Differential migratory properties of monocytes isolated from human subjects naïve and non-naïve to Cannabis

This study evaluates the migratory potential of monocytes isolated from two groups of human subjects: naïve and non-naïve to Cannabis. Phytocannabinoids (pCB), the bioactive agents produced by the plant Cannabis, regulate the phenotype and function of immune cells by interacting with CB₁ and CB₂ receptors. It has been shown that agents influencing the phenotype of circulating monocytes influence the phenotype of macrophages and the outcome of immune responses. To date, nothing is known about the acute and long-term effects of pCB on human circulating monocytes. Healthy subjects were recruited for a single blood draw. Monocytes were isolated, fluorescently labeled and their migration quantified using a validated assay that employs near infrared fluorescence and modified Boyden chambers. CB₁ and CB₂ receptor mRNA expression was quantified by qPCR. Monocytes from all subjects (n = 10) responded to chemokine (c–c motif) ligand 2 (CCL2) and human serum stimuli. Acute application of pCB significantly inhibited both the basal and CCL2-stimulated migration of monocytes, but only in subjects non-naïve to Cannabis. qPCR analysis indicates that monocytes from subjects non-naïve to Cannabis express significantly more CB₁ mRNA. The phenotype of monocytes isolated from subjects non-naïve to Cannabis is significantly different from monocytes isolated from subjects naïve to Cannabis. Only monocytes from subjects non-naïve to Cannabis respond to acute exposure to pCB by reducing their overall migratory capacity. Our study suggests that chronic exposure to Cannabis affects the phenotype of circulating monocytes and accordingly could influence outcome of inflammatory responses occurring in injured tissues.     

A reliable model of intravenous MDMA self-administration in naïve mice

Rationale

MDMA is one of the most widely consumed recreational drugs in Europe. However, the mechanisms involved in the reinforcing properties of MDMA are still unclear. In this sense, the establishment of a reliable model of MDMA self-administration in mice could represent an important approach to study the neuronal substrates associated with MDMA reward by using genetically modified mice.

Objectives

To develop a reliable model of operant intravenous MDMA self-administration in drug-naïve mice.

Materials and methods

Mice were trained to acquire intravenous self-administration of MDMA at different doses (0, 0.06, 0.125, 0.25, 0.5 and 1.0 mg/kg/infusion) on a FR1 schedule of reinforcement for 15 consecutive days. The motivational value of different doses of MDMA (0.125, 0.25 and 0.5 mg/kg/infusion) was then tested using a progressive ratio paradigm. Finally, [³H]-mazindol autoradiographic studies were carried out in order to quantitatively assess presynaptic dopamine transporter (DAT) binding sites in the striatum of mice trained to self-administer MDMA (0 and 1.0 mg/kg/infusion) during 15 days.

Results

The latency for discrimination between the active and inactive holes, as well as the number of animals acquiring stability criteria, varied as a function of the dose of MDMA. The mice responding for intermediate doses (0.125, 0.25 and 0.5 mg/kg/infusion) discriminated earlier than those responding for low (0.06 mg/kg/infusion) or high (1.0 mg/kg/infusion) doses. The percentage of animals achieving stability criteria increased with days of testing and was inversely proportional to the dose of MDMA. The breaking points achieved for doses of 0.125 and 0.25 mg/kg/infusion were significantly higher than for a dose of 0.5 mg/kg/infusion. No significant DAT neurotoxicity was observed in the striatum of animals self-administering MDMA at a dose of 1 mg/kg/infusion.

Conclusions

The present results show that MDMA can be reliably self-administered by drug-naïve mice.     

Use of almotriptan in triptan-experienced and triptan-naïve patients

ABSTRACT

Objective: To evaluate the efficacy of oral almotriptan 12.5?mg as an acute treatment for migraine with a focus on triptan-experienced versus triptan-naïve patients.

Research design and methods: Four recent Almirall-sponsored clinical trials of oral almotriptan 12.5?mg in acute migraine, in which data regarding previous acute therapy were collected, are reviewed. The results and conclusions are limited by the open-label and post hoc design of some of these trials and analyses.

Results: In two trials, almotriptan 12.5?mg was used to treat migraine sufferers who were dissatisfied with or were receiving inadequate results with their previous therapy. One of these trials enrolled only patients whose dissatisfaction with their current therapy was confirmed by a validated questionnaire; the other looked at almotriptan 12.5?mg efficacy in patients with previous poor response to sumatriptan. In the other two trials, patients had been achieving satisfactory results with their migraine therapy; one was a randomized, double-blind clinical trial of almotriptan 12.5?mg and zolmitriptan 2.5?mg, the other was an open-label almotriptan 12.5?mg satisfaction trial. Almotriptan 12.5?mg is shown to be effective, well-tolerated, and preferred to previous agents in both patients who were satisfied with, and those who were dissatisfied with, their previous therapy.

Conclusions: Almotriptan should, therefore, not only be considered as first-line therapy for acute migraine but should also be considered for patients who are not satisfied with or not receiving optimal relief from their current acute therapy.     

Comparison of airway response in naïve and ovalbumin-sensitized mice during short-term inhalation exposure to chlorine

Objective: It has been suggested that asthmatics are more susceptible than healthy individuals to airborne irritating chemicals in general. However, there is limited human data available to support this hypothesis due to ethical and practical difficulties. We explored a murine model of ovalbumin (OVA)-induced airway inflammation to study susceptibility during acute exposure to chemicals with chlorine as a model substance.

Methods: Naïve and OVA sensitized female BALB/c mice were exposed to chlorine at four different concentrations (0, 5, 30 and 80?ppm) for 15?minutes with online recording of the respiratory function by plethysmography. The specific effects on respiratory mechanics, inflammatory cells and inflammatory mediators (cytokines and chemokines) of the airways were measured 24?hours after the chlorine exposure as well as histopathological examination of the lungs.

Results: Similar concentration-dependent reductions in respiratory frequency were seen in the two groups, with a 50% reduction (RD₅₀) slightly above 5?ppm. Decreased body weight 24?hours after exposure to 80?ppm was also observed in both groups. Naïve, but not OVA-sensitized, mice showed increased bronchial reactivity and higher number of neutrophils in bronchoalveolar lavage fluid at 80?ppm.

Conclusions: The results do not support an increased susceptibility to chlorine among OVA-sensitized mice. This animal model, which represents a phenotype of eosinophilic airway inflammation, seems unsuitable to study susceptibility to inhalation of irritants in relation to asthma.     

Evaluating the cost of sustained virologic response in naïve chronic hepatitis C patients treated à la carte

Summary

Background

There is a tendency to individualize treatment in chronic hepatitis C patients depending on viral load and rapid clearance of HCV‐RNA.

Aim

To evaluate the cost (€, 2006) per sustained virologic response in naïve patients with therapy à la carte compared with standard combination therapy.

Methods

A decision analysis model was used to compare standard therapy with peginterferon alpha and ribavirin for 24 weeks for genotype (G) 2/3, and 48 weeks for G1 and therapy à la carte with the same drugs but different durations: G1 high viral load for 48 weeks, G1 low viral load with rapid virologic response for 24 weeks, and without rapid virologic response for 48 weeks, and G2/3 with rapid virologic response for 12 weeks, and without rapid virologic response for 24 weeks.

Results

Sustained virologic response was similar in both strategies. The cost per successfully treated patient for standard therapy is €17 812 and for therapy à la carte€12 313. Assuming that 13 309 patients with standard therapy and 14 450 patients with therapy à la carte achieve sustained virologic response, therapy à la carte has an overall cost‐saving of €59.13 million.

Conclusion

Therapy à la carte is a cost‐saving strategy for chronic hepatitis C infection compared to standard therapy, with lower investment requirement per patient to achieve sustained virologic response.

     

Anemia treatment with Q2W darbepoetin alfa in patients with chronic kidney disease naïve to erythropoiesis-stimulating agents*

ABSTRACT

Objective: To evaluate the efficacy and safety of darbepoetin alfa dosed every-other-week (Q2W) to treat anemia in subjects with chronic kidney disease (CKD), not receiving dialysis, who were naïve to erythropoiesis-stimulating agent (ESA) therapy.

Research design and methods: This was an open-label, multicenter, single-arm study enrolling ESA-naïve CKD subjects with baseline hemoglobin (Hb)?<?11.0?g/dL. Q2W darbepoetin alfa treatment was initiated at a dose of 0.75?µg/kg and titrated to achieve and maintain Hb levels at 11.0–13.0?g/dL. Treatment was administered from week 1 to week 19.

Main outcome measures: The primary endpoint was the proportion of subjects who achieved Hb?≥?11?g/dL at any study visit, except in week 1. Hb levels, darbepoetin alfa dose, and safety were also assessed.

Results: Of the 128 subjects who received at least one dose of darbepoetin alfa and of the subjects who completed the study, 118 (92%) and 112 (97%), respectively, achieved a Hb?≥?11?g/dL in a median time of 5 weeks. Median darbepoetin alfa dose at week 1 and at the time of achieving a Hb?≥?11?g/dL were 60 and 80?µg, respectively. Darbepoetin alfa was well-tolerated, and short-term adverse events were consistent with those expected in CKD subjects.

Conclusions: This study demonstrates that de novo Q2W darbepoetin alfa was effective in correcting and maintaining Hb levels in ESA-naïve subjects with CKD who were not receiving dialysis. Study limitations, including lack of a control arm for the study and multiple race information for subjects, must be considered in interpreting the results.

Trial registration: ClinicalTrials.gov identifier: NCT00112008.     

Systemic therapy for metastatic renal cell carcinoma in treatment naïve patients: a risk-based approach

Importance of the field: Kidney cancer is the ninth most common cancer in the USA, with an annual incidence of approximately 55,000 cases per year. Over 13,000 patients are estimated to die from this disease annually. Cloning of the VHL gene, recognition of the associated abnormalities in sporadic clear-cell carcinoma, and its role as a regulator of the hypoxic response, were important milestones in our understanding of renal-cell carcinoma (RCC) biology and the recognition of the vascular endothelial growth factor (VEGF) dependency of RCC. A variety of clinical features, including histologic features, prognostic factors, and patient history of comorbid illness, provide the framework in which the results of recent clinical trials and regulatory approvals of these agents are utilized to develop treatment recommendations for the largest metastatic patient RCC group, the therapy naïve individual.

Areas covered in this review: The rationale for use of VEGF-targeted therapy in advanced RCC patients and the recently developed treatment options for these individuals are reviewed. Regulatory approval of sorafenib for the treatment of metastatic RCC (mRCC), was followed by the approval of sunitinib, temsirolimus, bevacizumab plus interferon (IFNα), everolimus, and – most recently – pazopanib. These licences were granted from late 2005 through late 2009, a very short span of 4 years. In treatment-naïve mRCC patients, sunitinib, sorafenib, pazopanib, bevacizumab + IFNα, and temsirolimus were approved by the Food and Drug Administration (FDA) and/or the European Medicines Agency (EMEA). The clinical trials and data supporting these approvals are reviewed.

What will the reader gain: This review examines these developments and provides the reader an overview and understanding of available current systemic therapy options for treatment-naïve mRCC patients.

Take home message: As multiple treatment options are now available for treatment-naïve mRCC patients, an understanding of how to utilize this group of agents is required. The use of various clinical features allows a rational approach to therapy selection. These features include prior treatment status, histologic subtype, and prognostic group. Further refinement of therapy selection is required and will require further biologic information as well as comparative randomized trials.     

Effect of saxagliptin monotherapy in treatment-naïve patients with type 2 diabetes

ABSTRACT

Objective: To evaluate the efficacy and safety of once-daily saxagliptin monotherapy in treatment-naïve patients with type 2 diabetes (T2D) and inadequate glycemic control.

Research design and methods: This study included a main treatment cohort (MTC) with 401 patients (HbA_1c?≥?7% and ≤10%) randomized and treated with oral saxagliptin 2.5, 5, or 10?mg once daily or placebo for 24 weeks and a separate open-label cohort (OLC) with 66 patients (HbA_1c?>?10% and ≤12%) who received saxagliptin 10?mg once daily for 24 weeks. Primary endpoint was HbA_1c change from baseline to week 24. Secondary endpoints included change from baseline to week 24?in fasting plasma glucose (FPG), proportion of patients achieving HbA_1c?<?7%, and changes in postprandial glucose area-under-the-curve (PPG-AUC). Efficacy analyses for continuous variables were performed using an ANCOVA model with last-observation-carried-forward methodology.

Results: In the MTC, saxagliptin demonstrated statistically significant decreases in adjusted mean HbA_1c changes from baseline (mean, 7.9%) to week 24 (?0.43%, ?0.46%, ?0.54%) for saxagliptin 2.5, 5, and 10?mg, respectively, vs. +0.19% for placebo (all p?<?0.0001). Adjusted mean FPG was significantly reduced from baseline (?15, ?9, ?17?mg/dL) for saxagliptin 2.5, 5, and 10?mg, respectively, vs. +6?mg/dL for placebo (p?=?0.0002, p?=?0.0074, p?<?0.0001, respectively). More saxagliptin-treated patients achieved HbA_1c?<?7% at week 24 (35% [p?=?NS], 38% [p?=?0.0443], 41% [p?=?0.0133]) for saxagliptin 2.5, 5, and 10?mg, respectively, than placebo (24%). PPG-AUC was reduced for saxagliptin 2.5, 5, and 10?mg (?6868, ?6896, ?8084?mg·min/dL, respectively) vs. placebo (?647?mg·min/dL) with statistical significance demonstrated for saxagliptin 5?mg (p?=?0.0002) and 10?mg (p?<?0.0001). HbA_1c, FPG, and PPG-AUC reductions were also observed in the OLC at 24 weeks. In the MTC, adverse event frequency was similar across all study arms. No cases of confirmed hypoglycemia (symptoms, with fingerstick glucose ≤50?mg/dL) were observed in either cohort. Saxagliptin was not associated with weight gain. Study limitations included the lack of a control group for the OLC and the use of prespecified rescue criteria, which limited the exposure time during which patients could remain on their originally randomized medication without the introduction of additional antihyperglycemic rescue treatment.

Conclusions: Once-daily saxagliptin monotherapy for 24 weeks was generally well tolerated and demonstrated clinically meaningful reductions in key parameters of glycemic control vs. placebo.

Trial Registration: Clinical Trials NCT00121641     

The role of human chorionic gonadotropin in regulation of naïve and memory T cells activity in vitro

The role of human chorionic gonadotropin (hCG) in the regulation of molecular genetics factors determining the functional activity of human naïve and memory T cells in vitro was studied. It was found that hCG (10 and 100 IU/ml) inhibited CD28 and CD25 expression on the naïve T cells (CD45RA +) and CD25 expression on the memory T cells (CD45R0 +). hCG didn't affect the CD71 proliferation marker expression in total. Nevertheless, hCG reduced the percentage of proliferating memory T cells with simultaneous suppression of CD71 expression on proliferating CD45R0 + cells.In parallel, expression of U2af1l4, Gfi1, and hnRNPLL genes, which are Ptprc gene alternative splicing regulators was evaluated. It was established that hCG stimulated the expression of U2af1l4 and hnRNPLL genes, responsible for the assembly of CD45R0 in memory T cells, but reduced the expression of Gfi1 in these cells. In general, hCG promotes the differentiation of memory T cells by increasing of CD45R0 expression, but inhibits proliferation and CD25 expression which reflects their functional activity.     

Induction interferon therapy in naïve patients with chronic hepatitis C: increased end-of-treatment virological responses but absence of long-term benefit

BACKGROUND AND AIMS: The low efficacy of interferon monotherapy and data from viral kinetic studies led us to evaluate the efficacy of interferon administered daily in chronic hepatitis C. PATIENTS AND METHODS: Thirty-eight na?ve patients with chronic hepatitis C and active liver disease randomly received 3 or 5 MU IFN-alpha daily for 1 month, followed by the same dose three times a week for 11 months. Results were compared to a three-times-a-week scheme of 3 MU IFN-alpha for 1 year. RESULTS: At the end of the induction period, 27 out of 38 (71%) patients had cleared HCV-RNA with a significantly higher rate in the 5 MU than in the 3 MU group (17 out of 18 or 94% vs. 10 out of 20 or 50%, P=0.003). The end-of-treatment virological response rate was 66% (25 out of 38) in the induction groups and 40% (10 out of 25) in the control group (P=0.04). Six months after completion of therapy, the sustained response rate dropped to 29% (11 out of 38) compared to 28% (7 out of 25) in the standard regimen. CONCLUSIONS: In chronic hepatitis C, treatment with 5 or 3 MU IFN-alpha daily during the first month of a standard IFN regimen leads to significantly increased end-of-treatment virological responses, but long-term responses are similar to those of standard IFN monotherapy.     

A naturalistic study of grey matter volume increase after early treatment in anti-psychotic naïve,newly diagnosed schizophrenia

Background  

Anti-psychotic treatment appears to be associated with striatal volume increase, but how early this change occurs is still unknown.     

Changes in pro-inflammatory cytokines and body weight during 6-month risperidone treatment in drug naïve, first-episode schizophrenia

Objective

The present study aimed to examine the changes in pro-inflammatory cytokines and body weight during 6-month risperidone treatment in drug naïve, first-episode schizophrenia.

Methods

Sixty-two drug naïve, first-episode schizophrenia (SZ group) and 60 healthy individuals (control group) were enrolled in the study. Serum interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) levels, and body weight were measured at baseline for both groups, and repeated for the SZ group at five different time points during 6-month risperidone treatment.

Results

At baseline, serum IL-1β, IL-6, and TNF-α levels in the SZ group (53.28?±?12.62, 33.98?±?14.13, 50.08?±?12.86 pg/mL, respectively) were significantly higher than those in the control group (23.49?±?15.27, 15.53?±?7.16, 32.12?±?15.23 pg/mL, respectively) (p's?<?0.001). Within the SZ group, serum IL-1β levels decreased significantly at 2 weeks (48.02?±?16.00 pg/mL, p?<?0.01) and 1 month (44.70?±?16.63 pg/mL, p?<?0.001), but then gradually increased at 2 months (48.49?±?18.87 pg/mL), 3 months (50.59?±?18.48 pg/mL) and 6 months (53.64?±?16.22 pg/mL) to the levels comparable to baseline; serum IL-6 levels changed significantly over the course of treatment (p?=?0.001), but reached the levels comparable to baseline at 6 months (37.13?±?13.23 pg/mL); serum levels of TNF-α increased significantly at 3 months (55.02?±?16.69 pg/mL, p?<?0.01) and 6 months (58.69?±?13.57 pg/mL, p?<?0.001); steady and significant weight gain was observed at each follow-up time point (p's?<?0.001), from 56.71?±?9.25 kg at baseline to 62.72?±?9.53 kg at 6 months.

Conclusions

Risperidone treatment is associated with changes in serum pro-inflammatory cytokines levels and weight. There is an initial anti-inflammatory effect that reduces with treatment, potentially due to its weight gain side effect.     

Pharmacodynamic effects of zidovudine 600 mg once/day versus 300 mg twice/day in therapy-naïve patients infected with human immunodeficiency virus

STUDY OBJECTIVE: To compare the virologic activity of zidovudine monotherapy administered as 600 mg once/day versus 300 mg twice/day. DESIGN: Phase II, randomized (1:1), open-label study. SETTING: Thirteen medical centers in the United States. PATIENTS: Thirty-two antiretroviral-naive patients infected with human immunodeficiency virus (HIV). INTERVENTION: Patients were administered either zidovudine 600 mg every 24 hours (16 patients) or 300 mg every 12 hours (16 patients) for 13 days. MEASUREMENTS AND MAIN RESULTS: Plasma HIV-1 RNA concentration was measured daily. Study end points were between-group differences in change from baseline of log10-transformed HIV-1 RNA and in rates of viral load decline measured by the slope of HIV-1 RNA over time. At baseline, mean HIV-1 RNA was similar in the once/day and twice/day groups (4.33 and 4.40 log10 copies/ml, respectively). At day 14, a trend toward lower mean reduction in HIV-1 RNA from baseline was observed in the once/day group (-0.585, 95% confidence interval [CI] -0.728 to -0.442 log10 copies/ml) compared with the twice/day group (-0.849, 95% CI -1.067 to -0.630 log10 copies/ml, p=0.056). Viral load reduction also tended to be slower in the once/day group, as indicated by the smaller slope of viral load decline in the once/day group than in the twice/day group during days 1-14 (-0.045 vs -0.065 logic copies/ml/day, p=0.065). Both zidovudine regimens were similarly well tolerated. CONCLUSION: Zidovudine 600 mg once/day has antiviral activity, although less pronounced and more slowly achieved than that seen with zidovudine 300 mg twice/day. No differences were observed between the two treatment groups with respect to safety profile or tolerability