BackgroundCachexia is a wasting condition associated with cancer types and, at the same time, is a serious and dose‐limiting side effect of cancer chemotherapy. Skeletal muscle loss is one of the main characteristics of cachexia that significantly contributes to the functional muscle impairment. Calcium‐dependent signaling pathways are believed to play an important role in skeletal muscle decline observed in cachexia, but whether intracellular calcium homeostasis is affected in this situation remains uncertain. Growth hormone secretagogues (GHS), a family of synthetic agonists of ghrelin receptor (GHS‐R1a), are being developed as a therapeutic option for cancer cachexia syndrome; however, the exact mechanism by which GHS interfere with skeletal muscle is not fully understood.MethodsBy a multidisciplinary approach ranging from cytofluorometry and electrophysiology to gene expression and histology, we characterized the calcium homeostasis in fast‐twitch extensor digitorum longus (EDL) muscle of adult rats with cisplatin‐induced cachexia and established the potential beneficial effects of two GHS (hexarelin and JMV2894) at this level. Additionally, in vivo measures of grip strength and of ultrasonography recordings allowed us to evaluate the functional impact of GHS therapeutic intervention.ResultsCisplatin‐treated EDL muscle fibres were characterized by a ~18% significant reduction of the muscle weight and fibre diameter together with an up‐regulation of atrogin1/Murf‐1 genes and a down‐regulation of Pgc1‐a gene, all indexes of muscle atrophy, and by a two‐fold increase in resting intracellular calcium, [Ca2+]i, compared with control rats. Moreover, the amplitude of the calcium transient induced by caffeine or depolarizing high potassium solution as well as the store‐operated calcium entry were ~50% significantly reduced in cisplatin‐treated rats. Calcium homeostasis dysregulation parallels with changes of functional ex vivo (excitability and resting macroscopic conductance) and in vivo (forelimb force and muscle volume) outcomes in cachectic animals. Administration of hexarelin or JMV2894 markedly reduced the cisplatin‐induced alteration of calcium homeostasis by both common as well as drug‐specific mechanisms of action. This effect correlated with muscle function preservation as well as amelioration of various atrophic indexes, thus supporting the functional impact of GHS activity on calcium homeostasis.ConclusionsOur findings provide a direct evidence that a dysregulation of calcium homeostasis plays a key role in cisplatin‐induced model of cachexia gaining insight into the etiopathogenesis of this form of muscle wasting. Furthermore, our demonstration that GHS administration efficaciously prevents cisplatin‐induced calcium homeostasis alteration contributes to elucidate the mechanism of action through which GHS could potentially ameliorate chemotherapy‐associated cachexia.

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Muscle atrophy is a widespread ill condition occurring in many diseases, which can reduce quality of life and increase morbidity and mortality. We developed a new method using non-invasive ultrasonography to measure soleus and gastrocnemius lateralis muscle atrophy in the hindlimb-unloaded rat, a well-accepted model of muscle disuse. Soleus and gastrocnemius volumes were calculated using the conventional truncated-cone method and a newly-designed sinusoidal method. For Soleus muscle, the ultrasonographic volume determined in vivo with either method was linearly correlated to the volume determined ex-vivo from excised muscles as muscle weight-to-density ratio. For both soleus and gastrocnemius muscles, a strong linear correlation was obtained between the ultrasonographic volume and the muscle fiber cross-sectional area determined ex-vivo on muscle cryosections. Thus ultrasonography allowed the longitudinal in vivo evaluation of muscle atrophy progression during hindlimb unloading. This study validates ultrasonography as a powerful method for the evaluation of rodent muscle atrophy in vivo, which would prove useful in disease models and therapeutic trials.

Background and purpose: Mexiletine (Mex), an orally effective antiarrhythmic agent used to treat ventricular arrhythmias, has also been found to be effective for myotonia and neuropathic pain. It is extensively metabolized in humans but little information exists about the pharmacodynamic properties of its metabolites. Experimental approach: To determine their contribution to the clinical activity of Mex, p-hydroxy-mexiletine (PHM), hydroxy-methyl-mexiletine (HMM), N-hydroxy-mexiletine (NHM) (phase I reaction products) and N-carbonyloxy b-Dglucuronide (NMG) (phase II reaction product) were tested on sodium currents (I Na ) of frog skeletal muscle fibres. Sodium currents were elicited with depolarizing pulses from different holding potentials (HP ¼ À140, À100, À70 mV) and stimulation frequencies (0.25, 0.5, 1, 2, 5, 10 Hz) using the vaseline-gap voltage-clamp method. Key results: All the hydroxylated derivatives blocked the sodium channel in a voltage-and use-dependent manner. The PHM, HMM and NHM metabolites were up to 10-fold less effective than the parent compound. However, HMM showed a greater use-dependent behaviour (10 Hz), compared to Mex and the other metabolites. Similar to Mex, these products behaved as inactivating channel blockers. Conjugation with glucuronic acid (NMG) resulted in almost complete abolition of the pharmacological activity of the parent compound. Conclusions and Implications: Thus, although less potent, the phase I metabolites tested demonstrated similar pharmacological behaviour to Mex and might contribute to its clinical profile.

The aim of the present study was to compare long-term adalimumab (ADA) and infliximab (IFX) retention rates in patients with intermediate, posterior, or panuveitis. Additional aims are as follows: (i) to identify any difference in the causes of treatment discontinuation between patients treated with ADA and IFX; (ii) to assess any impact of demographic features, concomitant treatments, and different lines of biologic therapy on ADA and IFX retention rates; and (iii) to identify any correlation between ADA and IFX treatment duration and the age at uveitis onset, the age at onset of the associated systemic diseases, and the age at the start of treatment. Clinical, therapeutic, and demographic data from patients with non-infectious intermediate, posterior, or panuveitis treated with ADA or IFX were retrospectively collected. Kaplan-Meier plot and log-rank (Mantel-Cox) test were used to assess survival curves. One hundred eight patients (188 eyes) were enrolled; in 87 (80.6%) patients, uveitis was associated with a systemic disease. ADA and IFX were administered in 62 and 46 patients, respectively. No statistically significant differences were identified between ADA and IFX retention rates (p value = 0.22). Similarly, no differences were identified between ADA and IFX retention rates in relation to gender (p value = 0.61 for males, p value = 0.09 for females), monotherapy (p value = 0.08), combination therapy with conventional disease-modifying antirheumatic drugs (log-rank p value = 0.63), and different lines of biologic therapy (p value = 0.79 for biologic-naïve patients; p value = 0.81 for subjects previously treated with other biologics). In conclusion, ADA and IFX have similar long-term retention rates in patients with non-infectious intermediate, posterior, and panuveitis. Demographic, clinical, and therapeutic features do not affect their long-term effectiveness.