Safety of temozolomide use in adult patients with renal dysfunction.

PURPOSE: Temozolomide (TMZ), a cytotoxic DNA alkylating agent, is the main chemotherapy used for the treatment of high grade astrocytomas. The active alkylator, methylhydrazine, is not recovered in urine and thus renal function is not expected to affect clearance. Prescribing information for TMZ states pharmacokinetics have not been studied in adults with poor renal function, eGFR < 36 mL/min/1.73 m2. We reviewed our clinical experience with TMZ in patients with impaired renal function to evaluate safety of administering full dose TMZ. METHODS: The primary endpoint was to characterize the incidence and severity of thrombocytopenia in patients with eGFR < 60 mL/min/1.73 m2 who received TMZ for treatment of high grade gliomas (HGG) or primary CNS lymphoma (PCNSL). Secondary endpoints included incidence and severity of neutropenia, lymphopenia hepatotoxicity, and number of TMZ cycles administered. Medical records of patients with HGG or PCNSL treated with TMZ from October 1, 2016-September 30, 2019 were accessed to identify cases for this study. RESULTS: Thirty-two patients were eligible for this study. Of the seven patients with eGFR < 36 mL/min/1.73m2, 38/39 cycles (97%) were completed without grade 3-4 thrombocytopenia. No patients experienced grade 3-4 neutropenia, and grade 3-4 lymphopenia occurred in 5 cycles (15%). One patient discontinued TMZ 7 days prior to completion of radiation due to thrombocytopenia. CONCLUSION: Hematologic toxicity in patients with severe renal dysfunction, eGFR < 36 mL/min/1.73m2, is similar to that of patients with normal renal function. Severe renal impairment does not preclude use of temozolomide, but cautious monitoring of blood counts is warranted.

Hyperpolarized magnetic resonance shows that the anti-ischemic drug meldonium leads to increased flux through pyruvate dehydrogenase in vivo resulting in improved post-ischemic function in the diabetic heart.

The diabetic heart has a decreased ability to metabolize glucose. The anti-ischemic drug meldonium may provide a route to counteract this by reducing l-carnitine levels, resulting in improved cardiac glucose utilization. Therefore, the aim of this study was to use the novel technique of hyperpolarized magnetic resonance to investigate the in vivo effects of treatment with meldonium on cardiac metabolism and function in control and diabetic rats. Thirty-six male Wistar rats were injected either with vehicle, or with streptozotocin (55 mg/kg) to induce a model of type 1 diabetes. Daily treatment with either saline or meldonium (100 mg/kg/day) was undertaken for three weeks. in vivo cardiac function and metabolism were assessed with CINE MRI and hyperpolarized magnetic resonance respectively. Isolated perfused hearts were challenged with low-flow ischemia/reperfusion to assess the impact of meldonium on post-ischemic recovery. Meldonium had no significant effect on blood glucose concentrations or on baseline cardiac function. However, hyperpolarized magnetic resonance revealed that meldonium treatment elevated pyruvate dehydrogenase flux by 3.1-fold and 1.2-fold in diabetic and control animals, respectively, suggesting an increase in cardiac glucose oxidation. Hyperpolarized magnetic resonance further demonstrated that meldonium reduced the normalized acetylcarnitine signal by 2.1-fold in both diabetic and control animals. The increase in pyruvate dehydrogenase flux in vivo was accompanied by an improvement in post-ischemic function ex vivo, as meldonium elevated the rate pressure product by 1.3-fold and 1.5-fold in the control and diabetic animals, respectively. In conclusion, meldonium improves in vivo pyruvate dehydrogenase flux in the diabetic heart, contributing to improved cardiac recovery after ischemia.

Protective Effects of Meldonium in Experimental Models of Cardiovascular Complications with a Potential Application in COVID-19.

Right ventricular (RV) and left ventricular (LV) dysfunction is common in a significant number of hospitalized coronavirus disease 2019 (COVID-19) patients. This study was conducted to assess whether the improved mitochondrial bioenergetics by cardiometabolic drug meldonium can attenuate the development of ventricular dysfunction in experimental RV and LV dysfunction models, which resemble ventricular dysfunction in COVID-19 patients. Effects of meldonium were assessed in rats with pulmonary hypertension-induced RV failure and in mice with inflammation-induced LV dysfunction. Rats with RV failure showed decreased RV fractional area change (RVFAC) and hypertrophy. Treatment with meldonium attenuated the development of RV hypertrophy and increased RVFAC by 50%. Mice with inflammation-induced LV dysfunction had decreased LV ejection fraction (LVEF) by 30%. Treatment with meldonium prevented the decrease in LVEF. A decrease in the mitochondrial fatty acid oxidation with a concomitant increase in pyruvate metabolism was noted in the cardiac fibers of the rats and mice with RV and LV failure, respectively. Meldonium treatment in both models restored mitochondrial bioenergetics. The results show that meldonium treatment prevents the development of RV and LV systolic dysfunction by enhancing mitochondrial function in experimental models of ventricular dysfunction that resembles cardiovascular complications in COVID-19 patients.

News and views in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): The role of co-morbidity and novel treatments.

Though affecting many thousands of patients, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) should be considered an orphan disease, since the cause remains elusive and no treatment is available that can provide complete cure. There is reasonable insight into the pathogenesis of signs and symptoms, and treatments specifically directed to immunological, inflammatory and metabolic processes offer relief to an increasing number of patients. Particular attention is given to the importance of co-morbidity requiring appropriate therapy. Promising results are obtained by treatment with Metformin, or possibly Momordica charantia extract, which will correct insulin resistance, with Meldonium improving the transportation of glucose into the mitochondria, with sodium dichloroacetate activating pyruvate dehydrogenase, and with nutraceutical support reducing oxidative and inflammatory impairment.

The Effects of Meldonium on the Renal Acute Ischemia/Reperfusion Injury in Rats.

Acute renal ischemia/reperfusion (I/R) injury is a clinical condition that is challenging to treat. Meldonium is an anti-ischemic agent that shifts energy production from fatty acid oxidation to less oxygen-consuming glycolysis. Thus, in this study we investigated the effects of a four-week meldonium pre-treatment (300 mg/kg b.m./day) on acute renal I/R in male rats (Wistar strain). Our results showed that meldonium decreased animal body mass gain, food and water intake, and carnitine, glucose, and lactic acid kidney content. In kidneys of animals subjected to I/R, meldonium increased phosphorylation of mitogen-activated protein kinase p38 and protein kinase B, and increased the expression of nuclear factor erythroid 2-related factor 2 and haeme oxygenase 1, causing manganese superoxide dismutase expression and activity to increase, as well as lipid peroxidation, cooper-zinc superoxide dismutase, glutathione peroxidase, and glutathione reductase activities to decrease. By decreasing the kidney Bax/Bcl2 expression ratio and kidney and serum high mobility group box 1 protein content, meldonium reduced apoptotic and necrotic events in I/R, as confirmed by kidney histology. Meldonium increased adrenal noradrenaline content and serum, adrenal, hepatic, and renal ascorbic/dehydroascorbic acid ratio, which caused complex changes in renal lipidomics. Taken together, our results have confirmed that meldonium pre-treatment protects against I/R-induced oxidative stress and apoptosis/necrosis.

Normalization of heart rate variability with taurine and meldonium complex in post-infarction patients with type 2 diabetes mellitus.

The purpose of this study is to scrutiny the Dynamics of heart rate variability (HRV) in patients with PICS with 2nd type DM against the background of Taurine (TN) and meldonium (ME). The results of the investigations prove the decrease of the oxidative stress, which is basis of DACN, under the influence of sulfur-containing amino acid taurine (TN), and meldonium (ME) - a competitive inhibitor of gamma-butyrobetaine hydroxylase. Biochemical mechanisms of synergistic action of ME and TN are also described. The results of the studies of 98 patients with PICS and concomitant 2nd type diabetes mellitus were analyzed. They were distributed by simple randomization method into two groups, comparable according to age and sex: the main group (MG) (n = 68): and group of comparison (GoC) (n = 30). HRV was evaluated twice daily at the Cardiosense HMEGG system: at baseline and after 12 weeks of treatment. For the assessment of HRV the frequency and spectral parameters were used. While evaluating the different methods of treatment, their influence on the range of spectral and time indices of HRV was determined (p = 0.001 by the criterion of Kruskall-Wallis). It was learned that the combined application of ME and TN gives a statistically significant (p <0.01) increase of SDNN, HF at night, pNN - on 50% by day (p <0.01, p <0.001 and p <0.01 respectively), and statistically significant decrease in LF at night, compared to GHG.

Meldonium improves Huntington's disease mitochondrial dysfunction by restoring peroxisome proliferator-activated receptor γ coactivator 1α expression.

Mitochondrial dysfunction seems to play a fundamental role in the pathogenesis of neurodegeneration in Huntington's disease (HD). We assessed possible neuroprotective actions of meldonium, a small molecule affecting mitochondrial fuel metabolism, in in vitro and in vivo HD models. We found that meldonium was able to prevent cytotoxicity induced by serum deprivation, to reduce the accumulation of mutated huntingtin (mHtt) aggregates, and to upregulate the expression of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) in mHTT-expressing cells. The PGC-1α increase was accompanied by the increment of mitochondrial mass and by the rebalancing of mitochondrial dynamics with a promotion of the mitochondrial fusion. Meldonium-induced PGC-1α significantly alleviated motor dysfunction and prolonged the survival of a transgenic HD Drosophila model in which mHtt expression in the nervous system led to progressive motor performance deficits. Our study strongly suggests that PGC-1α, as a master coregulator of mitochondrial biogenesis, energy homeostasis, and antioxidant defense, is a potential therapeutic target in HD.

[Efficacy of Short-Term Therapy With Meldonium in Patients With Chronic Heart Failure of Ischemic Etiology and Type 2 Diabetes Mellitus].

PURPOSE: to assess efficacy and endotheliotropic properties of short-term addition of meldonium to basic therapy of patients with chronic ischemic heart failure and type 2 diabetes. RESULTS AND CONCLUSION: The study demonstrated the ability of meldonium to significantly improve endothelial function and the state of microcirculatory vascular bed, as well as to influence beneficially heart rate variability.

CLINICAL EFFICACY OF S-ADENOSYLMETHIONINE IN PATIENTS WITH NON-ALCOHOLIC STEATOHEPATITIS AND CHRONIC KIDNEY DISEASE I-II STAGE.

The article presents a theoretical generalization of the results of the clinical efficacy of S-adenosylmethionine in patients with non-alcoholic steatohepatitis (NASH) in comorbidity with obesity and chronic kidney disease (CKD) of the 1st-2nd stages. The objective of the article was to determine the likely effect of S-adenosylmethionine and Meldonium on the clinical course of non-alcoholic steatohepatitis (NASH) and chronic kidney disease (CKD) of the I-II stages. We examined 75 patients with NASH with comorbid obesity I degree and CKD I and II dgrees. To determine the efficacy of the treatment, 3 groups of patients were randomized according to age, sex, degree of obesity, activity of the cytolytic syndrome of NASH and the stage of the CKD. SAM possesses powerful membrane-stabilizing properties, stably eliminates the manifestations of cytolysis, cholestasis, mesenchymal-inflammatory syndrome, increases the albumin-synthesizing function of the liver in patients with NASH and prevents the loss of albumins in the conditions of CKD І-ІІ st. At the same time, complex therapy of SAM and vazonate is superior to the effectiveness of correction of these syndromes due to the implementation of powerful metabolic, antioxidant, antihypoxant, energy-specific properties of Meldonium and may be recommended for the introduction into the practice of internal medicine and gastroenterology for treatment NASH on the background of obesity and CKD I and II stages. The established nephroprotective properties of SAM that are potentiated by Meldonium are probably due to the ability of these drugs to eliminate endothelial dysfunction, improve microcirculation, and prevent the progression of kidney fibrosis. S-adenosylmethionine (ahepta) in a dose of 600 mg sublingually in patients with non-alcoholic steatohepatitis on the background of obesity and chronic kidney disease of the 1st and 2nd st. produces powerful membrane-stabilizing effects on the affected hepatocytes, stably eliminates the clinical manifestations of the disease, the intensity of cytolysis, cholestasis, mesenchymal-inflammatory syndrome, inhibits the progression of hepatic and renal dysfunction (increases the albumin-synthesizing function of the liver, the velocity of glomerular filtration) by optimizing the control of fibrosis of the liver and kidneys. Complex therapy with S-adenosylmethionine (ahape) and Meldonium (500 mg /day)(vasonate) is superior to the correction of these syndromes NASH and CKD, since the vasonate potentially potentiates the action of S-adenosylmethionine in acute and distant observation periods.

Pharmacological effects of meldonium: Biochemical mechanisms and biomarkers of cardiometabolic activity.

Meldonium (mildronate; 3-(2,2,2-trimethylhydrazinium)propionate; THP; MET-88) is a clinically used cardioprotective drug, which mechanism of action is based on the regulation of energy metabolism pathways through l-carnitine lowering effect. l-Carnitine biosynthesis enzyme γ-butyrobetaine hydroxylase and carnitine/organic cation transporter type 2 (OCTN2) are the main known drug targets of meldonium, and through inhibition of these activities meldonium induces adaptive changes in the cellular energy homeostasis. Since l-carnitine is involved in the metabolism of fatty acids, the decline in its levels stimulates glucose metabolism and decreases concentrations of l-carnitine related metabolites, such as long-chain acylcarnitines and trimethylamine-N-oxide. Here, we briefly reviewed the pharmacological effects and mechanisms of meldonium in treatment of heart failure, myocardial infarction, arrhythmia, atherosclerosis and diabetes.

[Clinical and Economic Aspects of Meldonium as Part of Physical Rehabilitation Programs in Patients With Coronary Heart Disease After Percutaneous Coronary Interventions].

PURPOSE: to analyze clinical and economical effectiveness of meldonium as component of integrated program of cardio-rehabilitation in patients with ischemic heart disease (IHD) in the early period after percutaneous coronary intervention (PCI) with incomplete revascularization. MATERIAL AND METHODS: A program of controlled physical training (CPT) was carried out in patients with stable IHD and positive post PCI exercise test (n=48, age less or equal 65 years) starting 8-10 days after PCI. CRT program consisted of 2 phases - inhospital (exercise on treadmill with max heart rate [HR] 80% of that achieved in initial test, 10 times during 2 weeks) and home (exercise on treadmill with max HR 60% of HR achieved in initial test, 3 times a week for 2 months). Before initiation of CRT patients were distributed into 2 groups: CRT without (n=23; 56.7+/-7.1 years) and with (n=25; 54.6+/-6.8 years) administration of meldonium (1000 mg/day intravenously). Control group (n=24; 50+/-8.4 years) consisted of patients who were under outpatient observation, received similar drug therapy, but were not subjected to CRT. After completion of CRT (in 2.5 months) all patients underwent clinical-instrumental examination with determination of exercise tolerance. RESULTS: Exercise duration and metabolic equivalent (MET) increased by 43.9, 36.6, 4.1% and 42.1, 34.8, 3.4% in CRT+ meldonium, CRT only, and control groups, respectively. CONCLUSION: In patients with documented ischemia after PCI inclusion of meldonium in the scheme of rehabilitation was associated with improved physical performance and optimal cost-effectiviness.

Endogenous Sensitizer of Beta-Adrenergic Receptors (ESBAR) as a Component of Humoral Links Element of Autonomic Nervous System and Its Analogs (Review).

Kirov State Medical Academy, Kirov The results of the 20-years studies of the presence in blood serum and other body fluids of endogenous modulators of adrenergic and M-cholinergic impact a A COMPONENT of humoral element of autonomic nervous system. The article is devoted to the endogenous sensitizer of beta-adrenergic receptor (ESBAR) - water-soluble low molecular weight substances, analogues of which are histidine, tryptophan, tyrosine, mildronat and preduktal. It is shown, that separate dilutions of human serum and animal (as a source of ESBAR) and ESBAR - analogues ways to enhance the effectiveness of activation of beta-adrenoceptors (AR) of smooth muscle (uterus, coronary and renal arteries, trachea, stomach), myocardium and erythrocytes and platelets (respectively influenced of histidine and tryptophan). It is reported? that content of ESBAR in human serum (according to the titers of its dilution) depends on the sex and the presence of somatic diseases, and at women are also on the stage of reproduction and obstetric complications It is discussed hossible mechanisms of ESBAR action, its physiological role, including as a component of beta-adrenoreceptor myometrium inhibitory mechanism, as well as the prospect of the use of analogues ESBAR, including for the prevention of preterm labor, and for the treatment of bronchial asthma, coronary heart disease, hypertension and heart failure.

[Effect of sanatorium treatment on endothelial function in children with primary arterial hypertension].

To study the effect of sanatorium treatment (ST) using sodium chloride baths and metabolic drug mildronat on the dynamics of the ambulatory blood pressure monitoring (ABPM), markers of endothelial function in children with primary arterial hypertension (PAH). ABPM and held defined level of asymmetric dimethylarginine (ADMA), endothelin-1 (ET-1) and nitric oxide (NO) in the serum of 114 children with PAH aged 12-17. The positive dynamics of ABPM in all groups, but significantly (P < 0.05) decrease in mean BP was noted in the group with combined ST using sodium chloride baths. When analyzing the level of NO a positive trend (P < 0.01) in the group was using metabolic therapy, but significantly (P < 0.001) pronounced effect was observed when it is combined balneotherapy and metabolic therapy. Analysis of ET-1 and ADMA at ST in conjunction with therapy and metabolic rate of sodium chloride baths there was a significant (P < 0.01) decrease in these parameters in comparison with those before treatment. In children with PAH have been identified violations of the functional activity of the endothelium, which is reflected in increased levels of ET-1, ADMA and reducing NO. Conducting rehabilitation inclusion complex balneotherapy and metabolic therapy helps to reduce average daily blood pressure, normalization of functional activity of the endothelium as a normalization of the synthesis of NO (P < 0.,001), a significant decrease of ET-1 (P < 0.01) and ADMA (P < 0.01).

[Parallel pharmacological correction of myocardial dysfunction, cognitive and psychopathological disordres in patients with congestive heart failure].

Was examined 92 patients with congestive heart failure III-IV FC with fraction of emission left ventricle < 45% against coronary artery disease. Patients of control group received basic therapy (according to recommendations of the Ukrainian society of cardiology), the 1 group--in addition received a preparation of Vazonat within 15 days intravenously in a dose of 1000 mg a day further are out-patient within 1 month on 250 mg 3 times per os; the 2 group--under the same scheme a preparation of Vazonat and a day tranquilizer of Adapto in a dose of 500 mg twice a day throughout all term of supervision. It is established that addition of Vazonat to basic treatment leads to additional effect concerning improvement of indicators cardio-hemodynamic, to improvement congestive functions. Joint appointment of preparations of Vazonat and Adaptol against basic treatment leads to more expressed improvement congestive functions, to progressive reduction of degree of trouble, depression.

[Use of meldonium in the combination treatment of patients with heart failure in the early postinfarction period].

AIM: To evaluate the impact of 10-14-day intravenous administration of meldonium as part of combination therapy in patients with chronic heart failure in the early post-infarction period on the recovery period, structural and functional parameters, and heart rate variability (HRV). SUBJECTS AND METHODS: The investigation enrolled 60 patients (men and women) aged 45 to 75 years at weeks 3-4 after post-myocardial infarction with symptoms of Functional Class II-III heart failure. All the patients underwent 24-hour electrochocardiography monitoring, cardiac echocardiography, and HRV study. After dividing the patients into 2 groups, Group 1 (a study group) (n = 30) was given intravenous meldonium (idrinol) 1000 mg/day in addition to the basic therapy of coronary heart disease. The patients in the study and control (Group 2; n = 30) groups were at baseline matched for age, gender, disease severity, and basic therapy pattern. RESULTS: Following 10-14 days of treatment, both groups showed clinical improvement and the favorable changes in cardiac structural and functional parameters and HRV values, which were more pronounced in the patients receiving meldonium. CONCLUSION: The patients with CHF using meldonium as part of combination therapy in the early post-infarction period were observed to have clinical improvement, a significant reduction in the rate of angina attacks and in the need for nitrates, a decrease in the number of arrhythmic and ischemic episodes, and favorable changes in cardiac structural and functional parameters and HRV values.

[Role of pFox inhibitors in the treatment of patients with acute myocardial ischemia].

AIM: To evaluate the anti-ischemic and anti-anginal efficacy of meldonium (Idrinol) in its short-term use as part of combination therapy in patients with chronic heart failure in the early post-infarction period. SUBJECTS AND METHODS: The investigation enrolled 60 patients (men and women) aged 45 to 75 years at weeks 3-4 after postmyocardial infarction with symptoms of Functional Class II-III heart failure. All the patients underwent physical examination, 24-hour ECG monitoring, heart rate variability (HRV) study, and quality of life assessment using the Seattle questionnaire. After randomization of the patients into 2 groups, Group 1 (a study group) (n = 30) was given intravenous Idrinol 1000 mg/day in addition to the basic therapy of coronary heart disease. The study and control (Group 2; n = 30) groups were matched for age, gender, disease severity, and basic therapy pattern. RESULTS: Following 10-14 days of treatment, both groups showed clinical improvement and the autonomically normalizing effect of meldonium (Idrinol), which were more pronounced in Group 1 patients. CONCLUSION: Meldonium (Idrinol) was effective when parenterally administered in a dose of 1000 mg/day for 10-14 days as part of combination therapy in the early post-infarction period, which showed up as clinical improvement, a significant reduction in the frequency of angina attacks and in the need to use nitroglycerin, a decrease in the number of arrhythmia episodes, and its normalizing effect of HRV.

Mildronate improves cognition and reduces amyloid-ß pathology in transgenic Alzheimer's disease mice.

Mildronate, a carnitine congener drug, previously has been shown to provide neuroprotection in an azidothymidine-induced mouse model of neurotoxicity and in a Parkinson's disease rat model. The aim of this study was to investigate the effects of mildronate treatment on cognition and pathology in Alzheimer's disease (AD) model mice (APP(SweDI)). Mildronate was administered i.p. daily at 50 or 100 mg/kg for 28 days. At the end of treatment, the animals were behaviorally and cognitively tested, and brains were assessed for AD-related pathology, inflammation, synaptic markers, and acetylcholinesterase (AChE). The data show that mildronate treatment significantly improved animal performance in water maze and social recognition tests, lowered amyloid-ß deposition in the hippocampus, increased expression of the microglia marker Iba-1, and decreased AChE staining, although it did not alter expression of proteins involved in synaptic plasticity (GAP-43, synaptophysin, and GAD67). Taken together, these findings indicate mildronate's ability to improve cognition and reduce amyloid-ß pathology in a mouse model of AD and its possible therapeutic utility as a disease-modifying drug in AD patients.

[Experience of Vasonat usage in treatment of patients with chronic toxic hepatitis].

The authors performed the clinical study of efficiency of Vasonat usage in complex treatment of chronic toxic hepatitis. Under observation there were 122 patients with chronic toxic hepatitis (37--with chronic medicament hepatitis and 85--with chronic alcohol hepatitis). During treatment with Vasonat the severity of clinical signs decreased to 0-1 points, GGTP level decreased in 2,2 times that showed the better efficiency of Vasonat usage compare with basis treatment. Thus Vasonat in dosage 500 mg per day may be recommend to inclusion on complex treatment of patients with chronic toxic hepatitis.

[Efficacy and safety of mildronate in emergency medical care].

Detailed clinical data about patients who used emergency services during 2011 are presented. The main attention is focused on the state of patients with acute and chronic brain ischemia before and after treatment with mildronate. Mean age of patients with ischemic stroke and chronic brain ischemia was 63.4 and 57.7 years, respectively. Mildronate was injected slowly intravenously in one dose 1000 mg (10 ml of 10% solution). The results obtained in the study allow to recommend mildronate for such patients and provide the useful information to physicians and medical attendants about current methods of diagnosis and treatment of patients with acute and chronic brain ischemia in out- and inpatient health services.