This study aims to investigate the effects and the underlying mechanism of Huangqi Shengmai Decoction(HQSMD) in the treatment of fatigue and myocardial injury in a joint rat model. Wistar rats were assigned into 4 groups: sham, model, diltiazem hydrochloride(positive control), and HQSMD. The joint model of fatigue and myocardial injury was established by 14-day exhausted swimming followed by high ligation of the left anterior descending coronary artery. The rats in the sham group underwent a sham operation without coronary artery ligation or swimming. Since the fourth day after the ligation, swimming was continued in the model group and the drug-treated groups for the following 4 weeks. Meanwhile, the rats in the positive control group and the HQSMD group were respectively administrated intragastrically with diltiazem hydrochloride(20 mg·kg~(-1)·d~(-1)) and HQSMD(0.95 g·kg~(-1)·d~(-1)) for 4 weeks, while the shams and the models were given the same volume of normal saline. The left ventricular ejection fraction(LVEF), left ventricular fractional shortening(LVFS), grip strength, and myocardial pathophysiological changes were measured to evaluate the anti-fatigue and cardioprotective effects of HQSMD. The protein levels of PTEN-induced putative kinase 1(PINK1) and parkin in the myocardium were measured by Western blot to preliminarily elucidate the mechanism of HQSMD in ameliorating myocardial injury by suppressing mitochondrial autophagy. Compared with the shams, the models showed weakened heart function(LVEF and LVFS, P<0.01), decreased grasping ability(P<0.05), elevated blood urea nitrogen(BUN) and aldosterone(ALD) levels(P<0.01), aggravated myocardial fibrosis and connective tissue hyperplasia(P<0.01), and up-regulated protein levels of PINK1(P<0.01) and parkin(P<0.05). Four-week treatment with HQSMD increased the LVEF and LVFS levels(P<0.01), enhanced the grip strength(P<0.01), reduced the serum levels of BUN(P<0.01) and ALD(P<0.05), alleviated the pathological injury and fibrosis in the myocardium(P<0.01), and down-regulated the protein levels of PINK1(P<0.01) and parkin(P<0.05) in heart tissue. The results demonstrate that HQSMD may alleviate myocardial fibrosis and protect myocardium by suppressing the excessive mitochondrial auto-phagic activity and reducing the excessively elevated ALD level, thereby ameliorating fatigue and myocardial injury.
Rats ; Animals ; Ventricular Function, Left ; Rats, Sprague-Dawley ; Stroke Volume ; Diltiazem/pharmacology* ; Rats, Wistar ; Cardiomyopathies ; Heart Injuries ; Fibrosis ; Protein Kinases ; Ubiquitin-Protein Ligases

OBJECTIVE: To investigate the effect of calcium channel blocker diltizem in reversing multi-drug resistance (MDR) and on metadherin expression in hepatocellular carcinoma cells and explore the molecular mechanism. METHODS: Hepatocellular carcinoma MHCC97H and 7402 cells were treated with diltiazem hydrochloride, a calcium channel blocker (0, 25, 50, 100, 200, and 400 μmol/L), for 12, 24, or 48 h. Wound healing assay was employed to assess the changes in the mobility and migration of the cells following the treatments, and the changes in the expression levels of metadherin mRNA and protein and P-gp protein were determined using RT-PCR and immunocytochemistry. RESULTS: Diltiazem hydrochloride could transiently inhibit the migration and movement of MHCC97H and 7402 cells in a time-and concentration-dependent manner ( < 0.05). Diltiazem hydrochloride at different concentrations also transiently up-regulated the expressions of metadherin mRNA and protein but did not inhibit the expression of P-gp protein in MHCC97H and 7402 cells. CONCLUSIONS Calcium channel blocker can transiently inhibit the migration of hepatocellular carcinoma cells and up-regulate the expression of metadherin mRNA and protein through a feedback mechanism, suggesting the potential risk of calcium channel blockers for promoting tumor progression during the treatment of malignant tumors.
Calcium Channel Blockers ; Carcinoma, Hepatocellular ; Cell Line, Tumor ; Diltiazem ; Humans ; Liver Neoplasms

PURPOSE: Although the economic and mortality burden of atrial fibrillation (AF) is substantial, it remains unclear which treatment strategies for rate and rhythm control are most cost-effective. Consequently, economic factors can play an adjunctive role in guiding treatment selection. MATERIALS AND METHODS: We built a Markov chain Monte Carlo model using the Korean Health Insurance Review & Assessment Service database. Drugs for rate control and rhythm control in AF were analyzed. Cost-effective therapies were selected using a cost-effectiveness ratio, calculated by net cost and quality-adjusted life years (QALY). RESULTS: In the National Health Insurance Service data, 268149 patients with prevalent AF (age ≥18 years) were identified between January 1, 2013 and December 31, 2015. Among them, 212459 and 55690 patients were taking drugs for rate and rhythm control, respectively. Atenolol cost $714/QALY. Among the rate-control medications, the cost of propranolol was lowest at $487/QALY, while that of carvedilol was highest at $1363/QALY. Among the rhythm-control medications, the cost of pilsicainide was lowest at $638/QALY, while that of amiodarone was highest at $986/QALY. Flecainide and propafenone cost $834 and $830/QALY, respectively. The cost-effectiveness threshold of all drugs was lower than $30000/QALY. Compared with atenolol, the rate-control drugs propranolol, betaxolol, bevantolol, bisoprolol, diltiazem, and verapamil, as well as the rhythm-control drugs sotalol, pilsicainide, flecainide, propafenone, and dronedarone, showed better incremental cost-effectiveness ratios. CONCLUSION: Propranolol and pilsicainide appear to be cost-effective in patients with AF in Korea assuming that drug usage or compliance is the same.
Amiodarone ; Atenolol ; Atrial Fibrillation ; Betaxolol ; Bisoprolol ; Compliance ; Cost-Benefit Analysis ; Diltiazem ; Flecainide ; Humans ; Insurance, Health ; Korea ; Markov Chains ; Mortality ; National Health Programs ; Propafenone ; Propranolol ; Quality-Adjusted Life Years ; Sotalol ; Verapamil

Concealed bypass tract (CBT) results from incomplete development of the atrioventricular (AV) annulus. CBT conducts only in a retrograde direction, and therefore does not cause pre-excitation on standard electrocardiograms. The most common tachycardia associated with CBT is an orthodromic atrioventricular reentrant tachycardia (AVRT): a pathway involving anterograde circuitry through the AV node and His Purkinje system and retrograde conduction over the accessory pathway. Orthodromic AVRT accounts for approximately 90%-95% cases of AVRT. Most incidences of CBT occur at the left free wall. Vagal maneuvers and/or intravenous (IV) adenosine are recommended for first line acute management of AVRT. However, pharmacological therapy with IV diltiazem, verapamil, or beta blockers can also be effective for acute treatment for orthodromic AVRT in patients who do not show pre-excitation on their resting ECG during sinus rhythm. The first-line ongoing therapy for AVRT is catheter ablation of CBT; when catheter ablation is not indicated or preferred, oral beta blockers, diltiazem, verapamil, flecainide, propafenone, or amiodarone are recommended.
Adenosine ; Amiodarone ; Atrioventricular Node ; Catheter Ablation ; Diltiazem ; Electrocardiography ; Flecainide ; Humans ; Incidence ; Propafenone ; Tachycardia ; Tachycardia, Supraventricular* ; Verapamil

PURPOSE: Calcium channel blockers diltiazem and nitrate have been used as selective coronary vasodilators for patients with significant coronary artery spasm (CAS). However, no study has compared the efficacy of diltiazem alone versus diltiazem with nitrate for long-term clinical outcomes in patients with CAS. MATERIALS AND METHODS: A total of 2741 consecutive patients without significant coronary artery disease with positive CAS by acetylcholine (Ach) provocation test between November 2004 and May 2014 were enrolled. Significant CAS was defined as a narrowing of >70% by incremental intracoronary injection of 20, 50, and 100 µg of Ach into the left coronary artery. Patients were assigned to either the diltiazem group (n=842) or the dual group (diltiazem with nitrate, n=1899) at physician discretion. To adjust for potential confounders, a propensity score matching (PSM) analysis was performed using the logistic regression model. After PSM analysis, two well-balanced groups (811 pairs, n=1622, C-statistic=0.708) were generated. RESULTS: At 5 years, there were similar incidences in primary endpoints, including mortality, myocardial infarction, revascularization, and recurrent angina requiring repeat coronary angiography between the two groups. Diltiazem alone was not an independent predictor for major adverse cardiovascular events or recurrent angina requiring repeat coronary angiography. CONCLUSION: Despite the expected improvement of endothelial function and the relief of CAS, the combination of diltiazem and nitrate treatment was not superior to diltiazem alone in reducing mortality and cardiovascular events up to 5 years in patients with significant CAS.
Acetylcholine ; Aged ; Angina Pectoris/diagnosis ; Calcium Channel Blockers/therapeutic use ; Cardiovascular Agents/*therapeutic use ; Coronary Angiography/adverse effects ; Coronary Artery Disease/prevention & control ; Coronary Vasospasm/diagnosis/*drug therapy ; Diltiazem/*therapeutic use ; Drug Therapy, Combination ; Female ; Humans ; Incidence ; Male ; Middle Aged ; Myocardial Infarction/prevention & control ; Nitrates/*therapeutic use ; Propensity Score ; Time Factors ; Vasodilator Agents/therapeutic use

Early life neuronal exposure to environmental toxicants has been suggested to be an important etiology of neurodegenerative disease development. Perfluorohexanesulfonate (PFHxS), one of the major perfluoroalkyl compounds, is widely distributed environmental contaminants. We have reported that PFHxS induces neuronal apoptosis via ERK-mediated pathway. Imperatorin is a furanocoumarin found in various edible plants and has a wide range of pharmacological effects including neuroprotection. In this study, the effects of imperatorin on PFHxS-induced neuronal apoptosis and the underlying mechanisms are examined using cerebellar granule cells (CGC). CGC were isolated from seven-day old rats and were grown in culture for seven days. Caspase-3 activity and TUNEL staining were used to determine neuronal apoptosis. PFHxS-induced apoptosis of CGC was significantly reduced by imperatorin and PD98059, an ERK pathway inhibitor. PFHxS induced a persistent increase in intracellular calcium, which was significantly blocked by imperatorin, NMDA receptor antagonist, MK801 and the L-type voltage-dependent calcium channel blockers, diltiazem and nifedipine. The activation of caspase-3 by PFHxS was also inhibited by MK801, diltiazem and nifedipine. PFHxS-increased ERK activation was inhibited by imperatorin, MK801, diltiazem and nifedipine. Taken together, imperatorin protects CGC against PFHxS-induced apoptosis via inhibition of NMDA receptor/intracellular calcium-mediated ERK pathway.
Animals ; Apoptosis* ; Calcium ; Calcium Channel Blockers ; Caspase 3 ; Diltiazem ; Dizocilpine Maleate ; In Situ Nick-End Labeling ; MAP Kinase Signaling System* ; N-Methylaspartate ; Neurodegenerative Diseases ; Neurons* ; Neuroprotection ; Nifedipine ; Plants, Edible ; Rats

BACKGROUND: Pigmented purpuric dermatosis (PPD) comprises a group of dermatoses characterized clinically by pinpoint petechiae and purpura with a brown, red, or yellow patchy pigmented base. Histopathologically, extravasation of erythrocytes with hemosiderin deposition, a perivascular lymphocytic infiltrate on the superficial capillaries, and endothelial cell swelling are observed; however, their etiology remains obscure. There have been few reports regarding the clinical and histopathological characteristics of PPD in Korea. OBJECTIVE: To investigate the epidemiology, etiology, clinical manifestations, and histopathological features of PPD in Korea. METHODS: We retrospectively evaluated the clinical manifestations and histopathological features of 84 patients with PPD diagnosed at our center between January 2003 and December 2013. RESULTS: Of the 84 patients, 44 were male and 40 were female. The mean age of occurrence was 44.6 years and, the most commonly involved sites were the lower extremities (95.2%). Most of the PPD patients were asymptomatic (65.5%), however, others complained of itching (25%), pain (3.6%), heat sensations (3.6%), or tingling sensations (2.3%). The majority (63.1%) had Schamberg's disease, 15.5% had Majocchi's disease, 10.7% had eczematid-like purpura of Doucas and Kapetanakis, 7.1% had Gougerot-Blum syndrome, and 3.6% had lichen aureus. Of the 84 patients, 35.7% of patients had medical problems and 32.1% had etiologic factors including orthostatic hypertension (13.2%), trauma (7.2%), contact dermatitis (4.8%), sex hormones (4.8%), postpartum (1.2%), and diltiazem (1.2%). Histopathologically, extravasation of erythrocytes with or without hemosiderin deposit and a mild-to-dense perivascular or lichenoid lymphocytic infiltrate in the upper dermis were common features. A review of the prognoses of 72 patients revealed that 52.8% were clinically improved and that the most common treatment modality was a topical steroid (79.2%). CONCLUSION: Study results suggested variable clinical manifestations with common histologic features of PPD, and that variable etiologic factors could trigger the occurrence of PPD. We recommend the addition of both trauma and sex hormones as etiologic factors. There was no significant difference between the treatment modalities and the level of clinical improvement.
Capillaries ; Dermatitis, Contact ; Dermis ; Diltiazem ; Endothelial Cells ; Epidemiology ; Erythrocytes ; Female ; Gonadal Steroid Hormones ; Hemosiderin ; Hot Temperature ; Humans ; Hypertension ; Korea ; Lichens ; Lower Extremity ; Male ; Pigmentation Disorders ; Postpartum Period ; Prognosis ; Pruritus ; Purpura ; Retrospective Studies ; Sensation ; Skin Diseases*

PURPOSE: To estimate the risk of recurrent fissure in ano after sphincter preserving treatments. METHODS: A retrospective case note review, combined with a telephone survey was conducted for all patients treated for a chronic anal fissure between 1998 and 2008. RESULTS: Six hundred and twelve patients (303 women: mean age, 39 years; range, 16-86 years) were treated for chronic anal fissure between 1998 and 2008. Topical diltiazem 2% was initially prescribed for 8 weeks. The fissure did not heal in 141 patients. These patients (61 women: mean age, 30 years; range, 15-86 years) were treated with 100 IU botulinum A toxin (Botox) injection combined with a fissurectomy under general anaesthesia. Thirty eight patients suffered a recurrence of their fissure within two years. Thirty-four healed with further medical or sphincter conserving surgical therapy while four required a lateral internal sphincterotomy. CONCLUSION: The vast majority of patients with chronic anal fissure can be treated with sphincter conserving treatments. This may require several interventions before healing can be achieved. Assessment for recurrence after 'conservative' treatments requires a minimum of two-year follow-up.
Botulinum Toxins, Type A ; Diltiazem ; Female ; Fissure in Ano* ; Follow-Up Studies ; Humans ; Recurrence ; Retrospective Studies ; Telephone

Dystrophic calcinosis cutis associated with spontaneous hyperadrenocorticism was diagnosed in a 8-year-old female Chihuahua dog with erythematous, erosive, numerous papules, plaques, and crusts on the bilateral trunk, and inguinal region. Serum biochemical abnormalities included increases in alkaline phosphatase (ALP), alanine aminotransferase (ALT), gamma-glutamyl transpeptidase (GGT), and cholesterol. Radiographs showed mild hepatomegaly and subcutaneous lobulated calcific deposits. Histopathologic examination demonstrated diffuse deposition of basophilic calcified material in the dermis. Von Kossa's stain confirmed calcium deposition. Therapy with diltiazem was useful in resolving calcinosis.
Adrenocortical Hyperfunction ; Alanine Transaminase ; Alkaline Phosphatase ; Animals ; Basophils ; Calcinosis* ; Calcium ; Child ; Cholesterol ; Dermis ; Diltiazem* ; Dogs* ; Female ; gamma-Glutamyltransferase ; Hepatomegaly ; Humans

Paragangliomas have been reported on multiple locations. A diagnosis of a catecholamine-secreting tumor was considered only after induction of anesthesia, when BP (blood pressure) increased. A 61-year-old male patient was referred for removal of a retroperitoneal mass suspected hemangiopericytoma. He was on medications for hypertension. There was a surge of ABP (arterial blood pressure) to 186/117 mmHg when the tumor was manipulated at the beginning of the surgery, and this was treated by bolus of diltiazem. After resection of the tumor, ABP dropped to 57/36 mmHg. In order to improve the patient's hemodynamic parameters, crystalloid fluid was given, and ephedrine was administered intravenously. Persistent hypotension was treated with titrated vasopressors (epinephrine and norepinephrine). When paraganglioma is suspected due to a sudden hypertensive crisis during surgery, the surgeon must decide whether to proceed with the surgical procedure or to stop and restart the surgery after proper management of the crisis.
Anesthesia ; Diltiazem ; Ephedrine ; Hemangiopericytoma ; Hemodynamics ; Humans ; Hypertension ; Hypotension ; Isotonic Solutions ; Male ; Paraganglioma