Suppressive effects of processed aconite root on dexamethasone-induced muscle ring finger protein-1 expression and its active ingredients.

Processed aconite root (PA), the tuberous root of Aconitum carmichaelii prepared by autoclaving, is a crude drug used in Japanese traditional Kampo medicine and traditional Chinese medicine for the symptoms of kidney deficiency, that is related to the muscle atrophy in modern medicine. The objective of the present study is to evaluate the effectiveness of PA on muscle atrophy and to find its active ingredients using dexamethasone-induced muscle ring finger protein-1 (MuRF1) mRNA expression in murine myoblast C2C12 cells. Dexamethasone-induced MuRF1 expression was significantly suppressed by methanol-soluble part of boiling water extract of PA in a concentration-dependent manner with its IC50 value of 1.5 mg/ml. By the activity-guided fractionations of PA extract using the partition between organic solvents and its aqueous solution, the activity of PA did not transfer into the fraction containing aconitine-type diterpenoid alkaloids but into BuOH layer. Then, we found higenamine and salsolinol as the active ingredients in PA. Higenamine and salsolinol significantly suppressed dexamethasone-induced MuRF1 expression, and their IC50 values were 0.49 and 50 µM, respectively. The contents of higenamine and salsolinol in the decoctions of commercially available fourteen PA products are 0.12 and 14 µg/ml as the average values, and varied with the coefficient of variation (CV) values of 97 and 63%, respectively. Higenamine also significantly suppressed dexamethasone-induced mRNA expressions of muscle atrophy F-box protein (MAFbx)/atrogin1, casitas B-lineage lymphoma-b (Cbl-b), troponin, branched-chain amino acid aminotransferase 2 (BCAT2), and Bcl-2 binding and pro-apoptotic protein3 (Bnip3). Although the quality control of PA is regulated by the contents of diterpene alkaloids, salsolinol and higenamine can be used as the marker compounds to certificate the pharmacological activities of PA.

Rehabilitation Nutrition and Exercise Therapy for Sarcopenia.

Sarcopenia is an age-related loss of skeletal muscle associated with adverse outcomes such as falls, fractures, disability, and increased mortality in older people and hospitalized patients. About half of older male nursing home residents have sarcopenia. The diagnostic criteria by the European Working Group on Sarcopenia in Older People (EWGSOP) and the Asian Working Group for Sarcopenia (AWGS) have led to increased interest in sarcopenia. Exercise and nutritional management are crucial for the prevention and treatment of sarcopenia. Nutritional therapy for sarcopenia that includes 20 g of whey protein and 800 IU of vitamin D twice a day improves lower limb strength. Exercise therapy for sarcopenia, such as resistance training and 6 months of home exercises, improves muscle strength and physical function. Combination therapy that includes both nutritional and exercise therapy improves gait speed and knee extension strength more than either exercise alone or nutrition therapy alone. Excessive bedrest and mismanagement of nutrition in medical facilities can lead to iatrogenic sarcopenia. Iatrogenic sarcopenia is sarcopenia caused by the activities of health care workers in health care facilities. Appropriate nutritional management and exercise programs through rehabilitation nutrition are important for prevention and treatment of iatrogenic sarcopenia. Nutritional and exercise therapy should be started very early after admission and adjusted to the level of inflammation and disease status. Repeated assessment, diagnosis, goal setting, interventions, and monitoring using the rehabilitation nutrition care process is important to maximize treatment effectiveness and improve patients' functional recovery and quality of life.

Physical Compatibility of Nafamostat with Analgesics, Sedatives, and Muscle Relaxants for Treatment of Coronavirus Disease 2019.

BACKGROUND: Severe coronavirus disease 2019 (COVID-19) may require continuous administration of analgesics, sedatives, and muscle relaxants. Nafamostat has recently been reported as a therapeutic agent for COVID-19. However, there is a lack of information on the compatibility of nafamostat with the aforementioned drug classes. This study evaluated the physical compatibility of nafamostat with these drug classes. METHODS: Nafamostat was combined with 1-3 target drugs (fentanyl, morphine, midazolam, dexmedetomidine, and rocuronium). Fifteen physical compatibility tests were conducted. Nafamostat was dissolved in 5% glucose solution; the final concentration was 10 mg/mL. All other medications were diluted in 0.9% sodium chloride to obtain clinically relevant concentrations. The power of hydrogen (pH) of all medications was measured during each test. Compatibility tests were conducted with 4 test solutions in which nafamostat and the target drugs were compounded at equal volume ratios (1:1, 1:1:1, or 1:1:1:1). Visual appearance, turbidity, and pH were evaluated immediately after mixing and at 1 and 3 hours. Physical incompatibilities were defined as gross precipitation, cloudiness, appearance of the Tyndall effect, or a turbidity change of ≥0.5 nephelometric turbidity units (NTU) based on nafamostat. RESULTS: The mean pH of nafamostat was 3.13 ± 0.03. The combination of nafamostat, fentanyl, and dexmedetomidine had the highest pH (3.39 ± 0.01; 3 hours after mixing). All drugs were compatible with nafamostat until 3 hours after admixture, with a mean turbidity value of ≤0.03 NTU. CONCLUSIONS: Infusions combining nafamostat with the tested sedatives, analgesics, and muscle relaxants could be safely administered.

Neoline, an active ingredient of the processed aconite root in Goshajinkigan formulation, targets Nav1.7 to ameliorate mechanical hyperalgesia in diabetic mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Goshajinkigan (GJG), a traditional Japanese Kampo formula, has been shown to exhibit several pharmacological actions, including antinociceptive effects. Processed aconite root (PA), which is considered to be an active ingredient of GJG, has also been demonstrated to have an ameliorative effect on pain, such as diabetic peripheral neuropathic pain. We recently identified neoline as the active ingredient of both GJG and PA that is responsible for its effects against oxaliplatin-induced neuropathic pain in mice. AIM OF THE STUDY: In the present study, we investigated whether GJG, PA, and neoline could inhibit Nav1.7 voltage-gated sodium channel (VGSC) current and whether neoline could ameliorate mechanical hyperalgesia in diabetic mice. MATERIALS AND METHODS: To assess the electrophysiological properties of GJG extract formulation, powdered PA, and neoline on Nav1.7 VGSCs, whole-cell patch clamp recording was performed using human HEK293 cells expressing Nav1.7 VGSCs. In addition, the ameliorative effects of neoline on diabetic peripheral neuropathic pain were evaluated using the von Frey test in streptozotocin (STZ)-induced diabetic model mice. RESULTS: GJG extract formulation significantly inhibited Nav1.7 VGSC peak current. Powdered PA also inhibited Nav1.7 VGSC peak current. Like GJG and PA, neoline could inhibit Nav1.7 VGSC current. When diabetic mice were treated with neoline by intraperitoneal acute administration, the mechanical threshold was increased in diabetic mice, but not in non-diabetic mice, in a behavioral study. CONCLUSION: These results suggest that neoline might be a novel active ingredient of GJG and PA that is one of responsible ingredients for ameliorating mechanical hyperalgesia in diabetes via the inhibition of Nav1.7 VGSC current at least.

Neoline is the active ingredient of processed aconite root against murine peripheral neuropathic pain model, and its pharmacokinetics in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Processed aconite root (PA), the root of Aconitum carmichaeli (Ranunculaceae), is a crude drug used in traditional Chinese or Japanese kampo medicine to treat pain associated with coldness. In our previous study, PA and its active ingredient, neoline, alleviated oxaliplatin-induced peripheral neuropathy in mice. AIM OF THE STUDY: The present study investigated the effects of PA on a murine peripheral neuropathy model induced by intraperitoneal injection of paclitaxel and partial ligation of the sciatic nerve (Seltzer model), and identified its active ingredients. MATERIALS AND METHODS: PA powder (1 g/kg/day) was orally administered, and either neoline or benzoylmesaconine (10 mg/kg/day) was subcutaneously injected into the murine model. Mechanical hyperalgesia was evaluated via the von Frey filament method. PA extract was orally administered to rats; blood samples were chronologically collected, and the plasma concentrations of Aconitum alkaloids were measured. The contents of Aconitum alkaloids in commercial PA products were also measured. RESULTS: PA extract and neoline significantly attenuated the mechanical hyperalgesia induced by either paclitaxel or partial ligation of the sciatic nerve in mice. In the plasma samples of rats treated with PA extract, higher concentrations of benzoylmesaconine and neoline were apparent among Aconitum alkaloids. The contents of benzoylmesaconine and neoline varied among PA products with different processing procedures. Subcutaneous injection of benzoylmesaconine did not attenuate the hyperalgesia induced by each paclitaxel, partial ligation of the sciatic nerve, or oxaliplatin in mice. CONCLUSIONS: The present results indicate that PA and its active ingredient, neoline, are promising agents for the alleviation of neuropathic pain. Neoline can be used as a marker compound to determine the quality of the PA products for the treatment of neuropathic pain.

Discovery of 5-Chloro-1-(5-chloro-2-(methylsulfonyl)benzyl)-2-imino-1,2-dihydropyridine-3-carboxamide (TAK-259) as a Novel, Selective, and Orally Active α1D Adrenoceptor Antagonist with Antiurinary Frequency Effects: Reducing Human Ether-a-go-go-Related Gene (hERG) Liabilities.

A novel structural class of iminopyridine derivative 1 was identified as a potent and selective human α1D adrenoceptor (α1D adrenergic receptor; α1D-AR) antagonist against α1A- and α1B-AR through screening of an in-house compound library. From initial structure-activity relationship studies, we found lead compound 9m with hERG K(+) channel liability. To develop analogues with reduced hERG K(+) channel inhibition, a combination of site-directed mutagenesis and docking studies was employed. Further optimization led to the discovery of (R)-9s and 9u, which showed antagonistic activity by a bladder strip test in rats with bladder outlet obstruction, as well as ameliorated cystitis-induced urinary frequency in rats. Ultimately, 9u was selected as a clinical candidate. This is the first study to show the utility of iminopyridine derivatives as selective α1D-AR antagonists and evaluate their effects in vivo.

Anticancer Effect of Ginger Extract against Pancreatic Cancer Cells Mainly through Reactive Oxygen Species-Mediated Autotic Cell Death.

The extract of ginger (Zingiber officinale Roscoe) and its major pungent components, [6]-shogaol and [6]-gingerol, have been shown to have an anti-proliferative effect on several tumor cell lines. However, the anticancer activity of the ginger extract in pancreatic cancer is poorly understood. Here, we demonstrate that the ethanol-extracted materials of ginger suppressed cell cycle progression and consequently induced the death of human pancreatic cancer cell lines, including Panc-1 cells. The underlying mechanism entailed autosis, a recently characterized form of cell death, but not apoptosis or necroptosis. The extract markedly increased the LC3-II/LC3-I ratio, decreased SQSTM1/p62 protein, and enhanced vacuolization of the cytoplasm in Panc-1 cells. It activated AMPK, a positive regulator of autophagy, and inhibited mTOR, a negative autophagic regulator. The autophagy inhibitors 3-methyladenine and chloroquine partially prevented cell death. Morphologically, however, focal membrane rupture, nuclear shrinkage, focal swelling of the perinuclear space and electron dense mitochondria, which are unique morphological features of autosis, were observed. The extract enhanced reactive oxygen species (ROS) generation, and the antioxidant N-acetylcystein attenuated cell death. Our study revealed that daily intraperitoneal administration of the extract significantly prolonged survival (P = 0.0069) in a peritoneal dissemination model and suppressed tumor growth in an orthotopic model of pancreatic cancer (P < 0.01) without serious adverse effects. Although [6]-shogaol but not [6]-gingerol showed similar effects, chromatographic analyses suggested the presence of other constituent(s) as active substances. Together, these results show that ginger extract has potent anticancer activity against pancreatic cancer cells by inducing ROS-mediated autosis and warrants further investigation in order to develop an efficacious candidate drug.

Novel and potent calcium-sensing receptor antagonists: discovery of (5R)-N-[1-ethyl-1-(4-ethylphenyl)propyl]-2,7,7-trimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide monotosylate (TAK-075) as an orally active bone anabolic agent.

The calcium-sensing receptor antagonist (CaSR) has been recognized as a promising target of anabolic agents for treating osteoporosis. In the course of developing a new drug candidate for osteoporosis, we found tetrahydropyrazolopyrimidine derivative 1 to be an orally active CaSR antagonist that stimulated transient PTH secretion in rats. However, compound 1 showed poor physical and chemical stability. In order to work out this compound's chemical stability and further understand its in vivo efficacy, we focused on modifying the 2-position of the tetrahydropyrazolopyrimidine. As a result of chemical modification, we discovered (5R)-N-[1-ethyl-1-(4-ethylphenyl)propyl]-2,7,7-trimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide monotosylate 10m (TAK-075), which showed improved solubility, chemical stability, and in vivo efficacy. Furthermore, we describe that evaluating the active metabolite is important during repeated treatment with short-acting CaSR antagonists.

Primary cardiac liposarcoma causing cardiac tamponade: report of a case.

The intracardiac growth and extension of liposarcoma was observed in a 60-year-old woman. The epicardial tumor was identified to originate from the anterior wall of the right ventricle. She initially showed symptoms associated with cardiac tamponade. A surgical operation was performed but it resulted in incomplete resection due to massive invasion and dissemination. The recurrence of the tumors led to congestive heart failure. Finally, she died of heart failure and liver dysfunction as a result of tumor metastasis and invasion. An autopsy detected the primary cardiac liposarcoma. Only a few cases of cardiogenic liposarcoma have so far been reported. A further elucidation of cardiac liposarcoma could reveal mechanisms of the disease, and thus contribute to development of complementary therapies after surgical intervention.