Pharmaceutical amorphous solid dispersion: A review of manufacturing strategies.

Amorphous solid dispersions (ASDs) are popular for enhancing the solubility and bioavailability of poorly water-soluble drugs. Various approaches have been employed to produce ASDs and novel techniques are emerging. This review provides an updated overview of manufacturing techniques for preparing ASDs. As physical stability is a critical quality attribute for ASD, the impact of formulation, equipment, and process variables, together with the downstream processing on physical stability of ASDs have been discussed. Selection strategies are proposed to identify suitable manufacturing methods, which may aid in the development of ASDs with satisfactory physical stability.

Effect of COVID-19 on the Organs.

The COVID-19 pandemic that first became apparent in Wuhan, China, is now infecting millions all over the world. This is a review of COVID-19's extensive effects on virtually all the organs. It causes inflammation, endotheliitis, vasoconstriction, hypercoagulability, and edema. Lymphocytopenia, elevated D-dimer, elevated fibrin degradation products (FDPs), and disseminated intravascular coagulation (DIC) are observed. Deep vein thrombosis (DVT), venous thromboembolism, pulmonary embolism (PE), systemic and pulmonary arterial thrombosis and embolism, ischemic stroke, and myocardial infarction (MI) are reported. In the heart it can cause acute coronary syndrome, congestive heart failure, myocarditis, and arrhythmias. Kidney injury is usually secondary to systemic abnormalities. Stroke occurs even in young patients. Delirium and seizures are common. Anosmia and impaired sense of taste are reported. Psychological problems are common among patients as well as providers. Stool may contain virus. Lactate dehydrogenase may be elevated. Various skin manifestations including patchy erythematous rash are reported.

Risk of COVID-19 due to Shortage of Personal Protective Equipment.

The supply of personal protective equipment (PPE) is inadequate throughout the United States and the world. This is especially true of N95 respirators. The cost of PPE is high. There are numerous cases of providers working with inadequate PPE and being disciplined on complaining. In the United States, thousands of providers have contracted COVID-19, in part due to inadequate PPE. Extended use and reuse of N95 respirators has been permitted by the Centers for Disease Control and Prevention (CDC). The N95 respirators can be sterilized utilizing vaporized hydrogen peroxide, ultraviolet germicidal irradiation, or dry heat at 70°C-80°C. The risk to providers due to inadequate PPE increases with their age and presence of comorbidities. African-Americans and Latinos are at a greater risk. CDC recommends that in the absence of appropriate PPE, "exclude healthcare personnel at higher risk for severe illness from COVID-19 from contact with known or suspected COVID-19 patients." Providing care without appropriate PPE should not be a condition of employment for any provider, especially for the ones in high-risk category.

Management of the Traumatized Airway.

There is a lack of evidence-based approach regarding the best practice for airway management in patients with a traumatized airway. General recommendations for the management of the traumatized airway are summarized in table 5. Airway trauma may not be readily apparent, and its evaluation requires a high level of suspicion for airway disruption and compression. For patients with facial trauma, control of the airway may be significantly impacted by edema, bleeding, inability to clear secretions, loss of bony support, and difficulty with face mask ventilation. With the airway compression from neck swelling or hematoma, intubation attempts can further compromise the airway due to expanding hematoma. For patients with airway disruption, the goal is to pass the tube across the injured area without disrupting it or to insert the airway distal to the injury using a surgical approach. If airway injury is extensive, a surgical airway distal to the site of injury may be the best initial approach. Alternatively, if orotracheal intubation is chosen, spontaneous ventilation may be maintained or RSI may be performed. RSI is a common approach. Thus, some of the patients intubated may subsequently require tracheostomy. A stable patient with limited injuries may not require intubation but should be watched carefully for at least several hours. Because of a paucity of evidence-based data, the choice between these approaches and the techniques utilized is a clinical decision depending on the patient's condition, clinical setting, injuries to airway and other organs, and available personnel, expertise, and equipment. Inability to obtain a definitive airway is always an absolute indication for an emergency cricothyroidotomy or surgical tracheostomy.

Prodrugs of perzinfotel with improved oral bioavailability.

Previous studies with perzinfotel (1), a potent, selective, competitive NMDA receptor antagonist, showed it to be efficacious in inflammatory and neuropathic pain models. To increase the low oral bioavailability of 1 (3-5%), prodrug derivatives (3a-h) were synthesized and evaluated. The oxymethylene-spaced diphenyl analogue 3a demonstrated good stability at acidic and neutral pH, as well as in simulated gastric fluid. In rat plasma, 3a was rapidly converted to 1 via 2a. Pharmacokinetic studies indicated that the amount of systemic exposure of 1 produced by a 10 mg/kg oral dose of 3a was 2.5-fold greater than that produced by a 30 mg/kg oral dose of 1. Consistent with these results, 3a was significantly more potent and had a longer duration of activity than 1 following oral administration in a rodent model of inflammatory pain. Taken together, these results demonstrate that an oxymethylene-spaced prodrug approach increased the bioavailability of 1.

Discovery of begacestat, a Notch-1-sparing gamma-secretase inhibitor for the treatment of Alzheimer's disease.

SAR on HTS hits 1 and 2 led to the potent, Notch-1-sparing GSI 9, which lowered brain Abeta in Tg2576 mice at 100 mg/kg po. Converting the metabolically labile methyl groups in 9 to trifluoromethyl groups afforded the more stable analogue 10, which had improved in vivo potency. Further side chain modification afforded the potent Notch-1-sparing GSI begacestat (5), which was selected for development for the treatment of Alzheimer's disease.

Three-year survival after four major post-cardiac operative complications.

OBJECTIVE: After cardiac surgery, major morbidities known to be primary contributors to perioperative mortality are cardiac failure, respiratory failure, renal failure, and the need for mediastinal exploration. The first aim of this study was to ascertain long-term survival in cardiac surgery patients with and without the occurrence of major morbidities to investigate if long-term survival was comparable. The second aim of this study was to evaluate the prevalences and risk factors related to the four major morbidities in this patient population. DESIGN: Retrospective observational outcome study. SETTING: Cardiothoracic intensive care unit at a university hospital. PATIENTS: We included 2,683 of 3,253 consecutive cardiac surgery patients cared for in a uniform fashion. METHODS AND MAIN RESULTS: Perioperative mortality was significantly increased by the occurrence of major morbidity. In-hospital mortality was 0.7% in the absence of major morbidity compared with 72% when all major morbidities occurred. Three-year mortality for the entire study population was 15%, whereas the 3-yr long-term survival was significantly less for patients with morbidities compared with those without. Various independent perioperative risk factors were found for perioperative major morbidity and mortality. CONCLUSIONS: Successful acute treatment and measures to identify and reduce the risk of major morbidities are necessary to improve outcome. In addition, long-term follow-up and management of morbidities are necessary to possibly improve long-term survival.

Increased interleukin-6 after cardiac surgery predicts infection.

Early diagnosis and treatment of infection after cardiac surgery with cardiopulmonary bypass (CPB) improves outcome. Conventional laboratory tests, such as C-reactive protein and white blood cell count can not distinguish patients with early infection from those with systemic inflammatory response syndrome but without infection. After CPB, there is a systemic release of proinflammatory and antiinflammatory cytokines, including tumor necrosis factor-alpha, interleukin (IL)-6, and IL-10. We investigated the predictive ability of these variables for infection after cardiac surgery. Forty-six patients with impaired left ventricular ejection fraction (<60%), scheduled for cardiac surgery, were included. Plasma samples were drawn 1 day before and immediately before surgery, on admission to the intensive care unit, and on days 1, 3, and 7 after surgery. Infection was identified according to the criteria of the Centers for Disease Control and Prevention. After surgery 13 patients developed an infection. In patients with infection, confirmed a median of 4 days after surgery, all measurements of IL-6, and IL-10 on postoperative day 3 were significantly increased. Tumor necrosis factor-alpha, leukocytes, and C-reactive protein were not increased in these patients. Immediately after surgery blood glucose was significantly increased in patients with infection. Increased IL-6 after CPB is predictive of infection after cardiac surgery in patients with impaired left ventricular function.

Small-dose epoprostenol decreases systemic oxygen consumption and splanchnic oxygen extraction during normothermic cardiopulmonary bypass.

Normothermic, nonpulsatile cardiopulmonary bypass (CPB) impairs systemic and splanchnic oxygen transport and increases gastrointestinal permeability. It is an important therapeutic goal to avoid splanchnic dysoxia during CPB. Small-dose prostacyclin therapy improves splanchnic oxygen transport and microcirculation in septic patients. In this study, we sought to determine if during cardiac surgery, the prostacyclin analog epoprostenol improves the balance of systemic and splanchnic oxygen transport. Eighteen patients undergoing cardiac valve replacement were randomized to receive either epoprostenol (3 ng x kg(-1) x min(-1)) or placebo during, and for 1 hour after, surgery. Systemic and splanchnic oxygen delivery, consumption, and extraction and arterial, mixed venous, and hepato-venous lactate concentrations were measured before, during, and after CPB. Gastrointestinal permeability was measured 1 day before and 1 day after surgery using the triple sugar permeability test. During CPB, the epoprostenol group had decreased systemic oxygen consumption and splanchnic oxygen extraction (P = 0.024). These effects were not present 1 hour after the end of epoprostenol infusion. The study was not adequately powered to determine whether epoprostenol altered the trend towards increased lactate metabolism and increased postoperative gastrointestinal permeability, nor could we demonstrate any differences between groups in clinically relevant end-points. In conclusion, these findings suggest that during normothermic CPB, small-dose epoprostenol therapy may reduce systemic oxygen consumption and splanchnic oxygen extraction.

Recombinant activated factor VII for refractory bleeding after cardiac surgery--a retrospective analysis of safety and efficacy.

OBJECTIVE: Analysis of safety and efficacy of recombinant activated factor VII (rFVIIa) used as the last resort for refractory bleeding after cardiac surgery. DESIGN: Retrospective cohort analysis and matched pairs analysis with historic controls were performed. In the rFVIIa group, which also received conventional hemostatic therapy, data were collected for a median of 14 hrs from admission to the intensive care unit (ICU) to the administration of rFVIIa and for the following 24 hrs. In the control group, which received only conventional hemostatic therapy, data were collected for 14 and then for 24 hrs after admission to the ICU. SETTING: University hospital. PATIENTS: Twenty-four patients matched with historic controls. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: No thromboembolic complications were observed in the rFVIIa group. Blood loss and transfusion requirements were significantly reduced in the period after the administration of rFVIIa. However, in the 24-hr period after rFVIIa administration, blood loss (p = .140) and transfusion of packed red blood cells (p = .442) and fresh frozen plasma (p = .063) were not different between the rFVIIa and control groups. Platelet concentrates (p = .004) were transfused less in the control group. Mortality and 6-month survival rates were not different between the groups. CONCLUSIONS: When used as a last resort, rFVIIa was safe but not incrementally efficacious over conventional hemostatic therapy.

Synthesis and SAR of 2-carboxylic acid indoles as inhibitors of plasminogen activator inhibitor-1.

We synthesized and evaluated a novel series of 2-carboxylic acid indole-based inhibitors of plasminogen activator inhibitor-1 (PAI-1). Systematic modification of the N-1 position and the 5-position of the indole scaffold resulted in the identification of several compounds that showed good potency against PAI-1 in the spectrophotometric assay. This potency did not always translate to the antibody assay. Solubility and serum protein binding studies on selected analogs revealed that protein binding might be a factor in the poor correlation between the two assays.

Myocardial ischemia and cytokine response are associated with subsequent onset of infections after noncardiac surgery.

UNLABELLED: Postoperative myocardial ischemia (POMI) is prevalent among patients after major noncardiac surgery. Surgery, as well as POMI, may modulate the immune system, potentially worsening patient outcome. We sought to investigate the modulation of soluble interleukin (IL)-6 and IL-10 by POMI and its association with increased postoperative infection rates. Two-hundred-three patients undergoing elective major abdominal, vascular, and orthopedic surgery participated in this prospective observational study. Perioperative management was standardized. Hemodynamic variables were kept within 20% of baseline. POMI was assessed by Holter electrocardiography starting at least 8 h before the induction of anesthesia and continued until 96 h after surgery. Twelve-lead electrocardiograms, cardiac enzymes, and immune variables were obtained at the time of admission to the hospital, before surgery, before the induction of anesthesia, after surgery, at the time of admission to the intensive care unit, and 6, 12, 18, 24, 36, 48, 72, 96, 120, 144, and 168 h after surgery. Infections were diagnosed according to the Centers for Disease Control criteria. The incidence of POMI was 27%, and the majority of cases (76%) occurred within the first 24 h after surgery. IL-6 and IL-10 levels significantly increased during surgery but did not differ between the POMI and Non-POMI groups. However, in the subset of patients who developed severe infections or sepsis (n = 47) a median of 3 days (range, 1-8 days) after surgery, the intraoperative increases of IL-6 and IL-10 in the POMI group were, respectively, 3 and 10 times higher compared with the increase in the Non-POMI group. By using a multifactorial analysis in these patients with severe infections, the type of surgical trauma was associated with an increased IL-6 response, whereas the increase in IL-10 was attributed to POMI. These findings suggest that immediate cytokine responses due to POMI and type of surgery might be relevant for the later onset of severe infections and sepsis. IMPLICATIONS: Postoperative myocardial ischemia (POMI) occurred in 27% of patients after major noncardiac surgery. This was associated with an immediate augmented cytokine response in the first 12 h after surgery in patients who developed severe infections or sepsis 3 days later. POMI was associated with an increased interleukin (IL)-10 response, whereas IL-6 was associated with the type of surgery.