Studying the factors that impact the dissolution characteristic of complex drug product

This article summarizes the critical factors involved in product development of a single dosage form formulated by compacting ethyl cellulose (EC) coated controlled release pellets into a tablet. The greatest challenge associated with this type of complex system is to minimize the effect of compression on the drug release. The effects of compression on the drug release were optimized with combination of the following factors (1) particle size of the core pellets, (2) the selection of the coating polymer’s viscosity grade, and (3) emergence of cushioning agents. The optimization of these factors provided superior protection for the controlled release coated pellets; therefore, the desired drug release from the tablet was successfully achieved as designed. However, the drug release rates from the coated pellets before and after the compression were minimized and exhibited only a slight difference.     

Exposure of blood from patients with sickle cell disease to air changes the morphological, oxygen-binding, and sickling properties of sickled erythrocytes

We collected venous blood samples from 7 steady-state patients with homozygous sickle cell disease under venous oxygen pressure without exposure to air (UnExp-blood) and compared the morphological, oxygen-binding, and sickling properties with those of SS cells in aliquots of the same venous blood samples that were oxygenated in room air or at a PO2 near 180 mmHg (Exp-blood). Results showed that (1) upon deoxygenation under nitrogen, UnExp-blood generated a significantly higher percentage of elongated reversibly sickled cells (RSCs) than did Exp-blood; (2) upon gradual oxygenation of completely deoxygenated sickled cells, RSCs in UnExp-blood converted to discocytes at a higher oxygen pressure than did those in Exp-blood; (3) the degree of hysteresis between the sickling/desickling curves of UnExp-blood was greater than that of Exp-blood; and (4) deoxy-Hb S in hemolysate prepared from SS cells in UnExp-blood polymerized without a delay time, while those from Exp-blood polymerized with a distinct delay time. The in vivo properties of RSCs significantly changed upon oxygenation. We also found that the various properties of blood samples collected from patients with SCD by the ordinary method were similar to those of Exp-blood, probably because such blood samples are exposed to oxygen through air in the needle, syringe, and Vacutainer. Once SS cells were oxygenated, the in vivo properties of RSCs could not be recovered by partial deoxygenation to venous oxygen pressure.     

Hyponatremia in Cirrhosis and End-Stage Liver Disease: Treatment with the Vasopressin V2-Receptor Antagonist Tolvaptan

Hyponatremia is common in patients with cirrhosis and portal hypertension, and is characterized by excessive renal retention of water relative to sodium due to reduced solute-free water clearance. The primary cause is increased release of arginine vasopressin. Hyponatremia is associated with increased mortality in cirrhotic patients, those with end-stage liver disease (ESLD) on transplant waiting lists, and, in some studies, posttransplantation patients. Clinical evidence suggests that adding serum sodium to model for ESLD (MELD) scoring identifies patients in greatest need of liver transplantation by improving waiting list mortality prediction. Hyponatremia is also associated with numerous complications in liver disease patients, including severe ascites, hepatic encephalopathy, infectious complications, renal impairment, increased severity of liver disease in cirrhosis, and increased hospital stay and neurologic/infectious complications posttransplant. Vasopressin receptor antagonists, which act to increase free water excretion (aquaresis) and thereby increase serum sodium concentration, have been evaluated in patients with hypervolemic hyponatremia (including cirrhosis and heart failure) and euvolemic hyponatremia (SIADH). Tolvaptan, a selective vasopressin V₂-receptor antagonist, is the only oral agent in this class approved for raising sodium levels in hypervolemic and euvolemic hyponatremia. The SALT trials showed that tolvaptan treatment rapidly and effectively resolved hyponatremia in these settings, including cirrhosis, and it has been shown that this agent can be safely and effectively used in long-term treatment. Fluid restriction should be avoided during the first 24?h of treatment to prevent overly rapid correction of hyponatremia, and tolvaptan should not be used in patients who cannot sense/respond to thirst, anuric patients, hypovolemic patients, and/or those requiring urgent intervention to raise serum sodium acutely.     

Modulation of erythrocyte arginase activity in sickle cell disease patients during hydroxyurea therapy

An elevated erythrocyte arginase activity with a corresponding decrease in nitric oxide (NO) level has been implicated in the pathophysiology of sickle cell disease (SCD). Recent studies have shown that hydroxyurea (HU) increases the production of NO, which increases the soluble guanylate cyclase activity and fetal haemoglobin (HbF) synthesis. To study the effects of HU on the arginase and nitric oxide synthase (NOS) activities in SCD patients, we compared levels of arginase activity and NO metabolites in red blood cells and plasma, respectively, from 23 patients with SCD (HbSS) receiving HU therapy, with those of 12 SCD patients not receiving HU treatment. Patients on HU therapy showed significantly lower arginase activity than that of HbSS patients not on HU therapy (1.36+/-0.2 U/10(8) cells vs. 3.31+/-0.29 U/10(8) cells). NOS activity was higher in patients on HU therapy than in untreated patients (0.72+/-0.4 nmol/ml/min vs. 0.35+/-0.15 nmol/ml/min, P<0.05). Among the HU-treated patients, the decreased level of arginase activity correlated (r=0.71) with HbF level as well as the mean corpuscular haemoglobin content. These data suggest that one of the beneficial effects of HU in vivo may involve the regulation of arginase activity and a concomitant induction of NOS activity, which may lead to an increased production of NO. The outcome of this study may lead to the development of improved NO-based treatments for SCD.     

Percentage of Reversibly and Irreversibly Sickled Cells Are Altered by the Method of Blood Drawing and Storage Conditions

ABSTRACT: We previously reported that the percentage of reversibly and irreversibly sickled cells (RSC and ISC, respectively) in the blood of patients with sickle cell disease is strongly influenced by the method of blood drawing (PNAS91:12589, 1994). We now document the effect of blood storage conditions on the percentage of RSC and ISC. The percentage of RSC was lowest when blood was stored at 0°C, while the percentage of RSC was highest in specimens kept at 37°C. At room temperature, the percentage of RSC increased slightly over 8 hours. The percentage of ISC was also temperature dependent and was reduced significantly upon cooling. Our results showed that many ISC reverted to a discoidal shape after 3 hrs of cooling after treatment of blood with oxygen or carbon monoxide. Since no Hb S polymers were detected in ISC treated with oxygen or carbon monoxide, the time required for shape restoration may be attributed to the membrane. We measured ISC levels of 10 patients with consideration of storage temperature and compared the values with those determined by the conventional method and also with those published previously.     

The clinical significance of platelet counts in the first 24 hours after severe injury

BACKGROUND: Admission platelet (PLT) counts are known to be associated with all‐cause mortality for seriously injured patients admitted to a trauma center. The course of subsequent PLT counts, their implications, and the effects of PLT therapy are less well known. STUDY DESIGN AND METHODS: Trauma center patients who were directly admitted from the scene of injury, received 1 or more units of uncrossmatched red blood cells in the first hour of care, survived for at least 15 minutes, and had a PLT count measured in the first hour were analyzed for the association of their admission and subsequent PLT counts in the first 24 hours with injury severity and hemorrhagic and central nervous system (CNS) causes of in‐hospital mortality. RESULTS: Over an 8.25‐year period, 1292 of 45,849 direct trauma admissions met entry criteria. Admission PLT counts averaged 228 × 10⁹ ± 90 × 10⁹/L and decreased by 104 × 10⁹/L by the second hour and 1 × 10⁹/L each hour thereafter. The admission count was not related to time to admission. Each 1‐point increase in the injury severity score was associated with a 1 × 10⁹/L decrease in the PLT count at all times in the first 24 hours of care. Admission PLT counts were strongly associated with hemorrhagic and CNS injury mortality and subsequent PLT counts. Effects of PLT therapy could not be ascertained. DISCUSSION: Admission PLT counts in critically injured trauma patients are usually normal, decreasing after admission. Low PLT counts at admission and during the course of trauma care are strongly associated with mortality.     

Access to health information,health literacy and health-related quality of life among women living with breast cancer: Depression and anxiety as mediators

ObjectiveThis study examined the direct and indirect influences of health literacy and access to health information on the quality of life among 205 women living with breast cancer in Ghana.MethodsA cross-sectional survey design was employed. The interviewer-administered instrument included the health literacy scale, questions on access and satisfaction with healthcare information, depression and anxiety scale, and the Functional Assessment of Cancer Therapy-Breast Cancer.ResultsAccess to health information and health literacy had significant indirect effects on quality of life through depression and anxiety. Whereas health literacy had direct influence on quality of life after controlling for other factors, access to information had no direct influence on quality of life.ConclusionHealth literacy and access to health information improve quality of life in women living with breast cancer by reducing the levels of depression and anxiety. Depression and anxiety serve as possible mechanisms for the positive impacts of access to health information and health literacy on improved quality of life among breast cancer patients.Practice implicationsHealth care providers need to ensure that the information needs of patients are met in oncology practice to reduce their negative emotional states which would lead to improved health and wellbeing.     

Psychological functioning among vertically infected HIV-positive children and their primary caregivers

The current study sought to explore the association between primary caregiver depressive symptoms and the psychological functioning in children vertically infected with human immunodeficiency virus (HIV) living in Eastern Cape, South Africa. A cross-sectional data were collected using the Beck Depression Inventory and Strength and Difficulties Questionnaire in a sample of 152 caregiver/child dyads. The results revealed that poorer psychological functioning in children was significantly associated with depressive symptoms in caregivers. This relationship existed whether or not the child was raised by a biological or non-biological caregiver as well as for both genders. Younger children's psychological functioning was more negatively influenced than that of older children raised by a caregiver with depressive symptoms. In the context of a large treatment gap for common mental disorders in South Africa, there is a need for interventions to address maternal mental health in families infected and affected by the HIV/AIDS pandemic as a mental health promotion strategy given that HIV-infected children are a particularly vulnerable population for poor mental and behavioural health outcomes.     

Cardiac conduction through engineered tissue

In children, interruption of cardiac atrioventricular (AV) electrical conduction can result from congenital defects, surgical interventions, and maternal autoimmune diseases during pregnancy. Complete AV conduction block is typically treated by implanting an electronic pacemaker device, although long-term pacing therapy in pediatric patients has significant complications. As a first step toward developing a substitute treatment, we implanted engineered tissue constructs in rat hearts to create an alternative AV conduction pathway. We found that skeletal muscle-derived cells in the constructs exhibited sustained electrical coupling through persistent expression and function of gap junction proteins. Using fluorescence in situ hybridization and polymerase chain reaction analyses, myogenic cells in the constructs were shown to survive in the AV groove of implanted hearts for the duration of the animal's natural life. Perfusion of hearts with fluorescently labeled lec-tin demonstrated that implanted tissues became vascularized and immunostaining verified the presence of proteins important in electromechanical integration of myogenic cells with surrounding re-cipient rat cardiomyocytes. Finally, using optical mapping and electrophysiological analyses, we provide evidence of permanent AV conduction through the implant in one-third of recipient animals. Our experiments provide a proof-of-principle that engineered tissue constructs can function as an electrical conduit and, ultimately, may offer a substitute treatment to conventional pacing therapy.