Profile of paritaprevir/ritonavir/ombitasvir plus dasabuvir in the treatment of chronic hepatitis C virus genotype 1 infection.

Over the last several years, many advances have been made in the treatment of chronic hepatitis C virus (HCV) infection with the development of direct-acting antivirals. Paritaprevir/ritonavir/ombitasvir with dasabuvir (PrOD) is a novel combination of a nonstructural (NS) 3/4A protein inhibitor boosted by ritonavir, an NS5A protein inhibitor, and an NS5B nonnucleoside polymerase inhibitor. This review aims to discuss the pharmacology, efficacy, safety, drug interactions, and viral drug resistance of PrOD in the treatment of HCV genotype 1 infections. Phase I, II, and III human and animal studies that describe the pharmacology, pharmacokinetics, efficacy, and safety of PrOD for HCV were identified and included. Studies that evaluated patients without cirrhosis (n=2,249) and with cirrhosis (n=422) demonstrated that PrOD for 12 or 24 weeks was effective at achieving sustained virologic response rates (>90%) in patients with genotype 1a or 1b HCV infection. Although indicated for the treatment of HCV genotype 1 infection, PrOD is also recommended for the treatment of HCV in patients coinfected with HIV. Additionally, promising data exist for the use of PrOD in liver-transplant recipients. The most common adverse drug events associated with PrOD included nausea, pruritus, insomnia, diarrhea, asthenia, dry skin, vomiting, and anemia. The high efficacy rates seen coupled with a favorable side effect profile seen with PrOD with or without ribavirin have led to its addition as a recommended treatment regimen for HCV genotype 1 infection.

Use of emergency departments by known epileptic patients: An underestimated problem?

BACKGROUND AND PURPOSE: Seizure is a frequent reason of admission in emergency department (ED) but little is known about the proportion and the characteristics of known epileptic patients (KEPs) who used emergency services. METHODS: Over a 12-month period, we prospectively recruited adults admitted for seizure to a tertiary hospital ED. For KEPs, clinical epilepsy features and characteristics of the admission were collected. RESULTS: Of the 60,578 ED admissions, 990 were related to seizure; 580 of these admissions concerned 448 different KEPs (257 males; median age: 44); 339 were residents in the health district. Epilepsy was structural/metabolic in 268 (59.8%) patients, genetic in 44 (9.8%) and unknown/undetermined in 136 (30.3%); 218 (48.7%) patients were under a single antiepileptic drug and 135 (30.1%) were followed by an epileptologist. Of the 580 KEP admissions, 440 (75.8%) concerned patients who had called the emergency medical assistance number, 252 (43.4%) with a discharge diagnosis of usual seizure and 43 (7.4%) of a status epilepticus. Half the KEPs were discharged without hospitalization. We estimated that 9.0% of KEPs residing in the district had used the ED during the period. CONCLUSION: Proportion of KEPs using ED is high. Most of the admissions concerned usual seizures suggesting that staff training and educational programmes for patients and for their relatives need to be improved. The organization of the prehospital and of the emergency medical services should also be adjusted to this specific need. Further research should be conducted to optimize the seizure care pathway for KEPs.

Biochemical and psychometric evaluation of Self-Healing Qigong as a stress reduction tool among first year nursing and midwifery students.

BACKGROUND: Qigong, a traditional Chinese exercise, has a potential role in the management of stress. OBJECTIVE: To examine the influence of Qigong training on depression, anxiety and stress. DESIGN: A randomised control trial among first year student participants. METHODS: Qigong was practised twice a week by the study group (n = 18) while a control group (n = 16) had no intervention. The Depression, Anxiety and Stress (DASS-21) and Patient Health Questionnaires (PHQ) were administered. Salivary biomarkers were also measured over a 10-week period. RESULTS: After 10 weeks, only the Qigong group showed a statistically significant improvement in their depression, anxiety and stress scores. Similarly, increases in secretion rates of salivary immunoglobulin-A, and decreases in salivary cortisol concentrations were seen only in the Qigong group. CONCLUSIONS: The practice of Qigong improves psychological states and mucosal immunity; as indicated by psychometric tests and biochemical markers of stress.

PI3K-δ and PI3K-γ inhibition by IPI-145 abrogates immune responses and suppresses activity in autoimmune and inflammatory disease models.

Phosphoinositide-3 kinase (PI3K)-δ and PI3K-γ are preferentially expressed in immune cells, and inhibitors targeting these isoforms are hypothesized to have anti-inflammatory activity by affecting the adaptive and innate immune response. We report on a potent oral PI3K-δ and PI3K-γ inhibitor (IPI-145) and characterize this compound in biochemical, cellular, and in vivo assays. These studies demonstrate that IPI-145 exerts profound effects on adaptive and innate immunity by inhibiting B and T cell proliferation, blocking neutrophil migration, and inhibiting basophil activation. We explored the therapeutic value of combined PI3K-δ and PI3K-γ blockade, and IPI-145 showed potent activity in collagen-induced arthritis, ovalbumin-induced asthma, and systemic lupus erythematosus rodent models. These findings support the hypothesis that inhibition of immune function can be achieved through PI3K-δ and PI3K-γ blockade, potentially leading to significant therapeutic effects in multiple inflammatory, autoimmune, and hematologic diseases.

Heat shock protein 90 is a promising target for effective growth inhibition of gastrointestinal neuroendocrine tumors.

Treatment of gastroenteropancreatic neuroendocrine tumors (GEP-NET) is still unsatisfactory and innovative therapeutic approaches are urgently needed. Heat shock protein 90 (Hsp90) is overexpressed in a wide range of tumor types and is an emerging target for the treatment of cancer. However, the potential activity of Hsp90 inhibitors in GEP-NET has not yet been investigated. We studied the antineoplastic activity of the Hsp90 inhibitor IPI-504 on GEP­NET cells, and characterized its mechanism of action. In human insulinoma (CM) and pancreatic carcinoid (BON) cells IPI-504 induced a dose-dependent growth inhibition by almost 70%. The antiproliferative effect of IPI-504 correlated with a reduction in protein levels of the IGF-1 receptor. Additionally, several proteins of the PI3K/AKT/mTOR pathway, downstream of IGF-1 receptor activation in GEP-NETs, were downregulated as a consequence of Hsp90 inhibition. Combination treatment of IPI-504 with mTOR- or AKT-inhibitors led to additive antiproliferative effects. In addition, effects of IGF-1 receptor tyrosine kinase inhibition were strongly enhanced by IPI-504. Cancer gene expression profiling and FACS analysis revealed that IPI-504 antiproliferative effects were due to both induction of cell cycle arrest and apoptosis. A modified chick chorioallantoic membrane (CAM) assay confirmed the antineoplastic activity of IPI-504 in GEP-NETs in vivo. In conclusion, this study showed that Hsp90 inhibition may be an attractive target for innovative GEP-NET treatment alone or in combination with either IGF-1R or mTOR inhibitors.

Antitumor activity of the Hsp90 inhibitor IPI-504 in HER2-positive trastuzumab-resistant breast cancer.

Hsp90 facilitates the maturation and stability of numerous oncoproteins, including HER2. The aim of this study was to assess the antitumor activity of the Hsp90 inhibitor IPI-504 in trastuzumab-resistant, HER2-overexpressing breast cancer cells. Therapy with trastuzumab, IPI-504, and the combination of trastuzumab and IPI-504 was evaluated in trastuzumab-sensitive and trastuzumab-resistant cells. Inhibition of protein targets, cell proliferation, and tumor growth was assessed in vitro and in xenograft models. IPI-504 inhibited proliferation of both trastuzumab-sensitive and trastuzumab-resistant cells. Administration of IPI-504 markedly reduced total levels of HER2 and Akt, as well as phosphorylated Akt and mitogen-activated protein kinase (MAPK), to an equal extent in trastuzumab-sensitive and trastuzumab-resistant cells. IPI-504, used as single agent or in combination with trastuzumab, also inhibited in vivo the growth of both trastuzumab-sensitive and -resistant tumor xenografts. As a mechanism for the observed antitumor activity, IPI-504 resulted in a marked decrease in the levels of HER2, Akt, p-Akt, and p-MAPK in trastuzumab-resistant xenografts as early as 12 hours after a single dose of IPI-504. IPI-504-mediated Hsp90 inhibition may represent a novel therapeutic approach in trastuzumab refractory HER2-positive breast cancer.

The antiproliferative activity of the heat shock protein 90 inhibitor IPI-504 is not dependent on NAD(P)H:quinone oxidoreductase 1 activity in vivo.

IPI-504, a water-soluble ansamycin analogue currently being investigated in clinical trials, is a potent inhibitor of the protein chaperone heat shock protein 90 (Hsp90). Inhibition of Hsp90 by IPI-504 triggers the degradation of important oncogenic client proteins. In cells, the free base of IPI-504 hydroquinone exists in a dynamic redox equilibrium with its corresponding quinone (17-AAG); the hydroquinone form binding 50 times more tightly to Hsp90. It has been proposed recently that the NAD(P)H:quinone oxidoreductase NQO1 can produce the active hydroquinone and could be essential for the activity of IPI-504. Here, we have devised a method to directly measure the intracellular ratio of hydroquinone to quinone (HQ/Q) and have applied this measurement to correlate NQO1 enzyme abundance with HQ/Q ratio and cellular activity of IPI-504 in 30 cancer cell lines. Interestingly, the intracellular HQ/Q ratio was correlated with NQO1 levels only in a subset of cell lines and overall was poorly correlated with the growth inhibitory activity of IPI-504. Although artificial overexpression of NQO1 is able to increase the level of hydroquinone and cell sensitivity to IPI-504, it has little effect on the activity of 17-amino-17-demethoxy-geldanamycin, the major active metabolite of IPI-504. This finding could provide an explanation for the biological activity of IPI-504 in xenograft models of cell lines that are not sensitive to IPI-504 in vitro. Our results suggest that NQO1 activity is not a determinant of IPI-504 activity in vivo and, therefore, unlikely to become an important resistance mechanism to IPI-504 in the clinic.

Circadian clockwork genes are expressed in the reproductive tract and conceptus of the early pregnant mouse.

Circadian genes are expressed in some peripheral tissues, but the expression status of the female reproductive tract and the conceptus over the preimplantation period is unknown. Oocytes, uterine, oviducal tissues and preimplantation conceptuses from days 1-4 of mouse pregnancy were analysed for transcript presence by reverse transcription polymerase chain reaction. Transcripts encoded by the seven known mammalian canonical circadian genes (Per1-3, Cry1-2, Bmal1 and Clock), plus the mammalian genetic homologue of the Drosophila canonical gene Timeless, were detected in the uteri and oviducts taken from mice on days 1-4 of pregnancy and in unfertilized oocytes. After fertilization, transcripts for Per1, Cry1, Bmal1, Clock and Tim have been detected unambiguously. Transcript levels for each of these five genes fall at the two-cell stage, but are restored rapidly for Per1, Cry1 and Bmal1, presumptively by zygotic gene expression. In contrast, transcripts for Clock and Tim recover more slowly. It is concluded that circadian genes are expressed, and may therefore have a role, during the early development of the mammal.