Cost-effectiveness of anticoagulants for suspected heparin-induced thrombocytopenia in the United States.

Despite the availability of multiple nonheparin anticoagulants for the treatment of heparin-induced thrombocytopenia (HIT), few data are available comparing the cost-effectiveness of these agents. This analysis is particularly important when considering differences in the risk of adverse effects, routes of administration, requirements for phlebotomy and laboratory monitoring, and overall drug costs. We conducted a cost-effectiveness analysis of argatroban, bivalirudin, and fondaparinux for the treatment of suspected HIT from the institutional perspective. A 3-arm decision-tree model was developed that employs standard practices for anticoagulation monitoring. We incorporated published data on drug efficacy and probability of HIT-related thromboembolism and major bleeding. We considered both institutional costs and average wholesale price (AWP) and performed probabilistic sensitivity analyses (PSA) to address any uncertainty in model parameters. Using institutional costs, fondaparinux prevailed over both argatroban and bivalirudin in terms of cost ($151 vs $1250 and $1466, respectively) and adverse events averted (0.9989 vs 0.9957 and 0.9947, respectively). Results were consistent when AWP was used, with fondaparinux being less expensive ($555 vs $3081 and $2187, respectively) and more effective in terms of adverse events averted (0.9989 vs 0.9957 and 0.9947, respectively). The PSA confirmed our findings using both institutional costs and AWP. In conclusion, fondaparinux subcutaneous injection afforded significant advantages in terms of cost savings and adverse events averted compared with IV argatroban or bivalirudin infusions. Our data strongly suggest potential cost savings with fondaparinux and underscore the critical need for larger clinical studies of fondaparinux in the treatment of suspected HIT.

Genistein ameliorated experimentally induced gastric ulcer in rats via inhibiting gastric tissues fibrosis by modulating Wnt/ß-catenin/TGF-ß/PKB pathway.

OBJECTIVES: Gastric ulcer (GU) is a prevalent chronic digestive disease affecting about 10% of the world's population leading to gastrointestinal perforation and bleeding. Genistein is a legume flavonoid with antioxidants, anti-inflammatory and antibacterial activities. Therefore, we aimed to investigate the ability of genistein to reduce experimentally induced GU in rats by affecting gastric tissue fibrosis Wnt/ß-catenin/TGF-ß/SMAD4 pathway. METHODS: Thirty rats were used. Ten rats served as control, and GU was induced in twenty rats using a single dose of indomethacin (80 mg/kg) orally. Following induction of GU, ten were treated with genistein 25 mg/kg orally. The gastric tissues were isolated to investigate markers of gastric fibrosis, Wnt, ß-catenin, transforming growth factor (TGF)-ß, SMAD4, and Protein kinase B (PKB). In addition, gastric sections were stained with PAS and anti-TGF-ß antibodies. RESULTS: Investigation GU micro-images revealed degeneration in both surface cells and glandular epithelial cells, which was improved by genistein. In addition, treatment with genistein significantly reduced the expression of Wnt, ß-catenin, TGF-ß, SMAD4, and PKB. CONCLUSION: Besides antioxidant activity, genistein improves experimentally induced GU in rats, at least in part, via reduction of gastric tissue fibrosis as indicated by reduction in expression of Wnt, ß-catenin, TGF-ß, SMAD4, and PKB.

Identification and functional characterization of two rare LDLR stop gain variants (p.C231* and p.R744*) in Saudi familial hypercholesterolemia patients.

BACKGROUND: Familial hypercholesterolemia (FH) is a globally underdiagnosed inherited metabolic disorder. Owing to limited published data from Arab world, this study was conducted with the aim of identifying the genetic and molecular basis of FH in highly consanguineous Saudi population. METHODS: We performed clinical screening, biochemical profiling, whole exome sequencing and variant segregation analysis of two Saudi FH families. Additionally, 500 normolipic individuals were screened to ensure the absence of FH variant in general Saudi population. Functional characterization of FH variants on secondary structure characteristics of RNA and protein molecules was performed using different bioinformatics modelling approaches. RESULTS: WES analysis identified two independent rare LDLR gene stop gain variants (p.C231* and p.R744*) consistent to the clinical presentation of FH patients from two different families. RNAfold analysis has shown that both variants were predicted to disturb the free energy dynamics of LDLR mRNA molecule and destabilize its folding pattern and function. PSIPRED based structural modelling analysis has suggested that both variants bring drastic changes disturbing the secondary structural elements of LDLR molecule. The p.C231* and p.R744* variants are responsible for partial or no protein product, thus they are class 1 variants causing loss of function (LoF) LDLR variants. CONCLUSIONS: This study highlights the effectiveness of the WES, sanger sequencing, and computational analysis in expanding FH variant spectrum in culturally distinct populations like Saudi Arabia. Genetic testing of FH patients is very essential in better clinical diagnosis, screening, treatment, and management and prevention of cardiovascular disease burden in the society.

The therapeutic effects of cycloastragenol in ulcerative colitis by modulating SphK/MIP-1α/miR-143 signalling.

Patients with ulcerative colitis (UC) experience diarrhoea, hematochezia and abdominal pain. UC is a well-known health challenge affecting 200-250 per 100 000 individuals worldwide, with a similar prevalence in both sexes and elevated upon activation of gut immune responses. We evaluated the potential therapeutic effects of cycloastragenol in experimentally induced UC rats and examined the modulation of sphingosine kinase (SphK), macrophage inflammatory protein (MIP)-1α and miR-143. We treated UC rats with 30 mg/kg cycloastragenol and assessed gene and protein expression levels of SphK, MIP-1α, B-cell lymphoma 2 (BCL2), BCL2-associated X (BAX), miR-143, NF-κB, tumour necrosis factor (TNF)-α and active caspase-3. Colon sections were examined using electron microscopy; additional sections were stained with haematoxylin-eosin or immunostained with anti-TNF-α and anti-caspase-3 antibodies. Electron microscopy of UC specimens revealed dark distorted goblet cell nuclei with disarranged mucus granules and a nondistinct brush border with atypical microvilli. Haematoxylin-eosin staining showed damaged intestinal glands, severe haemorrhage and inflammatory cell infiltration. Cycloastragenol treatment improved the induced morphological changes. In UC rats, cycloastragenol significantly reduced expression levels of SphK, MIP-1α, BAX, NF-κB, TNF-α and active caspase-3, associated with BCL2 and miR-143 overexpression. Therefore, cycloastragenol protects against UC by modulating SphK/MIP-1α/miR-143, subsequently deactivating inflammatory and apoptotic pathways.

Evaluating the Anticancer Activity of Blocking TNF Type 1 Receptors in Thioacetamide-Induced Hepatocellular Carcinoma in a Rat Model.

Background Hepatocellular carcinoma (HCC) can explicate about 90% of the total primary liver cancer cases, with approximately 800,000 new cases identified each year worldwide. In addition, any changes in the expression of the tumor necrosis factor α (TNF-α) type 1 receptor (TNFR1) might impact many biological processes, which may lead to cancer. Aims We conducted the following study to investigate the ability of CAY10500, a TNF-α inhibitor that prevents binding to the TNF receptor 1, to produce anticancer effects against hepatocellular carcinoma experimentally induced in rats and to discover its effect on nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1). Materials and methods HCC was induced in rats via 200 mg/kg thioacetamide followed by treating some rats with IV 1 mg/kg CAY10500. Assessment of the liver impairment was by measuring the serum α-fetoprotein (AFP) and investigation of liver sections stained with hematoxylin/eosin. The hepatic expression of both the messenger RNA (mRNA) and protein levels of TNF-α, TNFR1, Nrf2, and HO-1 was assessed. Results We found that CAY10500 increased the survival percent of rats associated with a reduction in serum AFP and the number of hepatic nodules. Besides, CAY10500 reduced the expression of TNFR1 without affecting the expression of TNF-α. Finally, CAY10500 increased the expression of both Nrf2 and HO-1. Conclusions Inhibition of TNFR1 expression in HCC by using CAY10500 produced therapeutic effects as indicated by increasing the survival rate, reducing the serum AFP level, decreasing liver nodules, and improving hepatocytes' structure. In addition, TNFR1 significantly enhanced the expression of Nrf2 and HO-1.

Curative effects of fucoidan on acetic acid induced ulcerative colitis in rats via modulating aryl hydrocarbon receptor and phosphodiesterase-4.

BACKGROUND: Ulcerative colitis (UC) is an inflammatory bowel disease. Fucoidan, sulfated polysaccharide of brown seaweed, demonstrates various pharmacological actions as anti-inflammatory, anti-tumor and anti-bacterial effects. Therefore, we opt to investigate the potential curative effects of fucoidan in experimentally induced UC in rats through modulating aryl hydrocarbon receptor (AhR), phosphodiesterase-4 (PDE4), nuclear factor erythroid 2-related factor 2 (Nrf2) and Heme Oxygenase-1 (HO-1). METHODS: UC was induced in rats using intracolonic 2 ml of 4% acetic acid. Some rats were treated with 150 mg/kg fucoidan. Samples of colon were used to investigate gene and protein expression of AhR, PDE4, Nrf2, HO-1 and cyclic adenosine monophosphate (cAMP). Sections of colon were stained with hematoxylin/eosin, Alcian blue or immune-stained with anti-PDE4 antibodies. RESULTS: Investigation of hematoxylin/eosin stained micro-images of UC rats revealed damaged intestinal glands, severe hemorrhage and inflammatory cell infiltration, while sections stained with Alcian Blue revealed damaged and almost absent intestinal glands. UC results in elevated gene and protein expression of PDE4 associated with reduced gene and protein expression of AhR, IL-22, cAMP, Nrf2 and HO-1. Finally, UC increased the oxidative stress and reduced antioxidant activity in colon tissues. All morphological changes as well as gene and protein expressions were ameliorated by fucoidan. CONCLUSION: Fucoidan could treat UC induced in rats. It restored the normal weight and length of colon associated with morphological improvement as found by examining sections stained with hematoxylin/eosin and Alcian Blue. The curative effects could be explained by enhancing antioxidant activity, reducing the expression of PDE4 and increasing the expression of AhR, IL-22 and cAMP.

Amelioration of Pterostilbene Antiproliferative, Proapoptotic, and Oxidant Potentials in Human Breast Cancer MCF7 Cells Using Zein Nanocomposites.

PURPOSE: This study aimed to explain the influence of zein nanosphere (ZN NS) formulation on the pharmacotherapeutic profile of PTS in MCF7 cells. METHODS: Liquid-liquid phase separation was used to formulate PTS-ZN NSs. The formulations developed were evaluated for particle-size analysis, encapsulation efficiency, and in vitro diffusion. Also, assays of cytotoxicity, uptake, cell-cycle progression, annexin V, apoptotic gene mRNA expression and biochemical assays were carried out. RESULTS: The PTS-ZN NS formulation selected showed 104.5±6.2 nm, 33.4±1.8 mV, 95.1%±3.6%, and 89.1%±2.65% average particle size, zeta-potential, encapsulation efficiency and in vitro diffusion, respectively. With MCF7 cells, IC50 was reduced approximately 15-fold, with increased cellular uptake, accumulation in the G2/M phase, increased percentage of cells in the pre-G1 phase, amelioration of early and late apoptosis, raised mRNA expression of CASP3 and CASP7, lower expression of cyclin-CDK1, and enhanced oxidant potential through decreased glutathione reductase (GR) activity, and enhanced reactive oxygen-species generation and lipid-peroxidation products. CONCLUSION: PTS-ZN NSs indicated enhanced antiproliferative, proapoptotic, and oxidant potential toward MCF7 cells compared to free PTS. Ameliorated results of nanosized carriers, cellular uptake, and sustained diffusion may contribute to these outcomes.

Optimization of Hyaluronate-Based Liposomes to Augment the Oral Delivery and the Bioavailability of Berberine.

Various perspectives had been utilized to enhance the poor intestinal permeability and bioavailability of drugs with low water solubility. Berberine (Brb) is a unique molecule that possesses multiple therapeutic activities such as antimicrobial, anti-inflammatory, antioxidant and anti-hyperglycemic effects. To improve Brb permeability and bioavailability, this study presents a newly developed formulation, namely Brb hyaluronate-based liposomes, prepared by using film hydration method and characterized by dynamic light scattering measurements, entrapment efficiency percentage (EE%), transmission electron microscope (TEM), in vitro drug release and physical stability. The bioavailability of the selected formulations was assessed in vivo after oral administration to rats. The results revealed an enhanced effect of hyaluronic acid on the entrapment efficiency, reaching 78.1 ± 0.1% with mean size 520.7 ± 19.9 nm. Sustained release of Brb was recorded up to 24 h in comparison to Brb solution. Physical stability was maintained for three months at refrigeration temperature. Results of pharmacokinetics studies indicated the potential of the liposomal formulation to increase the oral bioavailability of Brb and to accelerate its entry into the bloodstream. The obtained results are accredited to the lipophilic nature of the prepared system, resembling the structural features of bio-membrane, in addition to their small size that enhances intestinal penetration.

Selective cytotoxic activity and protective effects of sodium ascorbate against hepatocellular carcinoma through its effect on oxidative stress and apoptosis in vivo and in vitro.

Objectives: Hepatocellular carcinoma (HCC) is characterized by elevated in oxidative stress and inflammatory cytokines, which enhance destructive effects of the tumor. Therefore, we conducted this study to investigate the protective effects of sodium ascorbate against thioacetamide-induced HCC in rats through studying its effect on the apoptotic pathway in rats. In addition, in vitro activity of sodium ascorbate was investigated on HepG2 and compared with cisplatin.Methods: HCC was experimentally induced by injecting rats with 200 mg/kg thioacetamide intraperitoneally twice weekly for 16 weeks. Part of HCC rats was concomitantly treated with 100 mg/kg sodium ascorbate intraperitoneally during the 16-week period. Hepatic tissues were used for the determination of NFκB, Nrf2, TNF-α, caspase-3, caspase-8 and caspase-9.Results: Sodium ascorbate significantly attenuated HCC-induced reduction in the expression of NrF2 associated with a reduction in concentrations of hydrogen peroxide and superoxide anion. In addition, sodium ascorbate blocked HCC-induced increase in the expression of NFκB and TNF-α. Sodium ascorbate slightly increased the activity of caspase-3, -8 and -9 in vitro but inhibited their activities in vivo.Conclusion: In spite of the antioxidant and anti-inflammatory activity of sodium ascorbate, it produced selective cytotoxic activity via direct activation of the apoptotic pathway in cancer cells without affecting the apoptotic pathway in normal hepatic cells.

Optimizing pharmacotherapy in elderly patients: the role of pharmacists.

As the world's population ages, global health care systems will face the burden of chronic diseases and polypharmacy use among older adults. The traditional tasks of medication dispensing and provision of basic education by pharmacists have evolved to active engagement in direct patient care and collaborative team-based care. The care of older patients is an especially fitting mission for pharmacists, since the key to geriatric care often lies with management of chronic diseases and polypharmacy use, and preventing harmful consequences of both. Because most chronic conditions are treated with medications, pharmacists, with their extensive training in pharmacotherapy and pharmacokinetics, are in a unique and critical position in the management of them. Pharmacists have the expertise to detect, resolve, and prevent medication errors and drug-related problems, such as overtreatment, undertreatment, adverse drug events, and nonadherence. Pharmacists are also competent in critically reviewing and applying clinical guidelines to the care of individual patients, and in some instances confront the lack of data (common in older adults) to provide the best possible patient-centered care. The current review aimed to depict the evidence of geriatric pharmacy care, demonstrate current impact of pharmacists' interventions on older patients, survey the tools used by pharmacists to provide effective care, and explore their role in pharmacotherapy optimization in elders. The findings of the current review strongly support previous studies that showed positive impact of pharmacists' interventions on older patients' health-related outcomes. There is a clear role for pharmacists working directly or collaboratively to improve medication use and management in older populations. Therefore, in global health care systems, teams caring for elders should involve pharmacists to optimize pharmacotherapy.