough (38, 54.3%) were the most common symptoms. The majority developed pneumonia (63, 90%) and required intensive care (49, 70%). Infection commonly occurred in clusters. Independent risk factors for severe infection requiring intensive care included concomitant infections (odds ratio (OR) 14.13, 95% confidence interval (CI) 1.58-126.09; p=0.018) and low albumin (OR 6.31, 95% CI 1.24-31.90; p=0.026). Mortality was high (42, 60%), and age ≥65 years was associated with increased mortality (OR 4.39, 95% CI 2.13-9.05; p<0.001). CONCLUSIONS: MERS-CoV can cause severe infection requiring intensive care and has a high mortality. Concomitant infections and low albumin were found to be predictors of severe infection, while age ≥65 years was the only predictor of increased mortality.

Ribavirin and interferon alfa-2a for severe Middle East respiratory syndrome coronavirus infection: a retrospective cohort study.

BACKGROUND: Middle East respiratory syndrome coronavirus (MERS-CoV) infection is associated with high mortality and has no approved antiviral therapy. We aimed to compare ribavirin and interferon alfa-2a treatment for patients with severe MERS-CoV infection with a supportive therapy only. METHODS: In this retrospective cohort study, we included adults (aged ≥16 years) with laboratory-confirmed MERS-CoV infection and pneumonia needing ventilation support, diagnosed between Oct 23, 2012, and May 1, 2014, at the Prince Sultan Military Medical City (Riyadh, Saudi Arabia). All patients received appropriate supportive care and regular clinical and laboratory monitoring, but patients diagnosed after Sept 16, 2013, were also given oral ribavirin (dose based on calculated creatinine clearance, for 8-10 days) and subcutaneous pegylated interferon alfa-2a (180 µg per week for 2 weeks). The primary endpoint was 14-day and 28-day survival from the date of MERS-CoV infection diagnosis. We used χ(2) and Fischer's exact test to analyse categorical variables and the t test to analyse continuous variables. FINDINGS: We analysed 20 patients who received ribavirin and interferon (treatment group; initiated a median of 3 days [range 0-8] after diagnosis) and 24 who did not (comparator group). Baseline clinical and laboratory characteristics were similar between groups, apart from baseline absolute neutrophil count, which was significantly lower in the comparator group (5·88 × 10(9)/L [SD 3·95] vs 9·88 × 10(9)/L [6·63]; p=0·023). 14 (70%) of 20 patients in the treatment group had survived after 14 days, compared with seven (29%) of 24 in the comparator group (p=0·004). After 28 days, six (30%) of 20 and four (17%) of 24, respectively, had survived (p=0·54). Adverse effects were similar between groups, apart from reduction in haemoglobin, which was significantly greater in the treatment group than in the comparator group (4·32 g/L [SD 2·47] vs 2·14 g/L [1·90]; p=0·002). INTERPRETATION: In patients with severe MERS-CoV infection, ribavirin and interferon alfa-2a therapy is associated with significantly improved survival at 14 days, but not at 28 days. Further assessment in appropriately designed randomised trials is recommended. FUNDING: None.

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.

Central nervous system infection caused by Morganella morganii.

Central nervous system (CNS) infection with Morganella morganii is very rare. We describe a 38-year-old female patient with frontal brain abscess caused by M morganii who was unsuccessfully treated. We also review all reported cases of Morganella CNS infections with an emphasis on treatment modalities and outcomes. Aggressive surgical management and appropriate antimicrobial therapy can lead to cure, but the mortality rate for these infections remains high.

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.