Efficacy and safety of mirogabalin for the treatment of fibromyalgia: results from three 13-week randomized,double-blind,placebo- and active-controlled,parallel-group studies and a 52-week open-label extension study

Objective: To investigate the efficacy and safety of mirogabalin, an α₂δ ligand, in patients with fibromyalgia (FM).

Methods: In three 13-week, multicenter, double-blind, phase 3 studies (studies A, B, and C), patients with FM (n?=?1293, 1270, and 1301, respectively) were randomized (1:1:1:1) to placebo, pregabalin 150?mg twice daily, mirogabalin 15?mg once daily or mirogabalin 15?mg twice daily. The primary endpoint was the change in weekly average daily worst pain score (ADPS) at week 13. Key secondary endpoints included Patient Global Impression of Change and change in the Fibromyalgia Impact Questionnaire total score. Long-term safety of mirogabalin was assessed in a 52-week extension study.

Results: Neither mirogabalin dose demonstrated a significant ADPS reduction from baseline vs. placebo at week 13 in any of the three studies. Pregabalin significantly reduced ADPS from baseline vs. placebo in studies B and C (p?=?.0008 and .0001, respectively). The effect of mirogabalin compared with placebo on key secondary endpoints was variable across the studies. Mirogabalin was well tolerated by most patients in the phase 3 studies; no unexpected adverse events occurring during the 52-week extension study.

Conclusion: While both mirogabalin doses were well tolerated by most patients and showed potential for reducing pain associated with FM, the primary endpoint of significant pain reduction in patients on mirogabalin compared with placebo was not achieved in any of the three randomized controlled studies.

Clinical trial registration: NCT02146430; NCT02187159; NCT02187471; and NCT02234583 (extension study).     

Activity against Plasmodium falciparum of Lactones Isolated from the Endophytic Fungus Xylaria sp.

Three lactones were isolated from the culture medium of the endophytic fungus Xylaria sp. Grev. (Xylariaceae). The major compound, which showed weak activity (13 μ g/mL) against a chloroquine-resistant strain of Plasmodium falciparum, was identified as (+)-phomalactone (1). The others were 6-(1-propenyl)-3,4,5,6-tetrahydro-5-hydroxy-4H-pyran-2-one (2) and 5-hydroxymellein (3). Compounds 1 and 2 are reported for the first time as constituents of Xylaria. Also, this is the first report of the activity of the compounds 1–3 against a chloroquine-resistant Plasmodium falciparum strain.     

DIOXINS IN COMMERCIAL UNITED STATES BABY FOOD

This is the first known study of dioxins, dibenzofurans, and polychlorinated biphenyls (PCBs) in commercial American bottled baby foods purchased in the United States. Dioxins, persistent chlorinated organics, are inadvertent by-products of chemical synthesis or combustion and are toxic to humans and other animals. Almost all dioxins enter the body through food consumption, specifically from food products containing animal fat. Major-brand bottled baby food containing meat was purchased at U.S. supermarkets and 12 pooled samples were analyzed for dioxins using high-resolution gas chromatography with high-resolution mass spectrometry. Low levels of dioxins were found in these products. The range was from 28 to 226 parts per quadrillion (ppq) dioxin toxic equivalents (TEQ). This is reported on a whole or wet weight (as eaten) basis. As a comparison, findings of dioxins in U.S. supermarket meat ranged from 28 to 540 ppq. Although dioxin levels are generally lower in these baby foods than in meat or poultry, the presence of dioxins in commercial baby food containing meat is cause for concern.     

Rat Subchronic Inhalation Study of Smoke from Cigarettes Containing Flue-Cured Tobacco Cured Either by Direct-Fired or Heat-Exchanger Curing Processes

A subchronic, nose-only inhalation study compared the effects of mainstream smoke from a cigarette containing 100% flue-cured tobacco cured by a direct-fired process to that of a cigarette containing 100% flue-cured tobacco cured by a heat exchanger process. The tobaccos and mainstream smoke from tobaccos cured by the heat exchanger process have been shown to have significantly lower levels of tobacco-specific nitrosamines than tobaccos cured by a direct-fired process. Male and female rats were exposed for 1 h/day, 5 days/wk, for 13 wk to mainstream smoke at 0, 0.06, 0.20, or 0.80 mg wet total particulate matter per liter of air. Clinical signs, body and organ weights, clinical chemistry, hematology, carboxyhemoglobin, serum nicotine, plethysmography, gross pathology, and histopathology were determined. When histologic changes resulting from exposure to smoke from the two types of cigarettes were compared, the only significant difference was increased epithelial hyperplasia of the anterior nasal cavity in males in the high-exposure group for the heat-exchanger cigarette. At the end of the exposure period, subsets of rats from each group were maintained without smoke exposures for an additional 13 wk (recovery period). At the end of the recovery period, there were no statistically significant differences in histopathological findings observed between the heat-exchanger-cured tobacco cigarette when compared to the direct-fired cured tobacco cigarette. The complete toxicological assessment in this study of heat exchanger and direct-fired tobaccos suggests no overall biologically significant differences between the two cigarettes.     

A training programme to build cancer research capacity in low- and middle-income countries: findings from Guatemala

Problem

Guatemala is experiencing an increasing burden of cancer but lacks capacity for cancer prevention, control and research.

Approach

In partnership with a medical school in the United States of America, a multidisciplinary Cancer Control Research Training Institute was developed at the Instituto de Cancerología (INCAN) in Guatemala City. This institute provided a year-long training programme for clinicians that focused on research methods in population health and sociocultural anthropology. The programme included didactic experiences in Guatemala and the United States as well as applied training in which participants developed research protocols responsive to Guatemala’s cancer needs.

Local setting

Although INCAN is the point of referral and service for Guatemala’s cancer patients, the institute’s administration is also interested in increasing cancer research – with a focus on population health. INCAN is thus a resource for capacity building within the context of cancer prevention and control.

Relevant changes

Trainees increased their self-efficacy for the design and conduct of research. Value-added benefits included establishment of an annual cancer seminar and workshops in cancer pathology and qualitative analysis. INCAN has recently incorporated some of the programme’s components into its residency training and established a research department.

Lessons learnt

A training programme for clinicians can build cancer research capacity in low- and middle-income countries. Training in population-based research methods will enable countries such as Guatemala to gather country-specific data. Once collected, such data can be used to assess the burden of cancer-related disease, guide policy for reducing it and identify priority areas for cancer prevention and treatment.     

A randomized controlled trial of multiple tailored messages for smoking cessation among callers to the cancer information service

Self-help materials computer-tailored to the specific needs of smokers have shown promise as a high-reach, low-cost intervention for smoking cessation. Adding tailored cessation materials to telephone-based cessation counseling may be a way of generating greater efficacy in promoting and maintaining cessation. The objective of this study is to assess the efficacy of adding different types of behavioral smoking cessation materials to brief telephone-based cessation counseling.A total of 1,978 smokers calling the National Cancer Institute's (NCI's) Cancer Information Service (CIS) for help in quitting smoking initially received brief cognitive-behavioral cessation counseling from a CIS information specialist. Following a baseline interview administered by the information specialist, subjects were randomly assigned to one of four conditions, each delivered by U.S. mail: a single, untailored smoking cessation guide (SU); a single, tailored smoking cessation guide (ST); a series of four (multiple) printed materials tailored only to baseline data (MT); and a series of four (multiple) printed materials tailored to baseline as well as retailored using 5-month interim progress data (MRT). The primary outcome measure was 7-day point prevalence abstinence rates assessed using a computer-assisted telephone interview (CATI) at 12-month follow-up.At 12-month follow-up, using intent-to-treat, imputed, and per-protocol analyses, no differences were found among the four experimental conditions (linear trend), or when the ST, MT, and MRT groups were compared with the control (SU) group. Participants in the two multiple message group conditions combined (MT + MRT), however, had significantly higher abstinence rates than participants in the two single message group conditions combined (SU + ST). Moreover, among subjects who reported quitting at the 5-month follow-up, participants receiving the MRT materials reported higher abstinence rates at 12 months than the other three groups combined (SU + ST + MT). The results of this study support the effectiveness, over and above a single telecounseling interaction, of multiple tailored print material contacts on cessation. These effects, however may be due to tailoring, or the longitudinal nature of the two multiple tailored conditions, or both. The strongest evidence for tailoring occurred in the MRT condition for relapse prevention, suggesting that print materials tailored to interim progress may be especially effective in this context. The qualities of specific psychosocial and communication elements in tailored materials should receive attention in future research.     

The cessation of cancer treatment as a crisis

Although it is commonly acknowledged that a diagnosis of cancer can be a form of a crisis precipitating a period of disequilibrium, few researchers have examined the psychosocial issues associated with the completion of adjuvant cancer treatment. This exploratory study examines the responses of women in a community-based cancer support group to an open-ended question asking them to describe their experiences since their treatment ended. Subjects were asked to respond to whether they felt the loss of the "safety net" of treatment had caused them any type of distress. The narrative responses of the subjects support the notion that the period after treatment ceases may be viewed as a crisis that brings with it anxiety and uncertainty. The results of this study reinforce the need for additional research to better understand the issue so that services and programs can be enhanced to better meet patients' needs. Additionally, the results suggest that social workers may play a crucial role in helping women make the transition from cancer "patient" to cancer "survivor."     

Methylated arsenicals: the implications of metabolism and carcinogenicity studies in rodents to human risk assessment

Monomethylarsonic acid (MMA(V)) and dimethylarsinic acid (DMA(V)) are active ingredients in pesticidal products used mainly for weed control. MMA(V) and DMA(V) are also metabolites of inorganic arsenic, formed intracellularly, primarily in liver cells in a metabolic process of repeated reductions and oxidative methylations. Inorganic arsenic is a known human carcinogen, inducing tumors of the skin, urinary bladder, and lung. However, a good animal model has not yet been found. Although the metabolic process of inorganic arsenic appears to enhance the excretion of arsenic from the body, it also involves formation of methylated compounds of trivalent arsenic as intermediates. Trivalent arsenicals (whether inorganic or organic) are highly reactive compounds that can cause cytotoxicity and indirect genotoxicity in vitro. DMA(V) was found to be a bladder carcinogen only in rats and only when administered in the diet or drinking water at high doses. It was negative in a two-year bioassay in mice. MMA(V) was negative in 2-year bioassays in rats and mice. The mode of action for DMA(V)-induced bladder cancer in rats appears to not involve DNA reactivity, but rather involves cytotoxicity with consequent regenerative proliferation, ultimately leading to the formation of carcinoma. This critical review responds to the question of whether DMA(V)-induced bladder cancer in rats can be extrapolated to humans, based on detailed comparisons between inorganic and organic arsenicals, including their metabolism and disposition in various animal species. The further metabolism and disposition of MMA(V) and DMA(V) formed endogenously during the metabolism of inorganic arsenic is different from the metabolism and disposition of MMA(V) and DMA(V) from exogenous exposure. The trivalent arsenicals that are cytotoxic and indirectly genotoxic in vitro are hardly formed in an organism exposed to MMA(V) or DMA(V) because of poor cellular uptake and limited metabolism of the ingested compounds. Furthermore, the evidence strongly supports a nonlinear dose-response relationship for the biologic processes involved in the carcinogenicity of arsenicals. Based on an overall review of the evidence, using a margin-of-exposure approach for MMA(V) and DMA(V) risk assessment is appropriate. At anticipated environmental exposures to MMA(V) and DMA(V), there is not likely to be a carcinogenic risk to humans.     

Cytokine and IDO metabolite changes effected by calcium pterin during inhibition of MDA-MB-231 xenograph tumors in nude mice

In vivo studies of the effectiveness of various forms of calcium pterin reveal significant antitumor activity associated with (1:4, mol/mol) calcium pterin (CaPterin), (1:2, mol/mol) calcium pterin, dipterinyl calcium pentahydrate (DCP), as well as unexpectedly for a calcium chloride dihydrate solution in nude mice with MDA-MB-231 xenographs. Stepwise regression analysis of nine plasma cytokine and indoleamine 2,3-dioxygenase (IDO) metabolite levels identified four effects correlated to (1:4, mol/mol) calcium pterin administration: (1) decreased IL-6, (2) increased IL-10, (3) decreased IFN-gamma, and (4) increased kynurenine. CONCLUSION: (1:4, mol/mol) CaPterin exerts significant (by Spearman rank order correlation) dose-response antitumor activity in nude mice with MDA-MB-231 xenographs, and sustains both inflammatory and anti-inflammatory changes in the levels of certain plasma factors.