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.

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.

Search for stroke-protecting agents in endothelin-1-induced ischemic stroke model in rats.

BACKGROUND AND OBJECTIVE: Ischemic stroke may initiate a reperfusion injury leading to brain damage cascades where inflammatory mechanisms play a major role. Therefore, the necessity for the novel stroke-protecting agents whose the mechanism of action is focused on their anti-inflammatory potency is still on the agenda for drug designers. Our previous studies demonstrated that cerebrocrast (a 1,4-dihydropyridine derivative) and mildronate (a representative of the aza-butyrobetaine class) possessed considerable anti-inflammatory and neuroprotective properties in different in vitro and in vivo model systems. The present study investigated their stroke-protecting ability in an endothelin-1 (ET-1)-induced ischemic stroke model in rats. MATERIAL AND METHODS: Male Wistar rats were pretreated (for 7 days, per os) with cerebrocrast (0.1 mg/kg), mildronate (100 mg/kg), or their combination, followed by the intracerebral injection of ET-1. Functional and behavioral tests were carried out up to 14 days after the ET-1 injection. Ex vivo, the number of degenerated neurons and the infarction size in the cerebral cortical tissue were assessed histologically. RESULTS: Cerebrocrast and mildronate effectively normalized ET-1-induced disturbances in neurological status, improved the muscle tone, and decreased the number of degenerated cortical cells. Both drugs also reduced the infarction size, and cerebrocrast showed at least a 2-fold higher activity than mildronate. The combination of both drugs did not cause a more pronounced effect in comparison with the action of drugs administered separately. CONCLUSIONS: The 1,4-dihydropyridine and aza-butyrobetaine structures may serve for the design of novel stroke-protecting agents to prevent severe neurological poststroke consequences.

Mildronate treatment improves functional recovery following middle cerebral artery occlusion in rats.

Mildronate (3-(2,2,2-trimethylhydrazinium) propionate) is an inhibitor of l-carnitine biosynthesis and an anti-ischemic drug. In the present study, we investigated the effects of mildronate in rats following focal cerebral ischemia. Male Wistar rats were subjected to transient occlusion of the middle cerebral artery (MCAO) for 90min, followed by the intraperitoneal administration of mildronate at doses of 100 and 200mg/kg 2h after reperfusion and then daily for an additional 14days. The beam-walking, rota-rod and cylinder tests were used to assess sensorimotor function, and vibrissae-evoked forelimb-placing and limb-placing tests examined responses to tactile and proprioceptive stimulation. Following behavioural testing, the infarct volume was measured. The cerebellar concentrations of l-carnitine, γ-butyrobetaine (GBB) and mildronate were also measured. The results showed that saline-treated MCAO rats had minor or no spontaneous recovery in sensorimotor and proprioceptive function up to 14days post-stroke. Treatment with mildronate at a dose of 200mg/kg was found to accelerate recovery of motor and proprioceptive deficits in limb-placing, cylinder and beam-walking tests. Analysis of rat cerebellar tissue extracts revealed that l-carnitine and GBB concentrations changed with mildronate treatment; the concentration of l-carnitine was significantly decreased by mildronate treatment, whereas the concentration of GBB was significantly increased. Cerebellar concentrations of mildronate also increased in a dose-dependent manner following systemic administration. Infarct size did not differ among the experimental groups on post-stroke day 14. The present study suggests that mildronate treatment improves the functional outcome in MCAO rats without influencing infarct size.

[Effects of metabolic triad (25% polarizing solution, mildronat, preductal MR) in acute myocardial infarction].

The aim of the work was to study the effect of metabolic triad with different mechanisms of acting--high-dose Glucose-Insulin-Potassium--25% polarizing solution (25% glucose, 50 IU soluble insulin and 4% 144 ml KCL-GIK), mildronat, preductal MR on the functional condition of heart during the acute myocardial infarction. 20 patients from the main group and 20 from the control one have been under the study. Patients with diabetes and heavy forms of heart failure (killip class>2) were not included in the study. Evaluation of the functional condition of heart was based on ECG and echocardiography data received before and after the treatment. It was determined that the frequency of the rhythm disorder decreases in the conditions of metabolic triad as well as during the thrombolitic reperfusion. Average period of time for normalization of S-T segment elevation made up 5.4+/-1.8 days and 7.3+/-1.2 days in case of the control group. The received data make it relevant to include the complex metabolic triad for preventive purpose during the complications followed after the acute myocardial infarction.

Endothelium- and nitric oxide-dependent vasorelaxing activities of gamma-butyrobetaine esters: possible link to the antiischemic activities of mildronate.

Mildronate [3-(2,2,2-trimethylhydrazine) propionate (THP)] is an antiischemic drug acting mainly via inhibition of fatty acid beta-oxidation. Some effects of the drug cannot be explained by the latter mechanism. We tested the eventual nitric oxide (NO) dependence of the mildronate action. Mildronate, gamma-butyrobetaine (GBB) and GBB methyl ester induced transient increases in nitric oxide (NO) concentrations in rat blood and myocardium. In vitro, these compounds neither modified the activities of purified neuronal and endothelial recombinant nitric oxide synthases (NOSs) nor were able to interact with their active site. GBB induced vasodilatation at high concentrations only (EC50 = 5 x 10(-5) M) while mildronate alone displayed no vasodilating effect although it enhanced the GBB vasodilating activity. GBB methyl and ethyl esters were found more potent vasodilators (EC50 = 2.5 x 10(-6) M). Pretreatment of aortic rings with NOS inhibitor Nomega-nitro-L-arginine methyl ester (L-NAME) abolished vasodilating effects of the compounds. A hypothesis explaining NO and endothelium-dependent effects of mildronate and its analogues is proposed.

Cardioprotective effects of MET-88, a gamma-butyrobetaine hydroxylase inhibitor, on cardiac dysfunction induced by ischemia/reperfusion in isolated rat hearts.

Inhibition of fatty acid metabolite accumulation may be beneficial for treatment of cardiac dysfunction induced by ischemia. MET-88, 3-(2,2,2-trimethylhydrazinium)propionate dihydrate, inhibits gamma-butyrobetaine hydroxylase which catalyzes conversion of gamma-butyrobetaine to carnitine. In this study, we investigated whether MET-88 has cardioprotective effects against cardiac dysfunction induced by ischemia/reperfusion. Rats were divided into four groups: (1) control; (2) MET-88 at 50 mg/kg; (3) MET-88 at 100 mg/kg; (4) nifedipine at 30 mg/kg. MET-88 was administered orally once a day for 10 days, and nifedipine was administered orally 30 min before the experiments. Cardiac functions (heart rate, left ventricular systolic pressure and coronary flow) were measured in rat working heart preparations for 30 min under ischemia followed by 20 min under reperfusion. Myocardial carnitine levels were measured at the end of the experiments. Before ischemia, MET-88 did not affect cardiac functions, but nifedipine significantly increased only coronary flow. Under the ischemic condition, cardiac functions were markedly decreased in all groups. During reperfusion, MET-88 and nifedipine promoted recovery of cardiac functions and decreased the incidence of ventricular fibrillation. MET-88 also prevented the accumulation of long-chain acylcarnitine induced by ischemia. These results indicated that MET-88 protected against cardiac dysfunction in ischemia/reperfusion, and preventing the accumulation of long-chain acylcarnitine may be responsible for the cardioprotective effects.

[Approaches to decreasing polypragmasy in intensive care of patients with severe injuries]. / Puti umen'sheniia polipragmazii pri intensivnoi terapii u postradavshikh s tiazheloi travmoi.

A total of 277 patients with grave combined injuries were treated. Polypragmasy involved all the trends of intensive care and was most often observed in infusion-transfusion and drug therapy. Three main approaches to decreasing polypragmasy in intensive care of victims with grave combined injuries consist in decreasing the volume of infusion-transfusion therapy, use of a limited number of antihypoxants, and early short courses of antibiotics.

[Use of antihypoxants in the acute period of myocardial infarction]. / Primenenie antigipoksantov v ostrom periode infarkta miokarda.

A total of 620 patients with acute myocardial infarction were followed up in order to assess the efficacy of antihypoxants as a component of intensive care. 385 of these patients, divided into groups of 20-40 subjects, were administered one of 12 antihypoxants or sessions of hyperbaric oxygenation during the acute period of the disease, the rest were treated traditionally. Analysis of clinical, laboratory, and prognostic values showed the highest protective effect of amtizol, lithium hydroxybutyrate, piracetam, and ubiquinone. Cytochrome C, riboxine, mildronate, and olifen were somewhat less active, and solcoseryl, bemitil, trimethasidine, and aspisol were the least effective. The protective potentialities of standard sessions of hyperbaric oxygenation were virtually null. The author proposes a parameter D, reflecting the difference between actual and predicted mortality, and the rating (score) system for assessing the routine laboratory diagnostic tests to be used together with the known criteria for evaluation of the protective effects of antihypoxants in patients with acute myocardial infarction.

[The effect of mildronate on erythrocyte membrane permeability in experimental lung pathology]. / Vliianie mildronata na pronitsaemost' éritrotsitarnykh membran pri éksperimental'noi patologii legkikh.

With the use of the erythrocyte osmotic and acidic resistance methods, the experiments on intact albino rats by applying a model of chronic non-specific lung diseases and those in vitro have shown that mildronate has a membrane-stabilizing action only when given in high doses (500 mg/kg) and concentrations (10(-3)-10(-4) M). When used in low doses (5, 25, 50, and 200 mg/kg) and concentrations (10(-5)-10(-7) M), in produces no positive effect.

[Experimental and clinical studies of coronary circulation after administration of mildronate]. / Eksperimental'noe i klinicheskoe issledovanie koronarnogo krovoobrashcheniia pri primenenii mildronata.

In experiments on dogs, application of the cross-over circulation method revealed that mildronate increased coronary blood flow due to active coronary dilation. In experiments on cats, a cardioprotective effect of mildronate was found, which prevented the development of acute ischemic heart failure by stabilizing the major hemodynamic parameters. Clinical studies of patients with Functional Classes I-III angina provided evidence for positive effects of mildronate on coronary blood flow.

[The cardioprotective action of carnitine and its structural analog 3-(2,2,2-trimethylhydrazine)propionate on cardiac energy metabolism in experimental occlusion of the coronary artery in rats]. / Kardioprotektornoe deistvie karnitina i ego strukturnogo analoga 3-(2,2,2-trimetilgidrazinii)propionata na énergeticheskii obmen serdtsa pri éksperimental'noi okkliuzii koronarnoi arterii u krys.

The effects of carnitine and its structural analogue 3-(2,2,2-trimethylhydrazine) propionate (THP) were studied in rats with experimental myocardial infarction caused by occlusion of the left descending branch of the coronary artery. After one day in the group of untreated animals the relative lethality was 40.3 +/- 10.5%, the size of the infarction zone was 29.8 +/- 2.0%. Carnitine and THP decreased on the average twice the parameters as well as lactate level in the myocardium. THP prevented a reduction of ATP and AMP levels by 35 and 37%, respectively, and a decrease of adenine nucleotide pool by 30%. In this case carnitine was ineffective. It is suggested that inhibition of beta-oxidation of fatty acids by THP is energetically more beneficial for the myocardium during regional ischemia than substitution therapy with carnitine.

[The use of lysosomotropic preparations in treating severe experimental chemical eye burns]. / Primenenie lizosomotropnykh preparatov v lechenii tiazhelykh khimicheskikh ozhogov v éksperimente.

The action of membranotropic preparations--mildronat and phosphaden on the course of a severe burn process of the cornea with changes in lysosomal membranes revealed in pathogenesis has been studied in 80 rabbits. As a marking lysosomal enzyme, acid phosphatase was used. Besides this, peculiarities of the clinical course of the burn process have been studied, when treated by common methods and in a complex with the mentioned preparations. The results of the study have shown expressed stabilizing action of the preparations on lysosomal membranes of the cornea in early terms of the treatment, correlative relationship between results of biochemical investigations and clinical manifestations of the action of membranotropic preparations, high effectiveness of therapeutic action of mildronat as compared with phosphaden. The results obtained can serve as a foundation for the usage of the preparations in complex treatment of patients with severe chemical burns of the eye.

[Interferon-inducing and anti-influenzal properties of 3-(2,2,2-trimethylhydrazine)propionate in an experiment]. / Interferonindutsiruiushchie i protivogrippoznye svoistva 3-(2,2,2-trimetilgidrazinii)propionata v éksperimente.

An original compound, 3-(2,2,2-trimethylhydrazine)propionate, belonging to the class of hydrazine betaines, is an active interferon inducer in mice and shows a protective effect against influenza virus when used according to therapeutic and preventive schedules. The survival of the animals depends on the dose, time, and route of administration of the compound.

[Biochemical characteristics of the anti-ischemic action of the new structural analog of gamma-butyrobetaine 3-(2,2,2,-trimethylhydrazine)propionate]. / Biokhimicheskaia kharakteristika antiishemicheskogo deistviia novogo strukturnogo analoga gamma-butirobetaina 3-(2,2,2-trimetilgidrazinii)propionata.

A structural analogue of gamma-butyrobetaine 3-(2,2,2-trimethylhydrazine)propionate (THP) administered orally in doses of 50 and 150 mg/kg for 10 days prevented isoproterenol-induced increase of the activity of the hepatic isoform of lactate dehydrogenase in the rat blood serum and in a dose of 150 mg/kg prevented an increase of creatine phosphokinase activity. Against a background of the course administration of THP isoproterenol failed to cause the accumulation of acyl-insoluble acylcarnitine in the myocardium. In this case a dose-dependent decrease of free carnitine concentration and accumulation of fatty acids in the myocardium were noted. The cardioprotective effect of THP manifested itself in prevention of a decrease of ATP and ADP concentrations, accumulation of AMP and a reduction of energy charge under the influence of isoproterenol. The ability of THP to decrease the intracellular concentration of free carnitine and to depress as a result carnitine-dependent oxidation of free fatty acids may underlie the anti-ischemic effect of THP.