BACKGROUND: Angiotensin receptor neprilysin inhibitors (ARNIs), angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), β-blockers (BBs), and mineralocorticoid receptor antagonists (MRAs) are the cornerstones in treating heart failure with reduced ejection fraction (HFrEF). Sodium-glucose cotransporter 2 inhibitors (SGLT-2is) are included in HFrEF treatment guidelines. However, the effect of SGLT-2i and the five drugs on HFrEF have not yet been systematically evaluated. METHODS: PubMed, Embase, and the Cochrane Library were searched for randomized controlled trials (RCTs) from inception dates to September 23, 2022. Additional trials from previous relevant reviews and references were also included. The primary outcomes were changes in left ventricular ejection fraction (LVEF), left ventricular end-diastolic diameter/dimension (LVEDD), left ventricular end-systolic diameter/dimension (LVESD), left ventricular end-diastolic volume (LVEDV), and left ventricular end-systolic volume (LVESV), left ventricular end-systolic volume index (LVESVI), and left ventricular end-diastolic volume index (LVEDVI). Secondary outcomes were New York Heart Association (NYHA) class, 6-min walking distance (6MWD), B-type natriuretic peptide (BNP) level, and N-terminal pro-BNP (NT-proBNP) level. The effect sizes were presented as the mean difference (MD) with 95% confidence interval (CI). RESULTS: We included 68 RCTs involving 16,425 patients. Compared with placebo, ARNI + BB + MRA + SGLT-2i was the most effective combination to improve LVEF (15.63%, 95% CI: 9.91% to 21.68%). ARNI + BB + MRA + SGLT-2i (5.83%, 95% CI: 0.53% to 11.14%) and ARNI + BB + MRA (3.83%, 95% CI: 0.72% to 6.90%) were superior to the traditional golden triangle ACEI + BB + MRA in improving LVEF. ACEI + BB + MRA + SGLT-2i was better than ACEI + BB + MRA (-8.05 mL/m 2 , 95% CI: -14.88 to -1.23 mL/m 2 ) and ACEI + BB + SGLT-2i (-18.94 mL/m 2 , 95% CI: -36.97 to -0.61 mL/m 2 ) in improving LVEDVI. ACEI + BB + MRA + SGLT-2i (-3254.21 pg/mL, 95% CI: -6242.19 to -560.47 pg/mL) was superior to ARB + BB + MRA in reducing NT-proBNP. CONCLUSIONS: Adding SGLT-2i to ARNI/ACEI + BB + MRA is beneficial for reversing cardiac remodeling. The new quadruple drug "ARNI + BB + MRA + SGLT-2i" is superior to the golden triangle "ACEI + BB + MRA" in improving LVEF. REGISTRATION PROSPERO; No. CRD42022354792.
Humans ; Heart Failure/physiopathology* ; Stroke Volume/physiology* ; Angiotensin Receptor Antagonists/therapeutic use* ; Angiotensin-Converting Enzyme Inhibitors/therapeutic use* ; Sodium-Glucose Transporter 2 Inhibitors/therapeutic use* ; Randomized Controlled Trials as Topic ; Mineralocorticoid Receptor Antagonists/therapeutic use* ; Adrenergic beta-Antagonists/therapeutic use*

Humans ; Diabetes Mellitus, Type 2/drug therapy* ; Sodium-Glucose Transporter 2 Inhibitors/therapeutic use* ; Arrhythmias, Cardiac/etiology* ; Glucose ; Sodium

Humans ; Diabetes Mellitus, Type 2/drug therapy* ; Sodium-Glucose Transporter 2 Inhibitors/therapeutic use* ; Arrhythmias, Cardiac/etiology* ; Glucose ; Sodium

OBJECTIVE: To investigate the efficacy and safety of intravesical instillation of heparin/alkalized lidocaine (lidocaine mixed with sodium bicarbonate) combined with hydrodistension and transurethral fulguration in the treatment of female interstitial cystitis (IC). METHODS: Female patients who attended the Department of Urology at the First Hospital of China Medical University between January 2012 and December 2020 and met the diagnostic criteria proposed in the guidelines of the American Urological Association with a new diagnosis of IC were selected for retrospective analysis. Cystoscopy and biopsy of suspicious lesions were performed at the time of diagnosis. All the patients were treated with an intravesical instillation regimen of 2% lidocaine 10 mL + 5% sodium bicarbonate 5 mL + heparin 25 000 IU for a continuous period of 12 months, with or without water dilatation and transurethral electrocautery according to the patient's preference, categorized as hydrodistension and transurethral fulguration (HD/TF) group and non-HD/TF group. The patients were evaluated before and 1, 6, and 12 months after treatment for O'Leary-Sant interstitial cystitis patient symptom index scores (ICSI), interstitial cystitis patient problem index scores (ICPI), visual analog scale (VAS) of suprapubic pain, and functional bladder capacity (FBC) changes. RESULTS: A total of 79 patients were collected in this study. Four (5.1%) of these patients underwent cystectomy due to pathological diagnosis of cancer or treatment failure. The remaining patients were followed up 1, 6 and 12 months after treatment. Repeated-measures ANOVA showed a significant decrease in ICPI, ICSI and VAS and an increase in FBC after treatment compared with before treatment (P < 0.05). FBC continued to decrease during the 1, 6 and 12 months' post-treatment follow-ups, with statistically significant differences; ICSI continued to decrease during the 1 and 6 months post-treatment follow-ups, with statistically significant differences, while the difference between ICSI at 6 months post-treatment and at 12 months' post-treatment was not statistically significant. In the HD/TF group, ICPI continued to decrease in the follow-up from 1 and 6 months after treatment, and the difference was statistically significant, while the difference between ICPI 6 months after treatment and 12 months after treatment was not statistically significant. There was no statistically significant difference between the remaining indicators 1, 6 and 12 months after treatment. ICPI, ICSI, VAS and FBC improved earlier and the changes in VAS and FBC were more significant in the HD/TF group compared with the non-HD/TF group (P < 0.05). CONCLUSION Heparin/alkalized lidocaine combination of intravesical instillation with hydrodistension and transurethral fulguration for IC is an effective treatment option. Heparin/alkalized lidocaine combination of intravesical instillation may be the first choice of treatment, which can significantly reduce the economic burden of patients and medical insurance system. If patients can accept it, transurethral fulguration with hydrodistension may be considered.
Humans ; Female ; Cystitis, Interstitial/drug therapy* ; Administration, Intravesical ; Retrospective Studies ; Sodium Bicarbonate/therapeutic use* ; Treatment Outcome ; Lidocaine/therapeutic use* ; Heparin/therapeutic use* ; Electrocoagulation

Humans ; Tolvaptan/therapeutic use* ; Ascites/drug therapy* ; Receptors, Vasopressin ; Liver Cirrhosis/drug therapy* ; Sodium

Urea cycle disorder (UCD) is a group of inherited metabolic diseases with high disability or fatality rate, which need long-term drug treatment and diet management. Except those with Citrin deficiency or liver transplantation, all pediatric patients require lifelong low protein diet with safe levels of protein intake and adequate energy and lipids supply for their corresponding age; supplementing essential amino acids and protein-free milk are also needed if necessary. The drugs for long-term use include nitrogen scavengers (sodium benzoate, sodium phenylbutyrate, glycerol phenylbutyrate), urea cycle activation/substrate supplementation agents (N-carbamylglutamate, arginine, citrulline), etc. Liver transplantation is recommended for pediatric patients not responding to standard diet and drug treatment, and those with severe progressive liver disease and/or recurrent metabolic decompensations. Gene therapy, stem cell therapy, enzyme therapy and other novel technologies may offer options for treatment in UCD patients. The regular biochemical assessments like blood ammonia, liver function and plasma amino acid profile are needed, and physical growth, intellectual development, nutritional intake should be also evaluated for adjusting treatment in time.
Humans ; Child ; Citrullinemia/drug therapy* ; Urea Cycle Disorders, Inborn/therapy* ; Arginine ; Sodium Benzoate/therapeutic use* ; Liver Transplantation

OBJECTIVE: To investigate the clinical effect of Shenfu injection combined with glucocorticoid in the treatment of acute left heart failure complicated with bronchospasm. METHODS: A prospective study was conducted.Ninety patients with acute left heart failure complicated with bronchospasm admitted to Huai'an Second People's Hospital from January 2021 to July 2022 were selected and divided into conventional treatment group, hormone therapy group and combined treatment group according to random number table method, with 30 cases in each group. All patients in the 3 groups received basic Western medicine treatment. On this basis, the conventional treatment group was given 0.25-0.50 g aminophylline injection plus 5% glucose injection or 0.9% sodium chloride injection (diabetes patients) 100 mL slow intravenous infusion, 1-2 times a day. In the hormone treatment group, 1 mg of budesonide suspension for inhalation was diluted to 2 mL by 0.9% sodium chloride injection, twice a day, and applied until 48 hours after the pulmonary wheezing disappeared. The combined treatment group was given glucocorticoid combined with Shenfu injection 80 mL plus 5% glucose injection or 0.9% sodium chloride injection (diabetes patients) 250 mL intravenously, once a day. All treated for 1 week. The general data, traditional Chinese medicine (TCM) syndrome score, TCM syndrone efficacy index, acute left heart failure efficacy, bronchospasm efficacy, systolic blood pressure (SBP), mean arterial pressure (MAP), serum N-terminal pro-brain natriuretic peptide (NT-proBNP) level and safety of the 3 groups were compared. The patients were followed up for 6 months, and the mortality and re-hospitalization rate of the 3 groups were recorded. RESULTS: Among the 90 patients, a total of 83 patients completed the study, excluding the cases dropped due to death and other reasons. There were 29 cases in the combined treatment group, 25 cases in the hormone therapy group and 29 cases in the conventional treatment group. There were no significant differences in age, gender, course of disease, and previous history (history of diabetes, history of hypertension, history of hyperlipidemia) among the 3 groups. Therefore, they were comparable. The difference of TCM syndrome score before and after treatment, TCM syndrome efficacy index of combined treatment group and hormone therapy group were higher than those of conventional treatment group [difference of TCM syndrome score: 15.14±5.74, 13.24±5.75 vs. 10.62±5.87, TCM syndrome efficacy index: (67.84±14.31)%, (59.94±14.26)% vs. (48.92±16.74)%, all P < 0.05], and the difference of TCM syndrome score and TCM syndrome efficacy index of combined treatment group were higher than those of hormone treatment group (both P < 0.05). The total effective rate of acute left heart failure and bronchospasm in the combined treatment group was significantly higher than that in the conventional treatment group (total effective rate of acute left heart failure: 96.55% vs. 75.86%, total effective rate of bronchospasm: 93.10% vs. 65.52%, both P < 0.05). The difference of serum NT-proBNP before and after treatment in combination therapy group and hormone therapy group was significantly higher than that in conventional treatment group (ng/L: 7 922.86±5 220.31, 7 314.92±4 450.28 vs. 4 644.79±3 388.23, all P < 0.05), and the difference of serum NT-proBNP before and after treatment in the combined treatment group was significantly higher than that in the hormone treatment group (P < 0.05). There were no significant differences in SBP difference, MAP difference, mortality and re-hospitalization rate among the 3 groups. No adverse reactions occurred in the 3 groups during treatment. CONCLUSIONS Shenfu injection combined with glucocorticoid is effective in the treatment of patients with acute left heart failure complicated with bronchospasm. It is superior to glucocorticoid and aminophylline in relieving bronchospasm, reducing NT-proBNP level and improving total effective rate, and has good prognosis and safety.
Humans ; Glucocorticoids/therapeutic use* ; Bronchial Spasm ; Prospective Studies ; Aminophylline/therapeutic use* ; Sodium Chloride/therapeutic use* ; Natriuretic Peptide, Brain ; Peptide Fragments ; Heart Failure/drug therapy* ; Diabetes Mellitus ; Glucose

Metformin has robust glucose-lowering effects and multiple benefits beyond hypoglycemic effects. It can also be used in combination with various hypoglycemic drugs and is cost effective. In the absence of the strong indications of glucagon like peptide-1 receptor agonist (GLP-1RA) or sodium glucose cotransporter 2 inhibitor (SGLT2i) for cardiorenal protection, metformin should be used as the first-line pharmacological treatment for newly diagnosed type 2 diabetes and the basic drug for the combined treatment of hypoglycemic drugs. Metformin does not increase the risk of liver and kidney function damage, but patients with renal dysfunction should adjust the dosage of metformin based on estimated glomerular filtration rate (eGFR) levels. Moreover, the correct use of metformin does not increase the risk of lactic acidosis. Because long-term use of metformin is associated with a decrease in vitamin B₁₂ levels, patients with insufficient intake or absorption of vitamin B₁₂ should be regularly monitored and appropriately supplemented with vitamin B₁₂. In view of the new progress made in the basic and clinical research related to metformin, the consensus updating expert group updated the consensus on the basis of the Expert Consensus on the Clinical Application of Metformin (2018 Edition).
Humans ; Consensus ; Diabetes Mellitus, Type 2/complications* ; Hypoglycemic Agents ; Metformin/therapeutic use* ; Sodium-Glucose Transporter 2 Inhibitors/therapeutic use* ; Vitamins/therapeutic use* ; China

Objective: To determine the electrophysiological effects and related mechanisms of late sodium current inhibitors on hearts with short QT intervals. Methods: The electrophysiological study was performed on isolated Langendorff perfused rabbit hearts. A total of 80 New Zealand White rabbits were used and 34 hearts without drug treatment were defined as control group A, these hearts were then treated with I_KATP opener pinacidil, defined as pinacidil group A. Then, 27 hearts from pinacidil group A were selected to receive combined perfusion with sodium channel inhibitors or quinidine, a traditional drug used to treat short QT syndrome, including ranolazine combined group (n=9), mexiletine combined group (n=9), and quinidine combined group (n=9). Nineteen out of the remaining 46 New Zealand rabbits were selected as control group B (no drug treatments, n=19), and then treated with pinacidil, defined as pinacidil group B (n=19). The remaining 27 rabbits were treated with sodium inhibitors or quinidine alone, including ranolazine alone group (n=9), mexiletine alone group (n=9), and quinidine alone group (n=9). Electrocardiogram (ECG) physiological parameters of control group A and pinacidil group A were collected. In control group B and pinacidil group B, programmed electrical stimulation was used to induce ventricular arrhythmias and ECG was collected. ECG physiological parameters and ventricular arrhythmia status of various groups were analyzed. The concentrations of pinacidil, ranolazine, mexiletine and quinidine used in this study were 30, 10, 30 and 1 μmol/L, respectively. Results: Compared with control group A, the QT interval, 90% of the repolarization in epicardial and endocardial monophasic action potential duration (MAPD₉₀-Epi, MAPD₉₀-Endo) was shortened, the transmural dispersion of repolarization (TDR) was increased, and the effective refractor period (ERP) and post-repolarization refractoriness (PRR) were reduced in pinacidil group A (all P<0.05). Compared with the pinacidil group A, MAPD₉₀-Epi, MAPD₉₀-Endo, QT interval changes were reversed in quinidine combined group and mexiletine combined group (all P<0.05), but not in ranolazine combined group. All these three drugs reversed the pinacidil-induced increases of TDR and the decreases of ERP and PRR. The induced ventricular arrhythmia rate was 0 in control group B, and increased to 10/19 (χ²=13.6, P<0.05) in pinacidil group B during programmed electrical stimulation. Compared with the pinacidil group B, incidences of ventricular arrhythmia decreased to 11% (1/9), 11% (1/9) and 0 (0/9) (χ²=4.5, 4.5, 7.4, P<0.05) respectively in ranolazine group, mexiletine group and quinidine group. Conclusions: Inhibition of late sodium current does not increase but even decreases the risk of malignant arrhythmia in hearts with a shortened QT interval. The antiarrhythmic mechanism might be associated with the reversal of the increase of TDR and the decrease of refractoriness (including both ERP and PRR) of hearts with shortened QT interval.
Rabbits ; Animals ; Quinidine/therapeutic use* ; Mexiletine/therapeutic use* ; Pinacidil/therapeutic use* ; Sodium ; Ranolazine/therapeutic use* ; Electrophysiologic Techniques, Cardiac ; Arrhythmias, Cardiac/drug therapy*

The East Asian scorpion Buthus martensii Karsch (BmK) is one of the classical traditional Chinese medicines for treating epilepsy for over a thousand years. Neurotoxins purified from BmK venom are considered as the main active ingredients, acting on membrane ion channels. Voltage-gated sodium channels (VGSCs) play a crucial role in the occurrence of epilepsy, which make them become important drug targets for epilepsy. Long chain toxins of BmK, composed of 60-70 amino acid residues, could specifically recognize VGSCs. Among them, α-like neurotoxins, binding to the receptor site-3 of VGSC, induce epilepsy in rodents and can be used to establish seizure models. The β or β-like neurotoxins, binding to the receptor site-4 of VGSC, have significant anticonvulsant effects in epileptic models. This review aims to illuminate the anticonvulsant/convulsant effects of BmK polypeptides by acting on VGSCs, and provide potential frameworks for the anti-epileptic drug-design.
Animals ; Anticonvulsants/therapeutic use* ; Neurotoxins/pharmacology* ; Scorpion Venoms/pharmacology* ; Scorpions/chemistry* ; Voltage-Gated Sodium Channels