Impact and Other Factors: What's in a Number?

The journal impact factor is an index used to evaluate the relativequality and importance of a journal and is often used to comparejournals in the same field. It is recognized as a measuringstick by which all journals are evaluated. For many scientists,it is an important consideration when determining where     

In Vivo Efficacy Study of Milk Thistle Extract (ETHIS-094?) in STAM? Model of Nonalcoholic Steatohepatitis

Introduction

A subcategory of nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH) is characterized by accumulation of fat accompanied by inflammatory infiltration and hepatocellular damage. The active complex of milk thistle is a lipophilic extract from its seeds, comprising three isomers, collectively known as silymarin. Silymarin has demonstrated antioxidant, anti-inflammatory, and antifibrotic properties, and has been extensively studied in the treatment of liver diseases. The majority of published clinical research on silymarin has used Legalon^® (Rottapharm/Madaus), containing the patented extract of milk thistle ETHIS-094™ (Euromed). The current study was undertaken to examine the effects of ETHIS-094™ in the Stelic Animal Model (STAM™), a validated and widely used animal model for NASH.

Methods

After 4 h fasting from 4 to 8 weeks of age, 15 male mice in whom NASH had been induced were orally administered, once daily, either (1) vehicle (saline) at a volume of 10 mL/kg, (2) vehicle supplemented with milk thistle at a dose of 500 mg/kg, or (3) vehicle supplemented with milk thistle at a dose of 1,000 mg/kg.

Results

Mean liver weight and the liver-to-body weight ratio were significantly (P < 0.01) decreased in the milk thistle high-dose group compared with the vehicle group. NAFLD activity score (NAS) tended to decrease in the milk thistle treatment groups compared with vehicle group, as did steatosis scores.

Conclusion

Milk thistle extract administration induced a decreasing trend in NAS compared with the vehicle group. Milk thistle induced a numerical decrease of the steatosis score compared with vehicle, and this was accompanied by a statistically significant decrease in liver weight and the liver-to-body weight ratio, implying a potential anti-steatosis effect of milk thistle.

Electronic supplementary material

The online version of this article (doi:10.1007/s40268-014-0068-2) contains supplementary material, which is available to authorized users.     

Is Extrapolation of the Safety and Efficacy Data in One Indication to Another Appropriate for Biosimilars?

CT-P13, the world’s first biosimilar monoclonal antibody to infliximab, was approved for marketing in South Korea for all the six indications of infliximab, which Europe may follow, although the product was tested only in rheumatoid arthritis (RA) with a limited pharmacokinetic comparison in ankylosing spondylitis. However, the extrapolation of the efficacy and safety findings of CT-P13 in RA to the other indications appears scientifically challenging when assessed by the current regulatory requirements. RA is not a sensitive clinical model to detect potential differences between CT-P13 and infliximab, and other mechanisms of action than antagonizing tumor necrosis factor α appear to be also important, which could be different by the approved indications. Furthermore, the immunogenicity and safety profiles of CT-P13 were not sufficiently characterized in that immunogenicity potential was lowest in RA, which was even further suppressed by the concomitant use of methotrexate. Extrapolation of the safety and efficacy data in one indication to another may be inappropriate for biosimilars unless backed up by strong scientific justification, which may include the mechanistic exposure–relationship approach. Therefore, regulatory agencies need to exercise caution before granting extrapolated indications to biosimilars.     

Efficacy and Safety of Dorocontin? versus Sustac? in the Treatment of Stable Angina Pectoris: A Randomized,Double-Blind Comparative Trial

Background: Development of generic drugs has numerous benefits in terms of cost-efficiency and availability. Slow-release nitroglycerin is a vasodilator drug commonly prescribed for patients with angina pectoris. Objective: The objective of this study was to compare the efficacy and safety of generic slow-release nitroglycerin (Dorocontin^®) with that of the innovator brand (Sustac^®) in patients with stable angina pectoris. Methods: In this randomized, double-blind comparative trial, 110 patients were allocated to Dorocontin^® (n=67) or Sustac^® (n=43) at a dose of 6.4 mg TID, for a total period of two months. Maximum endurable MET (metabolic equivalent of task), MPI (myocardial perfusion imaging), along with changes in the ECG and biomarkers of renal (serum creatinine, BUN) and hepatic (AST, ALT, and ALP) function, lipid profile (total cholesterol, LDL-C, HDL-C, VLDL-C, and triglycerides), electrolytes (Na⁺ and K⁺), CBC-diff (RBC, WBC, Plt, Hb, Hct, MCV, MCH, MCHC, and RDW), and FBS were assessed at the baseline and at the end of the trial. The frequency of adverse events during the course of the trial was also recorded. Results: Apart from a significantly greater reduction in maximum ST depression in the Sustac^® versus the Dorocontin^® group (p=0.03), none of the functional (MET, MPI, and ECG) and paraclinical (renal function, hepatic function, lipid profile, electrolytes, and FBS) parameters significantly differed between the study groups. The mean Hb (p=0.035), Hct (p=0.045), and MCH (p=0.032) were decreased by the end of the trial in the Sustac^®, but not in the Dorocontin^® group, whilst there was no change in other CBC-diff parameters. Reported adverse events were not serious and included headache, vertigo, gastrointestinal upset, and orthostatic hypotension. The frequency of these adverse events was comparable between the study groups. Conclusion: The findings of the present trial showed comparable efficacy and safety of the generic and innovator products of slow-release nitroglycerin in the management of stable angina pectoris.     

Effects of Methylprednisolone and Its Liver-Targeted Dextran Prodrug on Ischemia–Reperfusion Injury in a Rat Liver Transplantation Model

Purpose To evaluate the effectiveness of a liver-targeted dextran prodrug (DMP) of methylprednisolone (MP) in cold preservation–warm reperfusion injury associated with liver transplantation. Methods The effects of donor pretreatment with single 5 mg/kg doses of MP or DMP on ischemia–reperfusion damage to the liver were studied after 8 or 24 h of cold preservation in both isolated perfused rat liver (IPRL) and syngeneic orthotopic rat liver transplantation (OLT) models. Results In IPRL studies, donor pretreatment with DMP, and to a lesser degree MP, significantly improved the uptake of hyaluronic acid (HA), a marker of endothelial cell function, following 8 h of cold preservation. However, neither pretreatment was protective after 24 h of preservation. In the OLT model using 24-h-preserved livers, the seven-day survival of untreated grafts was 50%. DMP pretreatment of donors significantly improved graft survival to 100%, whereas MP pretreatment was ineffective. Additionally, only DMP significantly increased the blood glucose concentrations and decreased the plasma concentrations of tumor necrosis factor-α after OLT. Other measured markers of liver injury were not affected by either pretreatment. Conclusions Selective delivery of methylprednisolone to the liver as a donor pretreatment strategy improves 24-h preserved graft survival in the OLT model.     

Proteolytic and Non-proteolytic Activation of Keratinocyte-Derived Latent TGF-β1 Induces Fibroblast Differentiation in a Wound-Healing Model Using Rat Skin

Transforming growth factor-β1 (TGF-β1) reportedly causes the differentiation of fibroblasts to myofibroblasts during wound healing. We investigated the mechanism underlying the activation of latent TGF-β1 released by keratinocytes in efforts to identify promising pharmacological approaches for the prevention of hypertrophic scar formation. A three-dimensional collagen gel matrix culture was prepared using rat keratinocytes and dermal fibroblasts. Stratified keratinocytes promoted the TGF receptor–dependent increase in α-smooth muscle actin (α-SMA) immunostaining and mRNA levels in fibroblasts. Latent TGF-β1 was found to be localized suprabasally and secreted. α-SMA expression was inhibited by an anti-α_v-integrin antibody and a matrix metalloproteinase (MMP) inhibitor, GM6001. In a two-dimensional fibroblast culture, α-SMA expression depended on the production of endogenous TGF-β1 and required α_v-integrin or MMP for the response to recombinant latent TGF-β1. In keratinocyte-conditioned medium, MMP-dependent latent TGF-β1 secretion was detected. Applying this medium to the fibroblast culture enhanced α-SMA production. This effect was decreased by GM6001, the anti-α_v-integrin antibody, or the preabsorption of latent TGF-β1. These results indicate that keratinocytes secrete latent TGF-β1, which is liberated to fibroblasts over distance and is activated to produce α-SMA with the aid of a positive-feedback loop. MMP inhibition was effective for targeting both keratinocytes and fibroblasts in this model. [Supplementary Figure: available only at http://dx.doi.org/10.1254/jphs.13209FP]     

Efficacy and Safety of Cerivastatin, 0.2 mg and 0.4 mg,in Patients with Primary Hypercholesterolemia: a Multinational,Randomised, Double-blind Study

Summary

Elevated serum cholesterol level is a key risk factor for cardiovascular morbidity and mortality. Cerivastatin is a highly effective lipid-lowering agent currently licensed at doses of 0.1, 0.2, 0.3 and 0.4?mg.

This was a multicentre, randomised, double-blind, parallel-group study comparing the efficacy and safety of cerivastatin OAmglday with that of cerivastatin 0.2?mg/day in patients with primary hypercholesterolemia. There was a six-week placebo run-in phase followed by a 24-week active treatment phase. A total of 494 patients were randomised to receive cerivastatin 0.4mg (n = 332) or 0.2mg (n = 162). Per-protocol (PP) analysis revealed that mean low-density lipoprotein cholesterol (LDL-C) level decreased by 38.4 ± 0.7% from baseline in the 0.4?mg group, compared with a decrease of 31.5 ± 0.9% in the 0.2mg group (p < 0.0001). There was a significant gender difference in the 0.4?mg group: LDL-C decreased by 44.4 ± 8.9% in women, compared with a decrease of 37.0 ± 0.9% in men (p < 0.046). In the PP group as a whole, total cholesterol decreased by 26.0 ± 0.5% from baseline in the 0.4mg group, compared with a decrease of 21.6 ± 0.7% in the 0.2mg group (p < 0.0001). Both doses were well tolerated; only eight (2.4 %) patients in the 0.4?mg group and five (3.1 %) patients in the 0.2?mg group withdrew owing to adverse events.

Cerivastatin 0.2?mg/day and 0.4?mg/day was found to lower low-density lipoprotein cholesterol and total cholesterol levels in a dose-dependent manner, with both doses exhibiting a good safety profile.     

Preclinical Safety and Pharmacology of Hematide™, a Peptidic Erythropoiesis Stimulating Agent (ESA), in Rats and Monkeys

The pharmacology, toxicokinetics, and safety of Hematide^TM, a synthetic peptidic erythropoiesis-stimulating agent (ESA), were characterized. Hematide was given intravenously (0, 0.5, 5, and 50 mg/kg) weekly for five weeks with a 6- (rat) and 12-week (monkey) recovery period. The pharmacological action of Hematide resulted in polycythemia. Histopathology consistent with drug-induced exaggerated pharmacology was observed primarily in rats. Secondary sequelae resulting from pronounced polycythemia was considered the cause of deaths in rats and a single high-dose monkey. Toxicokinetic analysis indicated prolonged exposure. In conclusion, Hematide is a potent ESA and the safety and efficacy profile support clinical development.     

Efficacy and Safety of hydroxychloroquine sulphate in rheumatoid arthritis: a randomized,double-blind,placebo controlled clinical trial – an Indian experience

ABSTRACT

Objective: Hydroxychloroquine (HCQ) has been used for a long time worldwide as a therapy for rheumatoid arthritis (RA). This trial was designed to determine whether HCQ was efficacious and safe in Indian patients with RA.

Research design and methods: The trial was a multicentre, placebo controlled, randomized and double-blind study. One hundred and twenty-two patients with RA were enrolled in 3 different centres for the trial (26 males and 96 females in the age group of 18–60 years). Patients were randomized to receive either hydroxychloroquine tablets (n = 61) two tablets of 200?mg daily or placebo (n = 61) two tablets daily. After 8 weeks all patients received one tablet of hydroxychloroquine 200?mg daily for 4 weeks. Every patient also received one tablet of Nimesulide 100?mg twice daily.

Main outcome measures: Assessment of response at 12 weeks using modified ACR 20 (American College of Rheumatology 20) criteria where Health Assessment Questionnaire (HAQ) was replaced by ARA (American Rheumatology Association) functional class.

Results: 40.4% of patients on hydroxychloroquine showed improvement by modified ACR response criteria whereas only 20.7% (?p = 0.02) showed improvement in the placebo group. No significant side effects were observed in any of the patients. There were no ocular toxicities.

Conclusions: Hydroxychloroquine was found to be an effective and well-tolerated drug in rheumatoid arthritis in Indian patients.     

Contribution of TRPV1 Receptor–Expressing Fibers to Spinal Ventral Root After-Discharges and Mechanical Hyperalgesia in a Spared Nerve Injury (SNI) Rat Model

Neuropathic pain induces allodynia and hyperalgesia. In the spared nerve injury (SNI) model, marked mechanical hyperalgesia is manifested as prolongation of the duration of paw withdrawal after pin stimulation. We have previously reported that spinal ventral root discharges (after-discharges) after cessation of noxious mechanical stimulation applied to the corresponding hindpaw were prolonged in anesthetized spinalized rats. Since these after-discharges occurred through transient receptor potential (TRP) V1–positive fibers, these fibers could contribute to mechanical hyperalgesia. Therefore, we examined whether selective deletion of TRPV1-positive fibers by resiniferatoxin, an ultrapotent TRPV1 agonist, would affect the behavioral changes and ventral root discharges in SNI rats. Mechanical allodynia in the von Frey test, mechanical hyperalgesia after pin stimulation, and enhancement of ventral root discharges, but not thermal hyperalgesia in the plantar test, appeared in Wistar rats with SNI. Mechanical hyperalgesia was abolished by treatment with resiniferatoxin, whereas mechanical allodynia was not affected. Moreover, resiniferatoxin eliminated after-discharges completely. These results show that TRPV1-positive fibers do not participate in the mechanical allodynia caused by sensitization of Aβ-fibers, but contribute to the enhancement of after-discharges and mechanical hyperalgesia following SNI. It is suggested that the mechanisms responsible for generating mechanical allodynia differ from those for prolongation of mechanical hyperalgesia.     

Does stage-of-change predict dropout in a culturally diverse sample of adolescents admitted to inpatient substance-abuse treatment? A test of the Transtheoretical Model

The Transtheoretical Model (TTM) (Prochaska, Diclemente, &; Norcross, 1992) proposes that the stages-of-change construct can serve as useful tool for identifying those most at-risk of treatment dropout [Prochaska, J. O. (1999). How do people change, and how can we change to help many more people? In M. A. Hubble, B. L. Duncan, &; S. D. Miller (Eds.), The heart and soul of change (pp. 227–255). Washington: American Psychological Association]. While researchers have found mixed support for this claim in adult samples, studies have not yet tested this issue in adolescent substance-abuse treatment settings. This paper reports findings from a Canadian study of adolescents (n = 130: 80 Caucasians, 50 Aboriginals) admitted to a hospital-based, residential substance-abuse treatment program. Two approaches were used to test the TTM's claim: (1) a hierarchical logistic regression model of dropout was developed using the subscales of the University of Rhode Island Change Assessment instrument (URICA), demographic variables, and subscales of the Addiction Severity Index (ASI); and (2) a chi-square analysis was employed to test the hypothesized relation between stage-of-change and dropout status. The findings demonstrated that the best predictive model of dropout included only the Precontemplation subscale of the URICA (OR: 4.3; 95% CI: 2.0–9.0). In addition, adolescents assigned to the Precontemplation stage manifested significantly higher rates of treatment attrition than individuals in the Contemplation or Preparation/Action stages. This study provides important empirical support for the predictive utility of the stage-of-change construct among a culturally diverse sample of adolescents admitted to an inpatient substance-abuse treatment program.     

Does interaction between zinc and glutamate system play a significant role in the mechanism of antidepressant action?

In the central nervous system, zinc modulates predominantly the excitatory amino acid (glutamatergic) neurotransmission. Recent studies demonstrated that chronic antidepressant treatment, which is required for clinical improvement, reduced the reactivity/function of the glutamate/NMDA receptor complex and altered zinc concentration/interaction with this receptor type in the rodent brain. In the cerebral cortex: chronic antidepressant treatment "down-regulated" (reduced density/affinity) of the cortical (but not hippocampal) NMDA receptors measured by radioligand-receptor binding methods. Moreover, chronic imipramine treatment increased the ability of zinc ion to inhibit the NMDA receptor complex in the cerebral cortex but not in the hippocampus. In the hippocampus: chronic treatment with antidepressant drugs (imipramine or citalopram) increased the hippocampus/brain region ratio of zinc concentration, which may indicate redistribution of the rat brain zinc. On the other hand, electroconvulsive shocks induced robust increase of zinc concentration in the hippocampus (with a slight effect in the rest of brain). In spite of the lack of alterations in the hippocampal NMDA receptors (measured by receptor binding methods), inhibitory effect of the increased hippocampal zinc concentration induced by chronic antidepressant treatment, may be responsible for reduction in the function of that receptor complex also in the hippocampus. These data indicate a critical and complex role of the interaction between zinc and NMDA receptor complex in the mechanism of antidepressant treatment and strongly support the glutamate hypothesis of the mechanism of antidepressant action.     

In Vivo Evaluation of Doxorubicin-Loaded (PEG)3-PLA Nanopolymersomes (PolyDoxSome) Using DMBA-Induced Mammary Carcinoma Rat Model and Comparison with Marketed LipoDox?

Purpose

To evaluate in vivo doxorubicin-loaded (PEG)₃-PLA nanopolymersomes (PolyDoxSome) using 7,12-dimethyl benz[??]anthracene (DMBA)-induced mammary carcinoma rat model compared to marketed formulation LipoDox?.

Methods

Sprague Dawley female rats with mean tumor volume of about 2?cm³ were used for pharmacokinetics, biodistribution, antitumor efficacy and toxicity studies.

Results

This study demonstrates that PolyDoxSome has higher AUC (569 vs. 4?h*??g/mL), longer plasma circulation half life (21.9 vs. 0.49?h), decreased clearance (10.5 vs. 1579?mL/h/kg) and volume of distribution (137.7 vs. 1091?mL/kg) as compared to free doxorubicin. Tissue distribution profile showed increased doxorubicin concentration in tumor and decreased concentration in heart as compared to free doxorubicin. The toxicity studies as measured from liver function tests, cardiac enzyme assays, hematology test and body weight has demonstrated that it is better tolerated than free doxorubicin. When PolyDoxSome was compared with LipoDox?, it differs in size (171 vs. <100?nm), plasma circulation half life (22 vs. 35?h), C_max (34 vs. 67???g/mL), and AUC (568 vs. 2291?h*??g/mL), however PolyDoxSome was comparable on efficacy and toxicity profile of LipoDox?.

Conclusions

Results suggest that PolyDoxSome has better in vivo profile than free doxorubicin and comparable efficacy and toxicity to LipoDox?.

Does the combination of alendronate and parathyroid hormone give a greater benefit than either agent alone in osteoporosis?

In osteoporosis, both the bisphosphonate alendronate and parathyroid hormone (1-34) (PTH (1-34) ) have been shown to reduce the incidence of fractures. As bisphosphonates and PTH have different mechanisms, it has been proposed that their effects in osteoporosis may be additive. However, a major clinical trial of PTH (1-84) and alendronate in postmenopausal women demonstrated that their effects were not additive. A further trial in men with osteoporosis showed that alendronate impaired the ability of PTH (1-34) to increase bone mineral density. The combination of alendronate and PTH does not have greater benefit than either agent alone, and may even be detrimental, thus should not be used.     

Does the combination of alendronate and parathyroid hormone give a greater benefit than either agent alone in osteoporosis?

In osteoporosis, both the bisphosphonate alendronate and parathyroid hormone_(1–34) (PTH_(1–34)) have been shown to reduce the incidence of fractures. As bisphosphonates and PTH have different mechanisms, it has been proposed that their effects in osteoporosis may be additive. However, a major clinical trial of PTH_(1–84) and alendronate in postmenopausal women demonstrated that their effects were not additive. A further trial in men with osteoporosis showed that alendronate impaired the ability of PTH_(1–34) to increase bone mineral density. The combination of alendronate and PTH does not have greater benefit than either agent alone, and may even be detrimental, thus should not be used.     

Efficacy and Tolerability of a Low-dose of Oesclim® (25 mcg Daily) in the Management of Symptomatic Menopausal Women: A French Open-label Study

Summary

Objective: To establish the proportion of symptomatic postmenopausal women, whose HRT treatment is initiated on Oesclim® 25, who can be satisfactorily maintained on this low dose after two months. Study design and patients: This was an open-label, multicentre, non-comparative, four-month treatment study. Treatment was initiated with Oesclim® 25 (17β-oestradiol transdermal patch, 25 mcg/day). Dosage could be increased to Oesclim® 50 if required after two months, according to clinical evaluation. Sequential treatment with an oral progestagen was also given for ≥12 days/month in all non-hysterectomised women. A total of 1465 women were included in the study.

Results: 82.3% (CI: 80.1–84.4) of patients remained on Oesclim® 25 across the whole study. The mean number of hot flushes was reduced similarly by 93% and 94% at month 4 in the Oesclim® 25 group and Oesclim® 50 group, respectively. However, at month 2 the decrease in hot flushes and other menopausal symptoms was less marked until the dose was adjusted, in patients switching to Oesclim® 50. In a global evaluation, 97.5% of the investigators and 95.7% of the patients rated the overall efficacy of the treatment as good/very good. Overall, treatment initiated at a low dose was well tolerated throughout the study, with a trend showing Oesclim® 25 as being better tolerated than Oesclim® 50.

Conclusion: Oesclim® low dose (25 mcg) can effectively reduce symptoms in most postmenopausal women with a very satisfactory level of tolerability. The risk/benefit ratio observed is probably one key reason for good patient compliance.     

Does nebivolol influence serum concentrations of proinflammatory cytokines in hypertensive (SHR) and normotensive (WKY) rats?

A growing body of evidence suggests that some drugs used in cardiovascular diseases may modulate the level of proinflammatory cytokines. In the present study we examined whether nebivolol, a third generation P-adrenergic blocker, influences lipopolysaccha-ride (LPS)-induced serum concentrations of TNF-α, IL-1P, and IL-6 in normotensive (WKY) and spontaneously hypertensive rats (SHR). Nebivolol (5 mg/kg and 10 mg/kg) or vehicle were administered by gavage once a day for 21 days. The drug (5 mg/kg and 10 mg/kg) did not modify LPS-stimulated serum concentrations of TNF-α, IL-1P and IL-6 in normotensive or hypertensive rats and did not affect the total cholesterol and HDL cholesterol level. Nebivolol, at the dose of 10 mg/kg, significantly increased the triglyceride concentration in SHR only. The results were accompanied by a statistically significant decrease in systolic, diastolic and mean blood pressure after 21 days of both of the drug doses. In hypertensive and normotensive rats, nebivolol had a hypotensive activity and neutral effect on lipid profile. In our in vivo model, the immunomodulating effect of the drug was not significant and probably did not depend on hemodynamic action.