A Chinese medicine warm compress (Wen Jing Zhi Tong Fang), combined with WHO 3-step analgesic ladder treatment for cancer pain relief: A comparative randomized trial.

Medicine (Baltimore). 2018 Mar;97(11):e9965

Authors: Cai P, Li L, Hong H, Zhang L, He C, Chai X, Liu B, Chen Z

Abstract
INTRODUCTION: This study aimed to assess the effectiveness of Chinese medicine warm compress (CMWC) on back meridians in relieving cancer pain, reducing adjuvant analgesic doses and adverse reactions, and improving the quality of life (QOL).
METHODS: A total of 62 patients (age range 39-82 years) diagnosed with a malignant tumor and suffering from cancer-related pain were randomly divided into a treatment group (group A) and a control group (group B) (n = 31 for each). The patients in both groups were administered appropriate drugs for 2 cycles of 7-day treatments according to the World Health Organization (WHO) 3-step ladder for cancer pain relief in adults. In addition, a CMWC was given to patients in group A. Pain relief was assessed using the visual analogue scale (VAS) at various time points before and after interventions in each group. Alteration of analgesic doses, adverse reactions, performance status (PS), and QOL were evaluated and any differences between groups A and B evaluated.
RESULTS: VAS scores at various time points after treatment were significantly decreased compared with the baseline level in group A. Overall response rate was significantly improved in group A compared with group B (70.97% vs 29.03%, P < .001). Significant differences in clinical pain relief efficacy in various locations were found in group A after treatment vs before treatment (P < .05). Adjuvant analgesic doses were significantly changed in the control group compared to the treatment group after 1 cycle of 7-day treatment (22.58% vs 12.90%, P = .023). QOL were improved more in group A than in group B (3.00 ± 4.23 vs -2.06 ± 2.38, P < .001). Significantly reduced adverse reactions were observed after treatment of group A compared with group B in terms of the overall incidence (3.23% vs 80.65%, P < .05) or incidence of constipation (3.23% vs 77.42%, P < .05).
CONCLUSIONS: The application of CMWC on back meridians combined with WHO 3-step analgesic ladder treatment was effective in relieving cancer-related pain with reduced doses, less adverse reactions, and improved QOL.

PMID: 29538220 [PubMed - indexed for MEDLINE]

Improving multiple sclerosis management and collecting safety information in the real world: the MSDS3D software approach.

Expert Opin Drug Saf. 2018 Apr;17(4):369-378

Authors: Haase R, Wunderlich M, Dillenseger A, Kern R, Akgün K, Ziemssen T

Abstract
INTRODUCTION: For safety evaluation, randomized controlled trials (RCTs) are not fully able to identify rare adverse events. The richest source of safety data lies in the post-marketing phase. Real-world evidence (RWE) and observational studies are becoming increasingly popular because they reflect usefulness of drugs in real life and have the ability to discover uncommon or rare adverse drug reactions. Areas covered: Adding the documentation of psychological symptoms and other medical disciplines, the necessity for a complex documentation becomes apparent. The collection of high-quality data sets in clinical practice requires the use of special documentation software as the quality of data in RWE studies can be an issue in contrast to the data obtained from RCTs. The MSDS3D software combines documentation of patient data with patient management of patients with multiple sclerosis. Following a continuous development over several treatment-specific modules, we improved and expanded the realization of safety management in MSDS3D with regard to the characteristics of different treatments and populations. Expert opinion: eHealth-enhanced post-authorisation safety study may complete the fundamental quest of RWE for individually improved treatment decisions and balanced therapeutic risk assessment. MSDS3D is carefully designed to contribute to every single objective in this process.

PMID: 29436244 [PubMed - indexed for MEDLINE]

The safety and tolerability of cariprazine in long-term treatment of schizophrenia: a post hoc pooled analysis.

BMC Psychiatry. 2017 Aug 24;17(1):305

Authors: Nasrallah HA, Earley W, Cutler AJ, Wang Y, Lu K, Laszlovszky I, Németh G, Durgam S

Abstract
BACKGROUND: Schizophrenia is a chronic and debilitating neuropsychiatric disorder that often requires long-term pharmacotherapy to manage symptoms and prevent relapse. Cariprazine is a potent dopamine D3 and D2 receptor partial agonist that is FDA-approved in the US for the treatment of schizophrenia and manic or mixed episodes associated with bipolar I disorder in adults; the recommended dose range is 1.5-6 mg/d.
METHODS: To further characterize the long-term safety of cariprazine, data from two 48-week open-label, flexible-dose extension studies were pooled for post hoc analyses. Outcomes were evaluated in the pooled safety population (patients who received ≥1 dose of cariprazine during an open-label extension period); findings were summarized using descriptive statistics for the overall cariprazine group and in modal daily dose groups (1.5-3, 4.5-6, and 9 mg/d).
RESULTS: Of the 679 patients in the overall cariprazine safety population, 40.1% completed the study. The only adverse events (AEs) leading to discontinuation of ≥2% of patients in any dose group were akathisia, worsening of schizophrenia, and psychotic disorder. Treatment-emergent AEs (TEAEs) of akathisia, insomnia, weight increased, and headache were reported in ≥10% of the overall population. Mean prolactin levels decreased in all dose groups (overall, -15.4 ng/mL). Clinically insignificant changes in aminotransferase levels and alkaline phosphatase were observed; no dose-response relationship was observed across groups. Mean total (-5.3 mg/dL), low-density lipoprotein (-3.5 mg/dL), and high-density lipoprotein (-0.8 mg/dL) cholesterol levels decreased; no dose-response relationship was observed for metabolic parameters. Mean change in body weight was 1.58 kg; body weight increase and decrease ≥7% occurred in 27% and 11% of patients, respectively. Mean changes in cardiovascular parameters, including blood pressure and pulse, were generally not considered clinically significant. EPS-related TEAEs that occurred in ≥5% of patients were akathisia, tremor, restlessness, and extrapyramidal disorder.
CONCLUSION: In these post hoc pooled analyses of data from 2 long-term open-label studies, treatment with cariprazine was generally safe and well tolerated. Results support the safety and tolerability of cariprazine within the FDA-recommended dose range of 1.5-6 mg/d for schizophrenia.
CLINICAL TRIALS REGISTRATION: NCT01104792, NCT00839852.

PMID: 28836957 [PubMed - indexed for MEDLINE]

Rapid Progressive Disease After Nivolumab Therapy in Three Patients with Metastatic Renal Cell Carcinoma.

In Vivo. 2017 Jul-Aug;31(4):769-771

Authors: Kobari Y, Kondo T, Takagi T, Omae K, Nakazawa H, Tanabe K

Abstract
BACKGROUND/AIM: Rapid progressive disease (RPD), accelerated tumour growth immediate after the initiation of immune checkpoint inhibitor therapy, has been reported in melanoma and lung cancer. Herein, we describe 3 cases of RPD during the initial phase of nivolumab treatment for metastatic renal cell carcinoma.
PATIENTS AND METHODS: The first and second patients received nivolumab in the fourth-line setting. The third patient received nivolumab therapy as third-line treatment.
RESULTS: The first patient developed severe respiratory failure due to carcinomatous lymphangiosis 14 days after initiation of nivolumab therapy. The second patient developed leg paraplegia due to rapid growth of the metastatic tumour at the sixth thoracic vertebrae 5 days later. The third patient developed grade 4 hypercalcemia due to RPD on day 3.
CONCLUSION: Clinicians should be aware of RPD during the initial phase of nivolumab therapy, especially in patients with critical lesions in the late-line setting.

PMID: 28652455 [PubMed - indexed for MEDLINE]

Study of adverse drug reactions in patients with diabetes attending a tertiary care hospital in New Delhi, India.

Indian J Med Res. 2017 Feb;145(2):247-249

Authors: Singh A, Dwivedi S

Abstract
The present prospective observational study was carried out in a tertiary care hospital in New Delhi, India from May 2014 to June 2015 to report adverse drug reactions (ADRs) in patients with type 2 diabetes mellitus (T2DM) using antidiabetic drugs. A total of 220 patients (121 males, 99 females) were enrolled. ADRs were recorded on the prescribed form. Causality and severity assessment was done using Naranjo's probability scale and modified Hartwig and Siegel's severity scale, respectively. Commonly prescribed drugs were biguanides, peptide hormone and sulphonylurea. A total of 26 ADRs were recorded (16 in males and 10 in females). Most commonly observed ADRs were related to endocrine and gastrointestinal system. Severity assessment of ADRs showed seven (26.9%) ADRs as moderate, and 19 (73.1%) as mild. No severe reactions were observed. ADRs were mostly related to endocrine and gastrointestinal system. More information on prescribed drugs and their side effects is required for ensuring patient safety.

PMID: 28639602 [PubMed - indexed for MEDLINE]

Entinostat: a promising treatment option for patients with advanced breast cancer.

Future Oncol. 2017 Jun;13(13):1137-1148

Authors: Connolly RM, Rudek MA, Piekarz R

Abstract
Entinostat is a synthetic benzamide derivative histone deacetylase (HDAC) inhibitor, which potently and selectively inhibits class I and IV HDAC enzymes. This action promotes histone hyperacetylation and transcriptional activation of specific genes, with subsequent inhibition of cell proliferation, terminal differentiation and apoptosis. This oral HDAC inhibitor has been evaluated in Phase I and II trials in patients with advanced malignancies, and is in general well tolerated. Entinostat does not currently have regulatory approval for clinical use; however promising preclinical and clinical data exist in hormone-resistant breast cancer. An ECOG-ACRIN Phase III registration study is ongoing in advanced breast cancer (E2112, NCT02115282) and aims to confirm the overall survival advantage observed with the combination of exemestane and entinostat/placebo in the Phase II setting (ENCORE301 trial). This article provides an overview of the chemistry, pharmacokinetics/pharmacodynamics and available clinical data for entinostat with a focus on advanced breast cancer.

PMID: 28326839 [PubMed - indexed for MEDLINE]

FDA Approval Summary: TAS-102.

Clin Cancer Res. 2017 Jun 15;23(12):2924-2927

Authors: Marcus L, Lemery SJ, Khasar S, Wearne E, Helms WS, Yuan W, He K, Cao X, Yu J, Zhao H, Wang Y, Stephens O, Englund E, Agarwal R, Keegan P, Pazdur R

Abstract
The FDA approved TAS-102 (Lonsurf; Taiho Oncology, Inc.) for the treatment of patients with metastatic colorectal cancer (mCRC) who have been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy; an anti-VEGF biological therapy; and if RAS wild type, an anti-EGFR therapy. In an international, multicenter, double-blinded, placebo-controlled trial (TPU-TAS-102-301, herein referred to as RECOURSE), 800 patients with previously treated mCRC were randomly allocated (2:1) to receive either TAS-102 35 mg/m2 orally twice daily after meals on days 1 through 5 and 8 through 12 of each 28-day cycle (n = 534) or matching placebo (n = 266). The trial demonstrated a statistically significant improvement in overall survival for those randomized to receive TAS-102, with a median survival of 7.1 months in the TAS-102 arm [confidence interval (CI), 6.5-7.8] and 5.3 months in the placebo arm [CI, 4.6-6.0; hazard ratio (HR), 0.68; 95% CI, 0.58-0.81; P < 0.001, stratified log-rank test]. The trial also demonstrated a statistically significant prolongation of progression-free survival (HR, 0.47; 95% CI, 0.40-0.55; P < 0.001). The most common adverse reactions, in order of decreasing frequency, observed in the patients who received TAS-102 were anemia, neutropenia, asthenia/fatigue, nausea, thrombocytopenia, decreased appetite, diarrhea, vomiting, abdominal pain, and pyrexia. Adverse events led to discontinuation of TAS-102 in 3.6% of patients, and 13.7% required a dose reduction. The most common adverse reactions leading to dose reduction were neutropenia, anemia, febrile neutropenia, fatigue, and diarrhea. Clin Cancer Res; 23(12); 2924-7. ©2017 AACR.

PMID: 28213365 [PubMed - indexed for MEDLINE]

Intra-laboratory validated human cell-based in vitro vasculogenesis/angiogenesis test with serum-free medium.

Reprod Toxicol. 2017 Jun;70:116-125

Authors: Toimela T, Huttala O, Sabell E, Mannerström M, Sarkanen JR, Ylikomi T, Heinonen T

Abstract
Vasculogenesis and angiogenesis are the processes by which new blood vessels are formed. We have developed a serum-free human adipose stromal cell and umbilical cord vein endothelial cell based vasculogenesis/angiogenesis test. In this study, the test was validated in our GLP laboratory following the OECD Guidance Document 34 [1] using erlotinib, acetylic salicylic acid, levamisole, 2-methoxyestradiol, anti-VEGF, methimazole, and D-mannitol to show its reproducibility, repeatability, and predictivity for humans. The results were obtained from immunostained tubule structures and cytotoxicity assessment. The performance of the test was evaluated using 26 suspected teratogens and non-teratogens. The positive predictive value was 71.4% and the negative predictive value was 50.0%, indicating that inhibition of vasculogenesis is a significant mechanism behind teratogenesis. In conclusion, this test has great potential to be a screening test for prioritization purposes of chemicals and to be a test in a battery to predict developmental hazards in a regulatory context.

PMID: 27915012 [PubMed - indexed for MEDLINE]

Association Between Commonly Prescribed Opioids and Androgen Deficiency in Men: A Retrospective Cohort Analysis.

Pain Med. 2017 04 01;18(4):637-644

Authors: Rubinstein AL, Carpenter DM

Abstract
Objective: Androgen deficiency is common among men who use opioids daily for chronic pain. In previous studies, we found that long-acting opioids are associated with greater odds of androgen suppression than equipotent doses of short-acting opioids. Here we examined whether specific commonly prescribed opioids were associated with greater odds of androgen deficiency compared to hydrocodone.
Design: Retrospective cohort study.
Setting and Patients: Within a large, integrated health care delivery system, this study was comprised of men ages 18-80 on a stable regimen of a single opioid for chronic non-cancer pain.
Methods: Morning serum total testosterone levels were measured in subjects prescribed one opioid for at least 90 days. The association between individual opioids and androgen deficiency was assessed with logistic regression, controlling for dose, obesity, age, hypertension, hyperlipidemia, and diabetes, using hydrocodone as a referent.
Results: This study included 1,159 men. Men on fentanyl (odds ratio [OR] 25.7, 95% CI 2.82-234.97), methadone (OR 7.33, 95% CI 3.29-16.33), or oxycodone (OR 3.15, 95% CI 1.87-5.33) were more likely to be androgen deficient than men on hydrocodone. Increases in dose affected the odds of androgen deficiency differently for different opioids. Increased doses of hydrocodone (OR 1.18 per 10-mg increase in drug, 95% CI 1.09-1.28) and oxycodone (OR 1.01, 95% CI 1.00-1.02) were associated with increased odds of androgen deficiency.
Conclusions: Our results suggest that certain opioids are associated with increased odds of androgen deficiency compared with hydrocodone. Transdermal fentanyl, methadone and oxycodone were associated with higher odds of androgen deficiency than hydrocodone.

PMID: 27516365 [PubMed - indexed for MEDLINE]

Occurrence of composite cardiac endpoints with change in resting heart rate among Chinese patients with coronary artery disease: Chinese cohort from the real-world BISO-CAD study.

Curr Med Res Opin. 2018 Mar 20;:1-11

Authors: Chen Y, Yang X, Huang S, Fu G, Chen X, Yang Y, Liu S, Xu H, Ma T, Zhou X, Lv Z, Yang M, Gan X, Xu D, Cao F, Liu H, Li J, Zheng Q, Wang N, Yuan Y, Liu W, Yang T

Abstract
OBJECTIVE: We evaluated change in resting heart rate (RHR) and its impact on the prognosis in Chinese coronary artery disease (CAD) patients treated with bisoprolol and also assessed the drug safety and tolerability.
METHODS: This phase IV, single arm observational study was a sub-study of the BISO-CAD study conducted across 20 hospitals in China, between October 2011 to July 2015 with follow-up at 6, 12 and 18 months after baseline. The primary endpoint was occurrence of composite cardiac events.
RESULTS: A total of 663 CAD patients (baseline RHR 75.47 ± 6.62 bpm) were enrolled in intent-to-treat (ITT) set, whereas efficacy analysis (EA) set enrolled 513 patients. In the ITT set, the risk and the number of composite cardiac events in patients with mean RHR 69-74bpm was significantly higher compared with <65 bpm group (ITT: estimate: 1.03 ± 0.47, P = 0.029). Incidence of composite cardiac endpoint was not affected by continuous mean RHR (P = 0.5070). RHR significantly decreased from baseline to 18-months, most obvious in first six months (p <0.0001). Ejection fraction and fractional shortening significantly improved in both ITT and EA sets. Average RHR of 69-74 bpm had significant effect on admission to hospital for acute coronary syndrome in ITT (estimate 1.10, HR 3.004, P = 0.0196) and EA (estimate 1.26, HR3.526, P = 0.0132) groups. 7 (1.1%) patients reported drug related adverse events.
CONCLUSION: Reduction in RHR with bisoprolol lowered the incidence of composite cardiac events along with an acceptable safety and tolerability profile.

PMID: 29557206 [PubMed - as supplied by publisher]

Atrial Septal Defect as Unexpected Cause of Pulmonary Artery Hypertension.

Tex Heart Inst J. 2018 Feb;45(1):42-44

Authors: Parikh RV, Boyd J, Lee DP, Witteles R

Abstract
Methamphetamine abuse is an increasingly prevalent cause of pulmonary artery hypertension in the United States. Conversely, an atrial septal defect rarely presents late as pulmonary artery hypertension. We present the case of a 44-year-old methamphetamine abuser who had a 3-month history of worsening fatigue and near-syncope. She had elevated cardiac enzyme levels and right-sided heart strain. Angiographic findings suggested methamphetamine-induced pulmonary artery hypertension; however, we later heard S2 irregularities that raised suspicion of an atrial septal defect. Ultimately, the diagnosis was pulmonary artery hypertension and a large secundum atrial septal defect with left-to-right flow. One year after defect closure, the patient was asymptomatic. In addition to discussing this unexpected case of a secundum atrial septal defect masquerading as methamphetamine-induced pulmonary artery hypertension, we briefly review the natural history of atrial septal defects and emphasize the importance of thorough examination in avoiding diagnostic anchoring bias.

PMID: 29556152 [PubMed - in process]

Thromboprophylaxis with enoxaparin and direct oral anticoagulants in major orthopedic surgery and acutely ill medical patients: a meta-analysis.

Intern Emerg Med. 2017 Dec;12(8):1291-1305

Authors: Cimminiello C, Prandoni P, Agnelli G, Di Minno G, Polo Friz H, Scaglione F, Boracchi P, Marano G, Harenberg J

Abstract
Subjects undergoing major orthopedic surgery and acutely ill hospitalized medical patients represent a population at medium-high risk for venous thromboembolism (VTE). They are treated with low molecular weight heparin (LMWH) and direct oral anticoagulants [DOACs] for VTE prevention. We conducted a meta-analysis of phase III randomized clinical trials evaluating LMWH enoxaparin versus DOACs for prophylaxis of VTE by combining studies including patients undergoing elective total hip and knee replacement surgery, and acutely ill hospitalized medical subjects. Studies were searched using PubMed, MEDLINE, and EMBASE databases until December 2016. Differences in clinical outcomes for efficacy and safety endpoints between treatment groups were expressed as risk differences with 95% confidence intervals (95% CI), using random effects regression models. Fourteen RCTs were considered (60,467 subjects). Overall mortality, symptomatic deep venous thrombosis, non-fatal pulmonary embolism (PE) major bleeding (MB) and clinically relevant non-major bleeding (CRNMB) are not different between treatment regimens. Treatment with LMWH enoxaparin is associated with a lower risk of fatal PE plus VTE-related death compared therapy with DOACs (RD = 0.040%, 95% CI 0.001-0.080%, p = 0.0434). Subgroup analysis shows an incidence of MB (RD = 0.181%, 95% CI 0.029-0.332%, p = 0.0033) and CRNMB (RD = 0.546%, 95% CI 0.009-1.082%, p = 0.0462) in patients treated with 40 mg OD enoxaparin compared to DOACs. In major orthopedic surgery and acutely ill hospitalized medical patients, DOACs do not offer clear advantages in terms of clinical efficacy compared to enoxaparin. The advantage of the latter in terms of major and CRNMB, when used at a dose of 40 mg, is statistically significant, but small in terms of clinical relevance.

PMID: 28756546 [PubMed - indexed for MEDLINE]

Ombitasvir/paritaprevir/ritonavir/dasabuvir ± ribavirin is safe and effective in HCV-infected patients in a real-life cohort from Latin America.

J Med Virol. 2017 Sep;89(9):1590-1596

Authors: Mendizabal M, Haddad L, Gallardo PE, Ferrada A, Soza AA, Adrover R, Aravena E, Roblero JP, Prieto J, Vujacich C, Romero G, Muñoz A, Anders M, Hernández N, Coccozella D, Gruz F, Reggiardo MV, Ruf AE, Varón A, Cartier M, Pérez Ravier R, Ridruejo E, Peralta M, Poncino D, Vorobioff J, Aballay Soteras G, Silva MO

Abstract
Information about the use of ombitasvir/paritaprevir/ritonavir/dasabuvir ± ribavirin (OBV/PTV/r/DSV ± RBV) in real-clinical practice in Latin America is scarce. We aimed to confirm safety and effectiveness of OBV/PTV/r/DSV ± RBV therapy in real-world setting. We analyzed a cohort of patients with genotype 1 infection treated with OBV/PTV/r/DSV ± RBV. Data on demographics, clinical features, safety, and virological response were retrospectively collected from 21 centers in Latin America. A total of 96 patients received OBV/PTV/r/DSV, associated with RBV in 68% of the cases. Most were genotype 1b (80%), 56 (58%) had cirrhosis, and 45 (47%) failed prior HCV treatment. Adverse events occurred in 62% of patients. The most common adverse events were pruritus (21%), hyperbilirubinemia (17%), and asthenia (17%). Five patients discontinued therapy prematurely due to hepatic decompensation, three of them were Child-Pugh B at baseline and one patient died due to multi-organ failure. Follow up HCV-RNA 12 weeks after completion of therapy was evaluated in all the patients and sustained virologic response rate was 97%. No virologic breakthrough was detected. Our study confirms that OBV/PTV/r/DSV treatment is highly effective in patients with chronic HCV without cirrhosis or with Child-Pugh A cirrhosis in non-European populations. Adverse events were often mild and rarely led to treatment discontinuation except for patients with Child-Pugh B cirrhosis or with previous history of hepatic decompensation. These results can support the development of public strategies to expand the access of OBV/PTV/r + DSV and other DAAs combinations in order to reduce the burden of HCV infection in our region.

PMID: 28370222 [PubMed - indexed for MEDLINE]

Systemic lupus erythematosus.

Nat Rev Dis Primers. 2016 06 16;2:16039

Authors: Kaul A, Gordon C, Crow MK, Touma Z, Urowitz MB, van Vollenhoven R, Ruiz-Irastorza G, Hughes G

Abstract
Systemic lupus erythematosus (SLE) is an autoimmune disease that can affect many organs, including the skin, joints, the central nervous system and the kidneys. Women of childbearing age and certain racial groups are typically predisposed to developing the condition. Rare, inherited, single-gene complement deficiencies are strongly associated with SLE, but the disease is inherited in a polygenic manner in most patients. Genetic interactions with environmental factors, particularly UV light exposure, Epstein-Barr virus infection and hormonal factors, might initiate the disease, resulting in immune dysregulation at the level of cytokines, T cells, B cells and macrophages. Diagnosis is primarily clinical and remains challenging because of the heterogeneity of SLE. Classification criteria have aided clinical trials, but, despite this, only one drug (that is, belimumab) has been approved for use in SLE in the past 60 years. The 10-year mortality has improved and toxic adverse effects of older medications such as cyclophosphamide and glucocorticoids have been partially offset by newer drugs such as mycophenolate mofetil and glucocorticoid-sparing regimes. However, further improvements have been hampered by the adverse effects of renal and neuropsychiatric involvement and late diagnosis. Adding to this burden is the increased risk of premature cardiovascular disease in SLE together with the risk of infection made worse by immunosuppressive therapy. Challenges remain with treatment-resistant disease and symptoms such as fatigue. Newer therapies may bring hope of better outcomes, and the refinement to stem cell and genetic techniques might offer a cure in the future.

PMID: 27306639 [PubMed - indexed for MEDLINE]

Combined application of tenuigenin and β-asarone improved the efficacy of memantine in treating moderate-to-severe Alzheimer's disease.

Drug Des Devel Ther. 2018;12:455-462

Authors: Chang W, Teng J

Abstract
Background: Alzheimer's disease (AD) is a slowly progressive neurodegenerative disease which cannot be cured at present. The aim of this study was to assess whether the combined application of β-asarone and tenuigenin could improve the efficacy of memantine in treating moderate-to-severe AD.
Patients and methods: One hundred and fifty-two patients with moderate-to-severe AD were recruited and assigned to two groups. Patients in the experiment group received β-asarone 10 mg/d, tenuigenin 10 mg/d, and memantine 5-20 mg/d. Patients in the control group only received memantine 5-20 mg/d. The Mini Mental State Examination (MMSE), Clinical Dementia Rating Scale (CDR), and Activities of Daily Living (ADL) were used to assess the therapeutic effects. The drug-related adverse events were used to assess the safety and acceptability. Treatment was continued for 12 weeks.
Results: After 12 weeks of treatment, the average MMSE scores, ADL scores, and CDR scores in the two groups were significantly improved. But, compared to the control group, the experimental group had a significantly higher average MMSE score (p<0.00001), lower average ADL score (p=0.00002), and lower average CDR score (p=0.030). Meanwhile, the rates of adverse events were similar between the two groups. Subgroup analysis indicated that the most likely candidates to benefit from this novel method might be the 60-74-years-old male patients with moderate AD.
Conclusion: These results demonstrated that the combined application of β-asarone and tenuigenin could improve the efficacy of memantine in treating moderate-to-severe AD. The clinical applicability of this novel method showed greater promise and should be further explored.

PMID: 29551889 [PubMed - in process]

The SPOTS System: An Ocular Scoring System Optimized for Use in Modern Preclinical Drug Development and Toxicology.

J Ocul Pharmacol Ther. 2017 Dec;33(10):718-734

Authors: Eaton JS, Miller PE, Bentley E, Thomasy SM, Murphy CJ

Abstract
PURPOSE: To present a semiquantitative ocular scoring system comprising elements and criteria that address many of the limitations associated with systems commonly used in preclinical studies, providing enhanced cross-species applicability and predictive value in modern ocular drug and device development.
METHODS: Revisions to the ocular scoring systems of McDonald-Shadduck and Hackett-McDonald were conducted by board-certified veterinary ophthalmologists at Ocular Services On Demand (OSOD) over the execution of hundreds of in vivo preclinical ocular drug and device development studies and general toxicological investigations. This semiquantitative preclinical ocular toxicology scoring (SPOTS) system was driven by limitations of previously published systems identified by our group's recent review of slit lamp-based scoring systems in clinical ophthalmology, toxicology, and vision science.
RESULTS: The SPOTS system provides scoring criteria for the anterior segment, posterior segment, and characterization of intravitreal test articles. Key elements include: standardized slit lamp settings; expansion of criteria to enhance applicability to nonrabbit species; refinement and disambiguation of scoring criteria for corneal opacity, fluorescein staining severity, and aqueous flare; introduction of novel criteria for scoring of aqueous and anterior vitreous cell; and introduction of criteria for findings observed with drugs/devices targeting the posterior segment. A modified Standardization of Uveitis Nomenclature (SUN) system is also introduced to facilitate accurate use of SUN's criteria in laboratory species.
CONCLUSIONS: The SPOTS systems provide criteria that stand to enhance the applicability of semiquantitative scoring criteria to the full range of laboratory species, in the context of modern approaches to ocular therapeutics and drug delivery and drug and device development.

PMID: 29239680 [PubMed - indexed for MEDLINE]

A single center, open label study of intradermal administration of an inactivated purified chick embryo cell culture rabies virus vaccine in adults.

Vaccine. 2017 Aug 03;35(34):4315-4320

Authors: Recuenco S, Warnock E, Osinubi MOV, Rupprecht CE

Abstract
In the USA, rabies vaccines (RVs) are licensed for intramuscular (IM) use only, although RVs are licensed for use by the intradermal (ID) route in many other countries. Recent limitations in supplies of RV in the USA reopened discussions on the more efficient use of available biologics, including utilization of more stringent risk assessments, and potential ID RV administration. A clinical trial was designed to compare the immunogenic and adverse effects of a purified chicken embryo cell (PCEC) RV administered ID or IM. Enrollment was designed in four arms, ID Pre-Exposure Prophylaxis (Pre-EP), IM Pre-EP, ID Booster, and IM Booster vaccination. Enrollment included 130 adult volunteers. The arms with IM administration received vaccine according to the current ACIP recommendations: Pre-EP, three 1mL (2.5 I.U.) RV doses, each on day 0, 7, and 21; or a routine Booster, one 1ml dose. The ID groups received the same schedule, but doses administered were in a volume of 0.1mL (0.25 I.U.). The rate of increase in rabies virus neutralizing antibody titers 14-21days after vaccination were similar in the ID and correspondent IM groups. The GMT values for ID vaccination were slightly lower than those for IM vaccination, for both naïve and booster groups, and these differences were statistically significant by t-test. Fourteen days after completing vaccination, all individuals developed RV neutralizing antibody titers over the minimum arbitrary value obtained with the rapid fluorescent focus inhibition test (RFFIT). Antibodies were over the set threshold until the end of the trial, 160days after completed vaccination. No serious adverse reactions were reported. Most frequent adverse reactions were erythema, induration and tenderness, localized at the site of injection. Multi use of 1mL rabies vaccine vials for ID doses of 0.1 was demonstrated to be both safe and inmunogenic.

PMID: 28688782 [PubMed - indexed for MEDLINE]

The incidence and relative risk of pulmonary toxicity in patients treated with anti-PD1/PD-L1 therapy for solid tumors: a meta-analysis of current studies.

Immunotherapy. 2017 Jun;9(7):579-587

Authors: Ciccarese C, Iacovelli R, Bria E, Modena A, Massari F, Brunelli M, Fantinel E, Bimbatti D, Zamboni GA, Artibani W, Tortora G

Abstract
AIM: Monoclonal antibodies (mAbs) directed against PD-1/PD-L1 have recently entered the therapeutic algorithm of several solid tumors. Among treatment-related adverse events pulmonary toxicity (PT) is of particular interest. We assess the incidence and relative risk (RR) of PT in patients treated with anti-PD1/PD-L1 mAbs.
RESULTS: 11 articles were selected. The incidence of any- and high-grade PT was low (2.9 and 1.0%, respectively). Compared with standard therapies, anti-PD-1 mAbs do not significantly increase the risk of both any-grade (RR: 2.65; p = 0.06) and high-grade PT (RR: 1.40; p = 0.25). Of note, the RR: of developing any-grade (RR: 3.13; p < 0.0001) and high-grade (RR: 2.42; p = 0.03) PT significantly increased when excluding the Checkmate-025 trial, with everolimus as control therapy. No differences were identified between the type of mAbs, the tumor type and treatment duration for both any-grade and high-grade PT.

PMID: 28595514 [PubMed - indexed for MEDLINE]

Diabetic Ketoacidosis as an Immune-related Adverse Event from Pembrolizumab in Non-Small Cell Lung Cancer.

J Immunother. 2017 Jul/Aug;40(6):249-251

Authors: Leonardi GC, Oxnard GR, Haas A, Lang JP, Williams JS, Awad MM

Abstract
Programmed cell death protein 1 pathway inhibitors are now routinely administered to patients with non-small cell lung cancer, and prompt recognition of immune-related adverse events is critical to managing serious drug toxicities. Here, we describe a 66-year-old man with no known history of diabetes who presented with diabetic ketoacidosis after receiving 3 doses of pembrolizumab for lung adenocarcinoma. Autoimmune diabetes is a rare but potentially life-threatening complication of programmed cell death protein 1 inhibitors.

PMID: 28557813 [PubMed - indexed for MEDLINE]

Inflammatory Myopathy and Axonal Neuropathy in a Patient With Melanoma Following Pembrolizumab Treatment.

J Immunother. 2017 Jul/Aug;40(6):221-223

Authors: Diamantopoulos PT, Tsatsou K, Benopoulou O, Anastasopoulou A, Gogas H

Abstract
Immune-mediated adverse effects of immune checkpoint inhibitors are rather common, but neuromyopathic immune-related adverse events are very rare. In this report, we present a unique case of a patient with a complex neuromyopathic syndrome with axonal neuropathy and inflammatory myopathy after a single dose of pembrolizumab. An 82-year-old patient with a previously untreated stage IIIc melanoma developed ptosis in the left eye, generalized weakness, and neck and shoulder pain 15 days after pembrolizumab administration. He had left-sided ptosis and miosis, with a normal pupillary light reflex, horizontal diplopia, and voice hoarseness, along with weakness of the neck muscles and a hypokinetic right vocal cord at laryngoscopy. The laboratory evaluation was remarkable for the marked increase in the serum lactate dehydrogenase and creatine phosphokinase levels. Further evaluation revealed findings compatible with axonal neuropathy and inflammatory myopathy. The patient was treated with corticosteroids, immunoglobulin, and plasmapheresis, with a minor response; the patient eventually died. This case represents a newly described syndrome probably associated with pembrolizumab administration.

PMID: 28498142 [PubMed - indexed for MEDLINE]