Melissa Officinalis L. aqueous extract pretreatment decreases methotrexate-induced hepatotoxicity at lower dose and increases 99mTc-phytate liver uptake,as a probe of liver toxicity assessment,in rats

Annals of Nuclear Medicine - Hepatotoxicity remains amongst the restricting factors of Methotrexate (MTX)-associated cancer therapy, especially in high doses of chemo-drugs or prolonged treatment....     

Evaluation of pseudoephedrine pharmacy sales before and after mandatory recording requirements in Western Australia: a case study

Background

A community pharmacy real-time electronic recording program, ProjectSTOP, enables Australian community pharmacists to verify pseudoephedrine requests. In Western Australia the program was available for voluntary use from April 2007 and became mandatory November 2010. This case study explores the effectiveness of the program by reviewing the total requests for pseudoephedrine products, and the proportion of requests which were classified as ‘denied sales’ before and after mandatory implementation. Seasonal and annual trends in these measures are also evaluated.

Methods

ProjectSTOP data recordings for Western Australia pharmacies between 1 December 2007 and 28 February 2014 were analysed. Data included a de-identified pharmacy number and date of each pseudoephedrine product request. The total number of requests and sale classification (allowed, denied, safety, or not recorded) were calculated for each month/pharmacy. The potential influence of mandatory reporting using ProjectSTOP was investigated using a Regression Discontinuity Design. Correlations between sales from the same pharmacy were taken into account by classifying the pharmacy number as a random effect. The main effects of year (continuous variable), and season (categorical variable) were also included in the model.

Results

There was a small but steady decline in the total requests for pseudoephedrine per month per 100,000 population (per pharmacy) from the time of mandatory reporting. The number of denied sales showed a steady increase up until mandatory reporting, after which it showed a significant decline over time. Total sales were heavily influenced by season, as expected (highest in winter, least in summer). The seasonal pattern was less pronounced for denied sales, which were highest in winter and similar across other seasons. The pattern over time for safety sales was similar to that for denied sales, with a clear change occurring around the time of mandatory reporting.

Conclusion

Results indicate a decrease in pseudoephedrine product requests in Western Australia community pharmacies. Findings suggest ProjectSTOP has been successful in addressing suspicious sales and potential diversion however ongoing data review is recommended.

     

Dendritic cell paucity in mismatch repair–proficient colorectal cancer liver metastases limits immune checkpoint blockade efficacy

Liver metastasis is a major cause of mortality for patients with colorectal cancer (CRC). Mismatch repair–proficient (pMMR) CRCs make up about 95% of metastatic CRCs, and are unresponsive to immune checkpoint blockade (ICB) therapy. Here we show that mouse models of orthotopic pMMR CRC liver metastasis accurately recapitulate the inefficacy of ICB therapy in patients, whereas the same pMMR CRC tumors are sensitive to ICB therapy when grown subcutaneously. To reveal local, nonmalignant components that determine CRC sensitivity to treatment, we compared the microenvironments of pMMR CRC cells grown as liver metastases and subcutaneous tumors. We found a paucity of both activated T cells and dendritic cells in ICB-treated orthotopic liver metastases, when compared with their subcutaneous tumor counterparts. Furthermore, treatment with Feline McDonough sarcoma (FMS)-like tyrosine kinase 3 ligand (Flt3L) plus ICB therapy increased dendritic cell infiltration into pMMR CRC liver metastases and improved mouse survival. Lastly, we show that human CRC liver metastases and microsatellite stable (MSS) primary CRC have a similar paucity of T cells and dendritic cells. These studies indicate that orthotopic tumor models, but not subcutaneous models, should be used to guide human clinical trials. Our findings also posit dendritic cells as antitumor components that can increase the efficacy of immunotherapies against pMMR CRC.

Immune checkpoint blockade (ICB) therapy has revolutionized cancer treatment in recent years. Anti–PD1 (anti–programmed cell-death protein 1) and anti–CTLA-4 (anti–cytotoxic T lymphocyte-associated protein 4) are two main types of ICB therapies that can be particularly effective (1). Metastatic melanoma, which was previously an incurable disease, now has cure rates of more than 50% when patients are treated with a combination of anti–PD1 and anti–CTLA-4 (2). However, ICB therapy is only effective in less than 15% of patients who receive the therapy (3), and efforts are ongoing to uncover the underlying mechanisms of intrinsic and acquired resistance.Colorectal cancer (CRC) is the second leading cause of cancer-related death in the United States (4) and in the world (5). Metastatic spread, especially to the liver, is a major cause of mortality in patients with CRC (6). The efficacy of ICB therapy in metastatic CRCs has been limited to patients with mismatch repair–deficient (dMMR) or microsatellite instability-high (MSI-H) tumors, where a 55% objective response rate has been achieved (7). However, dMMR or MSI-H metastatic CRCs represent only about 5% of total metastatic CRC cases. The remaining 95% are mismatch repair–proficient (pMMR) or microsatellite stable (MSS) tumors (8), which are typically unresponsive to ICB therapy (8). Therefore, there is an urgent need to better understand the resistance mechanisms in pMMR and MSS metastatic CRCs, and improve the efficacy of treatments against this disease.Preclinical mouse models of cancer are effective tools for studying and improving cancer therapy. MC38 and CT26 are syngeneic mouse CRC cell lines commonly used in preclinical immunocompetent mouse models of cancer. In most preclinical studies, these cells are injected under the skin into the hind flank of mice, where they grow as subcutaneous tumors. When treated with ICB therapies such as anti–PD1 and/or anti–CTLA-4, these tumors have been shown to respond well (9, 10). However, MC38 and CT26 lack coding somatic mutations in the DNA mismatch repair genes and should be considered as pMMR CRC cell lines (11, 12). Hence, experimental preclinical models using subcutaneously implanted pMMR CRC cell lines fail to recapitulate the disease resistance to ICB therapy that is observed in patients.We hypothesized that orthotopic pMMR CRC mouse models, where pMMR CRC cells are implanted in the colon to represent primary colon tumors or in the liver to represent liver metastases, would more accurately recapitulate progression of the human disease and its response to ICB treatment in the clinic. Indeed, we report here strikingly different sensitivities to ICB treatment for pMMR CRC tumors grown orthotopically when compared with their subcutaneous counterparts. We further take advantage of these differences to define local nonmalignant components that determine the sensitivity of pMMR CRCs to treatment.     

Simplification of gold nanoparticle synthesis with low cytotoxicity using a greener approach: opening up new possibilities

Gold nanoparticles (AuNPs) have diverse applications in the diagnosis and treatment of ailments. This study describes an extremely simplified synthesis of AuNPs using antioxidant-rich pollen extract as a local natural source. Ultraviolet-visible (UV-vis) spectroscopy, X-ray diffraction (XRD), Fourier-transform infrared spectroscopy (FTIR) and transmission electron microscopy (TEM) were used to characterize the synthesized AuNPs; strong UV-vis absorption at 534 nm confirmed their formation, the XRD pattern showed the presence of a crystalline structure, and TEM images showed them to be spherical nanoparticles with an average size of 9.3 ± 2.9 nm. As synthesized AuNPs remained stable for up to two months under laboratory conditions without any sedimentation or change in the absorption value, presumably due to the protection afforded by the capping agents from pollen. AuNPs revealed low toxicity effects on MCF-7 and HUVECs cell lines (with an IC₅₀ value of ∼400 μg mL⁻¹ for both the cell lines). The proposed method did not use any hazardous materials or high-energy consuming devices; thus this efficient protocol may be adapted for large-scale production using local resources.

This method described herein does not need any sophisticated laboratory devices and deploy local resource.     

Methylprednisolone pulse therapy plus adjuvant therapy for pemphigus vulgaris: an analysis of 10 years' experience on 312 patients

Steroid pulse therapy has shown satisfactory efficacy and safety in treating pemphigus vulgaris (PV). However, there is a paucity of data about the efficacy and safety of methylprednisolone, despite its frequent administration. The aim of this study is to evaluate the efficacy and safety of steroid pulse therapy in treating PV. In this 10‐year retrospective cohort study, 312 patients with PV, who had received methylprednisolone pulse therapy, were included. Data of pulse therapy sessions, adjuvant medications, dosages, remission rates, complications, and mortalities were collected from all patients. A total of 276 patients out of 312 underwent the final follow‐up at least 6 months after the last session of pulse therapy. Complete remission off therapy was achieved in 83 patients (30%), and 152 patients (55%) had complete remission on therapy. About 29 (10.5%) patients had lesions of pemphigus at the time of the study follow‐up, and 26.8% of remained patients were on the minimal therapy. Methylprednisolone pulse therapy could be considered as an option for proper control of PV in severe cases. It might lead to shorter periods of hospitalization and reduce the need to take long‐term high‐dose oral steroid therapy.     

Study of the anti-seizure effects of low-frequency stimulation following kindling (a review of the cellular mechanism related to the anti-seizure effects of low-frequency electrical stimulation)

Epilepsy affects about 1–2 % of world population as a chronic neurological disease that is manifested by repeated and consecutive seizures (Grone and Baraban, Nat Neurosci 18(3):339–343, 2015). There is no definitive therapy for epilepsy and antiepileptic drugs cannot offer a permanent and definitive cure for epilepsy, and most epileptic patients become drug resistant (Sasa, J Pharmacol Sci 100(5):487–494, 2006). Surgery and removal of the epileptic focus is a substitute method for treating drug-resistant patients and epilepsy surgery of either side of the brain improves seizure control. Temporal lobectomy is the most common epilepsy surgery and is associated with high success rates. Other studies have reported higher success rates for carefully selected temporal lobe seizure patients. Some physicians still consider temporal lobectomy an extreme procedure, citing the risks of side effects, including loss of memory, visual disturbances, and emotional change, associated with the removal of brain tissue (Spencer, Lancet Neurol 1(6):375–382, 2002; Wiebe et al., N Engl J Med 345(5):311–318, 2001; Yasargil et al., J Neurosurg 112(1):168–185, 2010). Nowadays, direct electrical stimulation (in the form of low- or high-frequency stimulation) in the location involved in seizures is used as a potentially suitable treatment method for this destructive disease in both laboratory animals and humans (Goodman et al., Epilepsia 46(1):1–7, 2005; Richardson et al., Epilepsia 44(6):768–777, 2003; Velasco et al., Epilepsia 41(2):158–169, 2000). Low-frequency stimulation causes less damage to the epileptic area and surrounding neuronal structures compared to high-frequency stimulation, and it can be a suitable option for patients suffering from epilepsy (Goodman et al., Epilepsia 46(1):1–7, 2005). Since the cellular mechanism of this stimulation is not clearly known, the purpose of this review research was to investigate the anticonvulsive effects of low-frequency electrical stimulation and the probable cellular mechanism involved in it.     

Preparation and quality control of the [sm]-samarium maltolate complex as a lanthanide mobilization product in rats

Development of lanthanide detoxification agents and protocols is of great importance in management of overdoses. Due to safety of maltol as a detoxifying agent in metal overloads, it can be used as a lanthanide detoxifying agent. In order to demonstrate the biodistribution of final complex, [(153)Sm]-samarium maltolate was prepared using Sm-153 chloride (radiochemical purity >99.9%; ITLC and specific activity). The stability of the labeled compound was determined in the final solution up to 24h as well as the partition coefficient. Biodistribution studies of Sm-153 chloride, [(153)Sm]-samarium maltolate were carried out in wild-type rats comparing the critical organ uptakes. Comparative study for Sm(3+) cation and the labeled compound was conducted up to 48 h, demonstrating a more rapid wash out for the labeled compound. The effective and biological half lives of 2.3 h and 2.46h were calculated for the complex. The data suggest the detoxification property of maltol formulation for lanthanide overdoses.     

The effect of inhaled corticosteroids on hypothalamic-pituitary-adrenal axis

Objectives:

The aim of this study was to compare systemic effects of high-dose fluticasone propionate (FP) and beclomethasone dipropionate (BDP) via pressurized metered dose inhaler on adrenal and pulmonary function tests.

Materials and Methods:

A total of 66 patients with newly diagnosed moderate persistent asthma without previous use of asthma medications participated in this single blind, randomized, parallel design study. FP or BDP increased to 1 500 μg/d in 62 patients who had not received oral or IV corticosteroids in the previous six months. Possible effects of BDP and FP on adrenal function were evaluated by free cortisol level at baseline and after Synacthen test (250 μg). Fasting plasma glucose and pulmonary function tests were also assessed. Similar tests were repeated 3 weeks after increasing dose of inhaled corticosteroids to 1 500 μg/d.

Results:

No statistically significant suppression was found in geometric means of cortisol level post treatment in both groups. After treatment in FP group, mean forced expiratory volume in one second (FEV1) and mean forced vital capacity (FVC) values improved by 0.17 l (5.66% ± 13.91, P=0.031) and 0.18 l (5.09% ± 10.29, P=0.010), respectively. Although FEV1 and FVC improved in BDP group but was not statistically significant. Oral candidiasis and hoarseness were observed in 6.5% patients receiving BDP, but hoarseness was found in 3.2% patients in FP group (P=0.288).

Conclusions:

The results indicate that safety profiles of high doses of BDP and FP with respect to adrenal function are similar, but FP is more efficacious than that of BDP in improving pulmonary function test.KEY WORDS: Adrenal cortex function tests, adrenal insufficiency, asthma, beclomethasone dipropionate, fluticasone