Inhibition of Chemoresistance in Primary Tumor Cells by Camellia sinensis non fermentatum Extract Noviphenone (NPE®).

BACKGROUND/AIM: Despite improvements in cancer therapy, life expectancy after tumor recurrence remains low. Relapsed cancer is characterized by drug resistance, often mediated through overexpression of multidrug resistance (MDR) genes. Camellia sinensis non fermentatum extract is known for its anticancer properties in several cancer cell lines and might improve cancer therapy outcome after tumor recurrence. MATERIALS AND METHODS: Embryonal rhabdomyosarcoma cell lines, alveolar rhabdomyosarcoma cell lines and primary rhabdomyosarcoma MAST139 cells were used to test NPE® effects on cell viability in combination with chemotherapeutic agents. Cell viability was measured by the WST-1 assay and CV staining. Gene expression levels of chemotherapy-induced efflux pumps and their activity was assessed upon NPE® treatment by measuring doxorubicin retention through evaluation of the autofluorescence signal. RESULTS: Administration of increasing doxorubicin concentrations triggered immediate adaptation to the drug, which was surprisingly overcome by the addition of NPE®. Investigating the mechanism of immediate adaptation, MDR1 gene overexpression was observed upon doxorubicin treatment. Although NPE® did not alter pump gene expression, it was able to reduce pump activity, thus allowing the chemotherapeutic agent to stay inside the cells to exert its full anticancer activity. CONCLUSION: NPE® might improve chemotherapeutic treatment by re-sensitizing relapsed tumors to anticancer drugs. Fighting MDR represents the key to overcome tumor relapse and improve the overall survival of cancer patients.

Prevention of Acute Radiation-Induced Skin Reaction with NPE® Camellia Sinensis Nonfermentatum Extract in Female Breast Cancer Patients Undergoing Postoperative Radiotherapy: A Single Centre, Prospective, Open-Label Pilot Study.

BACKGROUND: To assess effectiveness of NPE, a proprietary Camellia sinensis nonfermentatum (CSNF) extract, in prevention and recovery of acute radiation-induced skin reaction (ARSR) and skin care during postoperative whole breast radiotherapy (RT). METHODS: Twenty patients were enrolled in this single centre, prospective, open-label pilot study. The outcomes of 20 prospective data sets were compared with 100 retrospectively collected matched data sets derived from hospital records. The preventive CSNF gel (2.5%) was administered 1 to 2 hours before each session on the irradiated fields. The care CSNF lotion (0.4%) was administered as 7-day pretreatment after each RT session, twice daily between RT sessions, and 4 to 8 weeks thereafter. The control group was treated according to the hospital care guidelines. The primary endpoint was time to ARSR ≥ Grade 2 (CTCAE v4.03); secondary endpoints were frequencies of ARSR grades 1, 2, 3, and 4, recovery of ARSR, frequencies of interruption and RT stop, complications and required rescue interventions, and tolerability of CSNF. RESULTS: Time to ARSR ≥ G2 (censoring) was significantly longer (p = 0.014) in the CSNF group. The hazard ratio was 2.33 (95% CI: 1.15-4.72), demonstrating a 50% decrease in the risk of developing ARSR ≥ G2. There was a trend to faster recovery from ARSR G2 in the CSNF group (100% versus 47%; p = 0.078). The proportion of patients requiring rescue treatment during RT and follow-up was markedly higher in the control compared to the CSNF group (1% to 51% versus 0% to 15%). CSNF gel and lotion were well tolerated both during and after RT. CONCLUSIONS: This pilot study provides the first evidence on the potential pharmacological effectiveness of CSNF extract in prevention of RT-induced ARSR and recovery of skin irritation in patients undergoing postoperative whole breast RT and may reflect a novel concept for prevention of RT-induced ARSR and care of irritated skin.

Rivaroxaban for Thromboprophylaxis After Nonelective Orthopedic Trauma Surgery in Switzerland.

This study investigated the effectiveness and the outcomes of rivaroxaban vs the standard of care for venous thromboembolic prophylaxis in patients undergoing fracture-related surgery. A total of 413 patients undergoing fracture-related surgery from 9 Swiss orthopedic and trauma centers were enrolled. The authors selected the type of venous thromboembolic prophylaxis according to standardized medical practice at the participating centers before the inclusion of patients: 208 patients received rivaroxaban and 205 received the standard of care. Data on symptomatic thromboembolic and bleeding events, surgery-related complications, death, adverse events, time to mobilization, and hospital discharge were collected. Symptomatic thromboembolic events were reported in 1 patient (0.5%) and 2 patients (1.0%) and treatment-emergent major bleeding events were reported in 1 patient (0.5%) and 2 patients (1.0%) receiving rivaroxaban and the standard of care, respectively. The durations of hospital stay and venous thromboembolic prophylaxis were similar in the 2 groups. In both groups, adverse events related to venous thromboembolic prophylaxis were reported in 12 patients. The proportion of patients with minor and major fracture surgery was 74.3% and 25.7%, respectively. In patients undergoing minor fracture surgery receiving rivaroxaban (n=167) and the standard of care (n=140), no symptomatic thromboembolic events and no major bleeding events were reported. Outcomes of this study indicate that rivaroxaban might be an appropriate oral alternative for venous thromboembolic prophylaxis in routine medical care after fracture-related major and minor surgery. Reported results were comparable to those from other large-scale, noninterventional and randomized controlled studies. [Orthopedics. 2017; 40(2):109-116.].

Pharmaceutical quality of seven generic Levodopa/Benserazide products compared with original Madopar® / Prolopa®.

BACKGROUND: By definition, a generic product is considered interchangeable with the innovator brand product. Controversy exists about interchangeability, and attention is predominantly directed to contaminants. In particular for chronic, degenerative conditions such as in Parkinson's disease (PD) generic substitution remains debated among physicians, patients and pharmacists. The objective of this study was to compare the pharmaceutical quality of seven generic levodopa/benserazide hydrochloride combination products marketed in Germany with the original product (Madopar® / Prolopa® 125, Roche, Switzerland) in order to evaluate the potential impact of Madopar® generics versus branded products for PD patients and clinicians. METHODS: Madopar® / Prolopa® 125 tablets and capsules were used as reference material. The generic products tested (all 100 mg/25 mg formulations) included four tablet and three capsule formulations. Colour, appearance of powder (capsules), disintegration and dissolution, mass of tablets and fill mass of capsules, content, identity and amounts of impurities were assessed along with standard physical and chemical laboratory tests developed and routinely practiced at Roche facilities. Results were compared to the original "shelf-life" specifications in use by Roche. RESULTS: Each of the seven generic products had one or two parameters outside the specifications. Deviations for the active ingredients ranged from +8.4% (benserazide) to -7.6% (levodopa) in two tablet formulations. Degradation products were measured in marked excess (+26.5%) in one capsule formulation. Disintegration time and dissolution for levodopa and benserazide hydrochloride at 30 min were within specifications for all seven generic samples analysed, however with some outliers. CONCLUSIONS: Deviations for the active ingredients may go unnoticed by a new user of the generic product, but may entail clinical consequences when switching from original to generic during a long-term therapy. Degradation products may pose a safety concern. Our results should prompt caution when prescribing a generic of Madopar®/Prolopa®, and also invite to further investigations in view of a more comprehensive approach, both pharmaceutical and clinical.

End-digit preference in general practice: a comparison of the conventional auscultatory and electronic oscillometric methods.

INTRODUCTION: In clinical practice, end-digit preference is a common feature of blood pressure (BP) measurements. A wider use of electronic BP measuring machines could decrease this observer-linked artefact. The purpose of this analysis was to investigate the frequency of end-digit preference and to evaluate the impact of this observer bias on the assessment of the BP control induced in a large group of hypertensive patients treated with a calcium-channel blocker in whom BP was measured either with an automatic device or with a conventional sphygmomanometer. METHODS: Five hundred and four physicians participated in the study and 2199 patients were included. Treatment with lercanidipine was introduced at a dosage of 10 mg and titration to 20 mg was optional according to the physician's decision. BP was assessed at 4 and 8 weeks. To measure BP, physicians could use either a standard mercury sphygmomanometer or a pre-defined validated semi-automatic device (Microlife Average Mode, BP 3AC1-1, Microlife Corporation, Berneck, Switzerland) but they had to use the same method throughout the study. Physicians had to transcribe all BP measurements onto case report forms. RESULTS: Very marked digit preferences were observed for both the conventional and the automatic measurements, being most prominent for the digit "0" (52% and 25%, respectively) followed by a preference for the digit "5" (19% and 15%). The use of the semi-automatic device reduces to a certain extent the frequency of the bias but the problem remains if physicians have to transfer the BP values onto case report forms. The end-digit preference has a major impact on the evaluation of a treatment effect and on the assessment of the percentage of patients achieving target BP in a population. CONCLUSION: These results confirm that end-digit preference remains a serious bias in clinical practice. This bias has important consequences when evaluating the efficacy of a new antihypertensive drug. There is a need for training programmes and quality controls in clinical practice. The development of automatic systems with a direct transfer of BP values from the measuring device to the clinical chart or to the case report form should be encouraged.

Efficacy and tolerability of lercanidipine in patients with hypertension: results of a Phase IV study in general practice.

INTRODUCTION: Calcium antagonists are very effective drugs, recommended as first-line therapy in hypertension. However, their large use in clinical practice is often limited by a high incidence of peripheral oedema. Calcium antagonists of the third generation, such as lercanidipine, have been shown to be as effective as first- and second-generation calcium antagonists, while showing a better side-effect profile. OBJECTIVE AND METHODS: The purpose of the present Phase IV study was to investigate the efficacy and tolerability of lercanidipine in a large unselected population of hypertensive patients managed in private practice in Switzerland. A total of 504 physicians participated in this survey and 2199 patients were included. Treatment with lercanidipine was introduced at a dose of 10 mg and titration to 20 mg was optional according to the physician's decision. Evaluations of blood pressure control and tolerability were made after 4 and 8 weeks. RESULTS: The results of the present study show that lercanidipine is an effective and well tolerated antihypertensive agent in newly treated hypertensive patients. In this group of patients, 63% reached the target blood pressure (< or = 140/90 mmHg) with lercanidipine alone. Lercanidipine is also an effective alternative in patients who are insufficiently controlled with another therapy, or in patients not tolerating other calcium channel blockers. Finally, lercanidipine is well-tolerated, with a very low rate of drop-out (1-2%) because of adverse events, and a low occurrence of peripheral oedema. CONCLUSION: Lercanidipine is an effective and well tolerated calcium channel blocker of the third generation. This new calcium antagonist represents a very useful tool to improve blood pressure control in the community.

Differential sensitivity of three experimental pain models in detecting the analgesic effects of transdermal fentanyl and buprenorphine.

This is the first randomized controlled trial that tests the analgesic efficacy of transdermally delivered opioids in healthy volunteers and that assesses the sensitivity of different experimental pain tests to detect analgesia in this setting. Transdermal application of the full agonist fentanyl (TDF: 12.5 or 25 microg/h) and the partial agonist buprenorphine (TDB: 35 microg/h) was compared in three experimental models of acute pain (heat pain, painful electrical stimulation, cold pressor) in a double-blind, randomized, placebo-controlled, 4-arm crossover study with 20 healthy subjects (15 men, 5 women). Patches were administered for 72 h and pain levels measured at baseline and 24 and 72 h, with an 11-day wash-out. The cold pressor test was most sensitive to analgesic effects, with significant reductions in area under the pain intensity curve for all active compounds at 24 h (average reductions: 14% TDF 12.5 microg/h, 35% TDF 25 microg/h, 43% TDB 35 microg/h). There were significant increases in heat pain threshold for TDF 25 microg/h and TDB 35 microg/h. Painful electrical stimulation failed to demonstrate an analgesic effect. The magnitude of analgesia in the cold pressor model showed some correlation with TDF dosage and comparable effects for the full agonist fentanyl and the partial agonist buprenorphine. We conclude that the cold pressor test was most sensitive to analgesic effects in healthy subjects and that a transdermal dose of 12.5 microg/h fentanyl achieved significant pain reduction compared with placebo. Subjects experienced opioid-typical AEs including dizziness, nausea and vomiting. No serious AEs occurred.

A comparison of the skin irritation potential of transdermal fentanyl versus transdermal buprenorphine in middle-aged to elderly healthy volunteers.

OBJECTIVE: Establishing local tolerability of transdermal opioid systems is important as more systems become available for use in a range of indications. We compared the skin irritation potential of a single application of transdermal fentanyl (Durogesic D-trans; DDTDF) and transdermal buprenorphine (Transtec; TDB) patches in healthy volunteers. METHODS: 46 healthy males and females (mean age [range]: 59.6 [50-69] years) with healthy skin received a single dose of both the DDTDF 25 mug/h patch and the TDB 35 mug/h patch in a randomised order under naltrexone cover. The incidence and severity of erythema was assessed at various timepoints after patch removal. RESULTS: There was a non-significant trend towards a higher incidence of erythema 60 min after patch removal with TDB compared with DDTDF. The severity of erythema at 60 min and the incidence of erythema at 72 h after patch removal were significantly higher with TDB than with DDTDF (p = 0.01 and 22% versus 4.9%, p = 0.04, respectively). In general, the results from the chromametric assessment of treated skin were in agreement. The incidence of topical adverse events (AEs) was lower with DDTDF than with TDB (one versus six events) and subjects preferred the DDTDF patch and felt it was less noticeable on the skin. The DDTDF patch was considered less painful to remove, and, consistent with that, the TDB patch was judged to have better adhesion. Twenty-one subjects reported systemic AEs with DDTDF plus naltrexone and 22 with TDB plus naltrexone, most of which were considered treatment-related, 34 and 60 AEs, respectively. CONCLUSIONS: Local tolerability of transdermal opioid systems should be considered when making a therapeutic choice. Even after a single application in healthy volunteers, differences in local tolerability, assessed both clinically and by chromametry, and patch comfort were shown between DDTDF and TDB, in favour of DDTDF.