Deep brain stimulation as a possible treatment of hyperthermia in patients with serotonin syndrome.

Maintaining a body temperature within a narrow range is vital for the survival of all mammals, including humans. With the help of optogenetics, a better understanding of the thermoregulatory organs and pathways is achieved. Optogenetic activation of the GABAergic neurons in the ventral part of the lateral preoptic nucleus (VLPO) leads to decrease in the body temperature. On the other hand, number of drugs could alter the thermoregulatory balance, leading to a hyperthermic state, such as serotonin syndrome (SS). SS is a potentially life-threatening clinical condition that occurs as a result of a drug-induced increase in the intrasynaptic serotonin (5-hydroxytryptamine, 5-HT) levels due to overdose of a single drug or due to interaction between two or more drugs with serotonergic mechanism of action. In this hypothesis, we propose a novel method for the treatment of hyperthermia, a core clinical sign of serotonin syndrome, through deep brain stimulation (DBS). An electrode is stereotactically placed in the VLPO, which may lead to reduction of the core body temperature. If proven effective, this technique should be left as a salvage method for reduction of hyperthermia, where the drug treatment is insufficient or ineffective. This technique could be used for the treatment of other syndromes, where hyperthermia takes a central place, including malignant hyperthermia, neuroleptic malignant syndrome, etc. DBS, on the other hand, could be used alone to induce hyperthermia in patients with malignant diseases. Hyperthermia improves the immune response, improves the drug penetration and stop the repair of already damaged tumor cells after chemotherapy or radiotherapy.

Efficacy, safety and tolerability of vidofludimus in patients with inflammatory bowel disease: the ENTRANCE study.

BACKGROUND: Vidofludimus (SC12267) is a novel oral immunomodulator inhibiting dihydroorotate dehydrogenase (DHODH) and the expression of proinflammatory cytokines including interleukin-17 (IL17A and IL17F) and interferon-gamma. The objective of the study was to explore the efficacy, safety and tolerability of vidofludimus in steroid-dependent inflammatory bowel disease (IBD). METHODS: The open label uncontrolled ENTRANCE study (ClinicalTrials.gov NCT00820365) has been conducted at 13 study centers in Germany, Bulgaria and Romania. Thirty-four steroid-dependent patients with a confirmed diagnosis of Crohn's disease (CD) or ulcerative colitis (UC) were treated with a once daily 35mg oral dose of vidofludimus over 12weeks. Steroids were tapered during the first 8weeks followed by a steroid-free treatment period of 4weeks. Complete response was defined as steroid-free clinical remission at week 12; partial response was defined as being in remission at steroid dose equal or lower than the individual patient's threshold dose for relapse. RESULTS: Of the thirty-four patients enrolled in this trial 26 were evaluable for primary efficacy assessment. After completion of the 12weeks treatment phase 8 out of 14 (57.1%) patients with CD and 6 out of 12 (50.0%) patients with UC were in steroid-free remission (complete responders). Another 4 (28.6%) patients in CD and 5 (41.7%) patients in UC were partial responders. Vidofludimus was well tolerated, no drug-related serious adverse events were observed. CONCLUSIONS: This trial provides first evidence of clinical efficacy of vidofludimus in IBD. Although the safety and tolerability profile seems favorable, long-term controlled studies are needed to further investigate its potential as novel IBD therapy.

Localized eczema herpeticum with unilateral ocular involvement.

We report a case of eczema herpeticum with unilateral ocular involvement in a 16-year-old boy. The patient has had a mild form of atopic dermatitis (AD) since early childhood. Why AD patients are prone to herpes simplex virus (HSV) infections is still unclear. Ocular pathologic findings in these cases are rarely reported.

Influence of GABA-acting drugs on morphine-induced hyperthermia in rats.

A major inhibitory neurotransmitter of the nervous system, GABA (gamma-aminobutyric acid), is involved in mammalian thermoregulation. The present study investigated the influence of GABAergic neurotransmission-enhancing drugs, in a model of morphine-induced hyperthermia in conscious rats. We used body temperature assays to examine the effects of GABA-acting drugs on morphine-induced hyperthermia. In rats, low doses of morphine injected i.p. produced significant hyperthermia in a body temperature assay that was significantly attenuated upon pretreatment with GABA-acting drugs. These results suggest the existence of opioidergic-GABAergic interactions in a complex process of thermoregulation.

Dose-dependent effects of caffeine on behavior and thermoregulation in a chronic unpredictable stress model of depression in rats.

The effects of the non-selective adenosine A(1)/A(2) receptor antagonist caffeine on behavior and thermoregulation in chronic unpredictable stress (CUS) model of depression was studied in Wistar rats. In the open field (OF) test, caffeine dose-dependently increased motor activity while decreased grooming and time spent in the corner. Five-week exposure to CUS procedure had the opposite effect in rats. Caffeine reversed CUS-induced effects on the above mentioned parameters. Caffeine (40 mg/kg) increased the motor activity in plus maze (PM) test while at doses of 20 and 40 mg/kg it decreased the number of entries in the open arms. Whereas CUS did not change the level of anxiety, caffeine (2, 20 and 40 mg/kg) administered after CUS diminished it by increasing the time in open arms. Caffeine dose-dependently decreased the immobility time while CUS had the opposite increasing effect in forced swimming test (FST). Caffeine at doses of 20 and 40 mg/kg reversed the effect of CUS on immobility in FST. Caffeine produced dose-dependent rice of body temperature in both non-treated and CUS-treated rats. The hyperthermic effect in normal rats pretreated with caffeine lasted about 90 min while in caffeine-pretreated rats exposed to CUS it lasted about 150 min. High dose of caffeine (100mg/kg) induced significant hypothermia between 90th and 150th minute in control rats and hyperthermia between 30th and 60th minute in CUS-treated rats. These results suggest a putative role of this methylxanthine in the adaptive responses to chronic unpredictable stress stimuli.

Enhanced sensitivity of insulin-resistant adipocytes to vanadate is associated with oxidative stress and decreased reduction of vanadate (+5) to vanadyl (+4).

Vanadate (sodium orthovanadate), an inhibitor of phosphotyrosine phosphatases (PTPs), mimics many of the metabolic actions of insulin in vitro and in vivo. The potential of vanadate to stimulate glucose transport independent of the early steps in insulin signaling prompted us to test its effectiveness in an in vitro model of insulin resistance. In primary rat adipocytes cultured for 18 h in the presence of high glucose (15 mm) and insulin (10(-7) m), sensitivity to insulin-stimulated glucose transport was decreased. In contrast, there was a paradoxical enhanced sensitivity to vanadate of the insulin-resistant cells (EC(50) for control, 325 +/- 7.5 microm; EC(50) for insulin-resistant, 171 +/- 32 microm; p < 0.002). Enhanced sensitivity was also present for vanadate stimulation of insulin receptor kinase activity and autophosphorylation and Akt/protein kinase B Ser-473 phosphorylation consistent with more effective PTP inhibition in the resistant cells. Investigation of this phenomenon revealed that 1) depletion of GSH with buthionine sulfoximine reproduced the enhanced sensitivity to vanadate while preincubation of resistant cells with N-acetylcysteine (NAC) prevented it, 2) intracellular GSH was decreased in resistant cells and normalized by NAC, 3) exposure to high glucose and insulin induced an increase in reactive oxygen species, which was prevented by NAC, 4) EPR (electron paramagnetic resonance) spectroscopy showed a decreased amount of vanadyl (+4) in resistant and buthionine sulfoximine-treated cells, which correlated with decreased GSH and increased vanadate sensitivity, while total vanadium uptake was not altered, and 5) inhibition of recombinant PTP1B in vitro was more sensitive to vanadate (+5) than vanadyl (+4). In conclusion, the paradoxical increased sensitivity to vanadate in hyperglycemia-induced insulin resistant adipocytes is due to oxidative stress and decreased reduction of vanadate (+5) to vanadyl (+4). Thus, sensitivity of PTP inhibition and glucose transport to vanadate is regulated by cellular redox state.

[Adult respiratory distress syndrome--etiology and pathogenesis]. / Respiratoren distres-sindrom pri vuzrastni--etiologiia i patogeneza.

Adult respiratory distress syndrome (ARDS) is not a specific lung disease. It represents an acute respiratory insufficiency syndrome in patients with non-injured lung as a result of severe multiple lung lesions of different etiology and pathogenesis. ARDS is provoked by a great number of etiologic factors of two main groups: 1) etiologic factors directly injuring the alveolo-capillary wall and 2) etiologic factors indirectly injuring the alveolo-capillary wall. ARDS develops in three phases: phase of exudation, phase of injury of the alveolocapillary wall and phase of proliferation (chronic phase).

[Interleukins and endocrine function]. / Interlevkini i endokrinni funktsii.

Views and experimental data on the role of interleukins in the regulation of the endocrine functions of hypothalamus, pituitary gland, thyroid gland, suprarenal gland and pancreas are presented. The role of interleukin-1 and interleukin-6 in the regulation of normal and pathological processes is examined. Data on cellular and molecular operation mechanisms of some interleukins on functions of the endocrine glands are included in the survey. The clarification of these mechanisms leads to new pharmacotherapeutical approaches to endocrine diseases treatment.

[Macrolides: pharmacology and clinical use]. / Makrolidi: farmokologiia i klinichno prilozhenie.

Members of macrolides are Erythromycin, Oleandomycin, Spiramycin, Roxithromycin, Josamycin, Midecamycin, Clarithromycin, Azithromycin and Dirithromycin. This review present mechanism of action, pharmacokinetic, adverse drug reactions and main clinical uses of the macrolides.

Estrogen replacement therapy and Alzheimer's disease.

Estrogen replacement therapy (ERT) is increasingly recommended for postmenopausal women due to its numerous beneficial effects on bone, cardiovascular system, brain function and quality of life. Data from retrospective epidemiological studies have shown that ERT has a potential to reduce the risk for developing Alzheimer's disease (AD) and to delay its progression. In addition, recent clinical studies have reported improvement of cognitive functions in women with AD. Findings from basic science indicated that the possible mechanisms of action by which estrogen may affect AD include interaction with cholinergic neurotransmitter system, cholinergic neurotrophic and neuroprotective effect, improvement of learning and memory, improvement of cerebral blood flow and metabolism, antioxidant and antiinflammatory action, and interference with beta-amyloid protein metabolism and toxicity. Estrogen use in postmenopausal women may offer a new approach for improving cognitive functions in nondemented and demented women, delaying the onset and progression of AD and reducing its occurrence. However, prospective clinical trials are required to establish the efficacy of ERT for prevention and treatment of AD.

Antiamyloid strategies for the treatment of Alzheimer's disease.

Although the specific causes of Alzheimer's disease have not yet been determined, considerable circumstantial evidence implicates beta-amyloid, an insoluble polypeptide made up of 39 to 42 amino acids, in the continuing destruction of brain cells that results in the progressive deterioration of the patient's mental ability. The toxic actions of beta-amyloid appear to be due to free radicals generated by a portion of the beta-amyloid molecule. These free radicals damage various parts of the neuron and lead to increased intracellular calcium which is also toxic. beta-Amyloid is formed by the aberrant processing of a much larger precursor protein that is made when cells are damaged. The normal processing of this precursor protein not only prevents the formation of beta-amyloid, but produces a soluble protein that regulates the entry of calcium into neurons and has cytoprotective actions. Interventions to prevent the destruction of neurons and the disruption of brain function by beta-amyloid include the administration of antioxidants and free radical scavengers to reduce further neural damage from deposits of beta-amyloid, the activation of various growth factors to repair damaged cells and restore their functions, and the stimulation of the normal processing of the precursor protein not only to aid in neural repair but more importantly to prevent the formation of additional beta-amyloid.

Alzheimer's disease therapy - an update.

The 5th International Geneva/Springfield Symposium on Advances in Alzheimer Therapy focused on new therapeutic approaches for the treatment of Alzheimer 's disease (AD) based on the latest basic science data. The two major pharmacological principles of cholinergic therapy are 1) reduction of acetylcholine hydrolysis by means of acetylcholinesterase (AChE) inhibitors; and 2) direct stimulation of nicotinic or muscarinic receptors with selective agonists. Currently used AChE inhibitors are tacrine, donepezil hydrochloride, rivastigmine and metrifonate. In the area of muscarinic and nicotinic receptor modulation, studies were presented on AF-102B and AF-150(S), BIBN-99, CI-1017, RJR-2403, ABT-418, ABT-089, GTS-21 and SIB-1553A. Based on evidence of inflammatory mechanisms in the pathogenesis of AD, selective COX-2 inhibitors for the prevention and treatment of AD are a target of several pharmaceutical companies. Concerning known antiinflammatory drugs, results from controlled trials are expected soon. Estrogen replacement has been reported to produce cognitive and affective improvement in women with AD, and results from a number of studies were presented. Age-associated increases in oxidative stress may play a role in AD and thus antioxidants may also have a place in the therapy of this disease. The antioxidants vitamin E and selegiline are being investigated. Other drugs under investigation are propentofylline, Cerebrolysin, citicoline sodium, CDP-choline, memantine, Egb-761, calagualine and AIT-082. Iododoxorubicin may represent a new class of compounds able to interfere with the beta-amyloid cascade in AD and other brain amyloid diseases. Future preventive strategies in AD include genotype analysis and screening, presymptomatic diagnosis and avoidance of environmental risk factors.

Evaluation of an ion-selective electrolyte analyzer: Microlyte 6.

Microlyte 6 (Kone, Finland) is an ion-selective analyzer designed to measure simultaneously the concentration of six important electrolyte parameters--potassium, sodium, chloride, ionized calcium, ionized magnesium and pH in whole blood, serum and plasma. Two values are obtained in analyzing the ionized fractions of magnesium and calcium--one at the actual pH and another at a recalculated measurement for pH = 7.4. Direct determination of ionized calcium and ionized magnesium simultaneously with that of the other electrolytes is of great clinical significance. It is only recently that ion-selective analysis of ionized magnesium has been proposed. The analytical reliability of the results and the operational characteristics of the Microlyte 6 ion-selective analyzer were evaluated for approximately one year. The coefficient of variation of the results in the reference and pathological range was 0.49%-2.23%, and 0.68%-4.42% for the within-run and between-run series, respectively. The inaccuracy of the results expressed by d% was from -4.23% to +4.06%. The comparative evaluation of the results for potassium, sodium, chloride, and ionized calcium between Microlyte-6 and the clinical chemistry analyzer Dynamic (Kone) showed a high correlation (correlation coefficient in the range 0.9868-0.9970). The correlation between the results for the ionized fraction and those obtained for total magnesium was consistent with that generally given in the literature.

Central effects of endothelin-1 (ET-1) and endothelin-3 (ET-3) in mice.

The central effects of endothelin-1 (ET-1, 0.5, 1, 2.5 and 10 pmol/mouse) and endothelin-3 (ET-3, 2.5, 5, 10, 20 and 25 pmol/mouse) have been studied after intracerebroventricular (i.c.v.) administration in mice. The following methods were used: behavioral observations, rotarod, spontaneous and amphetamine-stimulated motor activity, and hexobarbital-induced narcosis. ET-1 and ET-3 evoked a dose-dependent behavioral syndrome with a short excitatory period in the higher doses lasting for 5-10 min, followed by a prolonged depressive phase (about 90 min). ET-1 and ET-3 produced central depressive effects demonstrated by depressive behavior signs, decrease of the spontaneous and amphetamine-stimulated motor activity, and prolongation of the hexobarbital-induced narcosis.

Involvement of Ca2+ and alpha 1-adrenoceptors in endothelin-1 effects on the tone and electrically evoked contractions of rabbit ear central artery.

Endothelin-1 (ET-1) is a neuropeptide strongly involved in the functions of the cardiovascular system. The aim of the present study was to reveal the role of alpha1-adrenoceptors and of Ca2+ in the effects of ET-1 on blood vessels. Preparations isolated from the proximal part of ear central arteries (REA) of male Chinchilla rabbits were used. A 30-40 mm long segment, cannulated at both ends, was fixed in an organ bath with Krebs-Henseleit solutions aerated with 95% O2 and 5% CO2. The preparations were perfused at a rate of 3.0 ml/min maintaining the arterial pressure in the range of 40-60 HPa and were allowed a 120-min adaptation at 37.5 degree C. Contractions were induced by low-frequency electrical stimulation (ES) and the effects of ET-1 (applied intralumenally or extralumenally) on the arterial tone and on the Es-evoked contractions were studied. Extralumenal ET-1 (1 x 10(-12)M-1 x 10(-9)M) did not change the tone and ES evoked contractions of REA. In concentrations of 1 x 10(-8)M-1 x 10(-7)M ET-1 slightly increased arterial tone and moderately potentiated ES contractions. ET-1, in concentrations higher than 1 x 10(-7)M, sharply, strongly and long-lastingly increased the smooth muscle tone and slightly enhanced the ES contractions. A 100 microM bolus injection with ET-1 (1 x 10(-9)M-1 x 10(-8)M) resulted in potentiation of the ES contractions and the arterial tone was not markedly affected. 100 microM of 1 x 10(-7)M ET-1 increased more than 2-fold the tone of the segments and moderately reduced the ES-evoked contractions. A 30-min perfusion with ET-1 (1 x 10(-12)M-1 x 10(-9)M) strongly increased the arterial tone and completely abolished the ES contractions. Perfusion with 1 x 10(-8)M ET-1 resulted in a 3-fold increase of the tone of the isolated segments. A 30-min perfusion with 1 x 10(-6)M prazosin (PRZ) did not affect the arterial tone and prevented the ES-evoked contractions. PRZ markedly reduced the contractile effects of 1 x 10(-12)M-1 x 10(-9)M ET-1 and the effect of 1 x 10(-8)M ET-1 on REA tone was even enhanced by PRZ. Under the same conditions 1 x 10(-6)M flunarizine (FLU) inhibited the ES-induced contractions of the isolated preparations and decreased their tone. FLU reduced the contractile effects of ET-1 (1 x 10(-12)M-1 x 10(-8)M). Applied extralumentally 1 x 10(-6)M FLU also decreased EG-1 effects on REA. The results obtained strongly support the assumption that alpha1-receptors and Ca2+ are involved in ET-1 contractile effects on blood vessels smooth muscles.

L-NAME augments the antinociceptive effects of intracerebroventricularly applied ET-1 and ET-3.

The interaction between endothelin-1 (ET-1) (5 pmol/mouse, i.c.v.) and endothelin-3 (ET-3) (5 pmol/mouse, i.c.v.) with NG-nitro-L-arginine methyl ester (L-NAME) (5 mg/kg i.p., 30 min pretreatment) was investigated in mice by the use of two experimental procedures: hot plate and tail flick tests in mice. L-NAME showed slight insignificant antinociceptive action, but augmented significantly the antinociceptive effects of i.c.v. administered ET-1 and ET-3 in both experimental tests.

Effects of endothelin-1 (ET-1) and endothelin-3 (ET-3) on convulsive seizures.

Endothelins (ET-1 and ET-3) are produced in the brain and may act as neuropeptides. The effects of two endothelins (ET-1 and ET-3) were investigated using pentylenetetrazole- (PTZ), strychnine- (STR), picrotoxin- (PIC) and bicuculline-induced (BIC) convulsions. ET-1 did not exert any anticonvulsive effect. ET-3, being more specific for the brain, showed anticonvulsive activity on PTZ and BIC seizures, but not on PIC and STR seizures. Different mechanisms underlie the action of the convulsants. PTZ, BIC and PIC realized their convulsive effects through the GABAergic inhibitory transmitter system; STR exerted an excitatory effect on the spinal cord by blocking the glycine transmitter system. The results suggest that the anticonvulsive effects of ET-3 might be due to an indirect influence on the GABAergic system in the brain.

Antinociceptive effect of centrally administered endothelin-1 and endothelin-3 in the mouse.

The antinociceptive effects of centrally administered (i.c.v.) endothelin-1 (ET-1) and endothelin-3 (ET-3) were studied in mice by the use of 3 experimental procedures: hot plate, tail flick and acetic acid writhing tests. ET-1 (0.625-5 pmol/mouse) and ET-3 (2.5-25 pmol/mouse) produced statistically significant increase of the hot plate and tail flick latencies with duration of about 120 min. ET-3 showed weaker antinociceptive effect. ET-1 inhibited acetic acid-induced writhings with ED50 = 1.9 (1.1-2.7) pmol/mouse. With ET-3 a maximum effect of 45.2% suppression of the writhing response was achieved at 5 pmol/mouse. The antinociception due to ET-1 and ET-3 was not antagonized by naloxone and is thus independent of endogenous opioid release.

Endothelin-1 exacerbates focal cerebral ischemia without exerting neurotoxic action in vitro.

In a model of focal cerebral ischemia in mice, intracisternal injection of 5 and 10 pmol/mouse endothelin-1 significantly increased the infarcted surface area by 15.5% and by 23.5%, respectively. Endothelin-1 (0.01, 1, and 100 nmol/l) added to the primary neuronal cultures of chick embryo cerebral hemispheres for 1 h and 24 h did not influence the viability of the neurons or the protein content of the cultures. When applied simultaneously with 1 mmol/l sodium cyanide for 30 min, endothelin-1 (0.01, 1, and 100 nM) did not modify the hypoxia-induced changes. The results show that exogenously applied endothelin-1 could exacerbate cerebral ischemia, probably due to its vasoconstrictive properties and not to a direct neurotoxic effect.