Oral TNFα Modulation Alters Neutrophil Infiltration, Improves Cognition and Diminishes Tau and Amyloid Pathology in the 3xTgAD Mouse Model.

Cytokines such as TNFα can polarize microglia/macrophages into different neuroinflammatory types. Skewing of the phenotype towards a cytotoxic state is thought to impair phagocytosis and has been described in Alzheimer's Disease (AD). Neuroinflammation can be perpetuated by a cycle of increasing cytokine production and maintenance of a polarized activation state that contributes to AD progression. In this study, 3xTgAD mice, age 6 months, were treated orally with 3 doses of the TNFα modulating compound isoindolin-1,3 dithione (IDT) for 10 months. We demonstrate that IDT is a TNFα modulating compound both in vitro and in vivo. Following long-term IDT administration, mice were assessed for learning & memory and tissue and serum were collected for analysis. Results demonstrate that IDT is safe for long-term treatment and significantly improves learning and memory in the 3xTgAD mouse model. IDT significantly reduced paired helical filament tau and fibrillar amyloid accumulation. Flow cytometry of brain cell populations revealed that IDT increased the infiltrating neutrophil population while reducing TNFα expression in this population. IDT is a safe and effective TNFα and innate immune system modulator. Thus small molecule, orally bioavailable modulators are promising therapeutics for Alzheimer's disease.

Synthesis, anti-inflammatory and analgesic evaluation of thioxoquinazolinone derivatives.

A series of 3-substituted-2-thioxoquinazolin-4(3H)-one derivatives have been synthesized and their structures have been elucidated on the basis of IR, (1)H-NMR, elemental analysis and mass spectroscopic studies. Anti-inflammatory and analgesic activity of the synthesized compounds was evaluated by Carrageenan induced rat paw edema method and Eddy's hot plate method respectively. Among the synthesized compounds N-(4-hydroxyphenyl)-N-(4-oxo-3-phenyl-2-thioxo-3,4-dihydroquinazolin-1(2H)methyl)acetamide (PTQ01) showed excellent anti-inflammatory activity. N-(4-ethoxyphenyl)-N-(3-(naphthalen-2yl)-4-oxo-2-thioxo-3,4-dihydroquinazolin-1(2H)-yl)methyl)acetamide (NTQ02), N-(4-Hydroxyphenyl)-N-((3-naphthalen-2-yl)-4-oxo-2-thioxo-3,4-dihydorquinazolin-1(2H)-ylmethyl)acetamide (NTQ01), N-((3-(4-ethoxyphenyl)-4-oxo-2-thioxo-3,4-dihydoquinazolin-1(2H)-yl)methyl)-N-(4-hydroxyphenyl)acetamide (ETQ01) N-(3-(4-ethoxyphenyl)-4-oxo-2thioxo-3,4-dihydroquinazolin-1(2H)-ylmethyl)-N-(4-hydroxyphenyl)acetamide (ETQ04), N-(4-ethoxyphenyl)-N-((4-oxo-3-phenyl-2-thioxo-3,4-dihydoquinazolin-1(2H)-yl)methyl)acetamide (PTQ02) and N-(4-ethoxyphenyl)-N-(3-(4-ethoxyphenyl)-4-oxo-2-thioxo-3,4-dihydoquinazolin-1(2H)-yl)methyl)acetamide (ETQ02) at a dose of 20 mg/kg exhibited significant anti-inflammatory activity compared to that of standard drug diclofenac sodium. The compound 2-(2,3-dimethylphenyl)(3-(4-ethoxyphenyl)-4-oxo-2-thioxo-3,4-dihydroquinazolin-1-2H)-1ylmethylamino)benzoic acid PTQ03 and sodium 2-(2-((2,6-dichlrophenyl)(3-(4-oxo-2-thioxo-3,4-dihydroquinazolin-1(2H)-yl)methyl)amino)phenylacetate (PTQ04) showed moderate anti-inflammatory activity. The compounds PTQ01, PTQ02, PTQ04, ETQ01 and ETQ02 showed significant analgesic activity compared with that of standard drug pentazocin.

Cross-reactions between xanthates and rubber additives.

BACKGROUND: We previously described allergic contact dermatitis from xanthates used in the recovery of metals from mining ores. We observed cross-reactions with carbamates, believed to be due to the common "dithio" nucleus shared by both groups. OBJECTIVE: The present study was undertaken to establish the rate of cross-reactions between xanthates and rubber additives. METHODS: Between November 2002 and December 2005, 1,220 consecutive patients were patch-tested with sodium isopropyl xanthate 10% in petrolatum (pet) and with potassium amyl xanthate 10% pet and later 5% pet, in addition to the North American Contact Dermatitis Group standard series and other series as required by their conditions. RESULTS: Fifty-one patients reacted to xanthates, carbamates, or thiurams; 26 reacted to xanthates only, and these reactions were felt to be irritant. Twenty-five patients reacted to xanthates and/or to one or more of the rubber additives, 12 had positive reactions to xanthates and to either carba mix or thiuram mix, 10 reacted to xanthates and carba mix, 9 reacted to xanthates and thiuram mix, and 8 showed positive reactions to xanthates and both mixes. However, 13 patients had positive reactions to carba mix and thiuram mix but did not react to xanthates. Six patients reacted to other rubber additives such as mercaptobenzothiazole, black rubber mix, and mixed dialkyl thioureas. Five of these patients also reacted to xanthates, 4 reacted to xanthates and carba mix, and 3 reacted to xanthates, carba mix, and thiuram mix. CONCLUSIONS: Of patients sensitized to carbamates, thiurams, or mercaptobenzothiazole, 50% exhibit cross-reactions with xanthates. Xanthates are irritants, and their patch-test concentrations should be lowered to 5% or less.

Antioxidants and phase 2 enzymes in cardiomyocytes: Chemical inducibility and chemoprotection against oxidant and simulated ischemia-reperfusion injury.

The increasing recognition of the role for oxidative stress in cardiac disorders has led to extensive investigation on the protection by exogenous antioxidants against oxidative cardiac injury. On the other hand, another strategy for protecting against oxidative cardiac injury may be through upregulation of the endogenous antioxidants and phase 2 enzymes in the myocardium by chemical inducers. However, our current understanding of the chemical inducibility of cardiac cellular antioxidants and phase 2 enzymes is very limited. In this study, using rat cardiac H9c2 cells we have characterized the concentration- and time-dependent induction of cellular antioxidants and phase 2 enzymes by 3H-1,2-dithiole-3-thione (D3T), and the resultant chemoprotective effects on oxidative cardiac cell injury. Incubation of H9c2 cells with D3T resulted in a marked concentration- and time-dependent induction of a number of cellular antioxidants and phase 2 enzymes, including catalase, reduced glutathione (GSH), GSH peroxidase, glutathione reductase (GR), GSH S-transferase (GST), and NAD(P)H:quinone oxidoreductase-1 (NQO1). D3T treatment of H9c2 cells also caused an increase in mRNA expression of catalase, gamma-glutamylcysteine ligase catalytic subunit, GR, GSTA1, M1 and P1, and NQO1. Moreover, both mRNA and protein expression of Nrf2 were induced in D3T-treated cells. D3T pretreatment led to a marked protection against H9c2 cell injury elicited by various oxidants and simulated ischemia-reperfusion. D3T pretreatment also resulted in decreased intracellular accumulation of reactive oxygen in H9c2 cells after exposure to the oxidants as well as simulated ischemia-reperfusion. This study demonstrates that a series of endogenous antioxidants and phase 2 enzymes in H9c2 cells can be induced by D3T in a concentration- and time-dependent fashion, and that the D3T-upregulated cellular defenses are accompanied by a markedly increased resistance to oxidative cardiac cell injury.

Synthesis and anti-inflammatory activity of 1-acylthiosemicarbazides, 1,3,4-oxadiazoles, 1,3,4-thiadiazoles and 1,2,4-triazole-3-thiones.

Sixteen 1-(2-naphthyloxyacetyl)-4-substituted-3-thiosemicarbazide, 2-(2-naphthyloxymethyl)-5-substitutedamino-1,3,4-oxadiazole, 2-(2-naphthyloxymethyl)-5-substitutedamino-1,3,4-thiadiazole and 5-(2-naphthyloxymethyl)-4-substituted-1,2,4-triazole-3thione derivatives have been prepared and evaluated as orally active anti-inflammatory agents with reduced side-effects. The structures of the compounds were confirmed by IR and 1H NMR spectral data and microanalysis. The anti-inflammatory and ulcerogenic activities of the compounds were compared with naproxen, indomethacin and phenylbutazone. In carrageenan-induced foot pad edema assay, 2-(2-naphthyloxymethyl)-5-methylamino-1,3,4-oxadiazole, 5-(2-naphthyloxymethyl)-4-methyl-1,2,4-triazole-3-thione and 5-(2-naphthyloxymethyl)-4-ethyl-1,2,4-triazole-3-thione showed an interesting anti-inflammatory activity. In the air-pouch test, 1,3,4-oxadiazole and 1,2,4-triazole-3-thione derivatives reduced total number of leukocytes of the exudate that indicates excellent inhibition of prostaglandin production. Side effects of the compounds were examined on gastric mucosa, liver and stomach and none of the compounds showed significant side effects compared with reference nonsteroidal anti-inflammatory drugs (NSAIDs).

Dopamine-beta-hydroxylase inhibition: a novel sympatho-modulatory approach for the treatment of congestive heart failure.

Pre-clinical and clinical studies suggest that chronic sympathetic activation in congestive heart failure (CHF) is a maladaptive response which accelerates the progressive worsening of the disease. Consequently, therapeutic interventions which inhibit sympathetic nerve function are likely to favorably alter the natural course of the disease. Indeed, recent clinical studies have shown that treatment with carvedilol, a beta-blocker, reduces mortality and the risk of death and hospitalization. The therapeutic value of beta-blockers, however, may be limited by their propensity to cause acute hemodynamic deterioration which results from abrupt withdrawal of sympathetic support. Thus, although the introduction of beta-blockers represents an important advance in the treatment of CHF, a better tolerated means of modulating the sympathetic nervous system would be highly desirable. An alternative strategy for directly modulating sympathetic nerve function is to inhibit the biosynthesis of norepinephrine (NE) via inhibition of dopamine-beta-hydroxylase (DBH), the enzyme which catalyzes the conversion of dopamine (DA) to NE in sympathetic nerves. This approach may have the following three merits over beta-blockade. First, this class of drugs would be expected to produce gradual modulation, as opposed to abrupt blockade, of sympathetic nerve function and, consequently, would not be associated with acute hemodynamic worsening thereby obviating the need for dose-titration. Second, from a theoretical standpoint, DBH inhibitors, at low doses, would preferentially inhibit NE release in the heart since the storage pool of NE in this organ is selectively depleted in CHF. Lastly, inhibition of DBH would augment the levels of DA which, via agonism of dopamine receptors, could have beneficial effects on renal function. Nepicastat is a novel, selective and potent (IC50 = 9 nM) inhibitor of DBH. Preclinical studies have shown that nepicastal produces gradual modulation of catecholamine levels (reduction in NE and elevation of DA and DA/NE ratio) in cardiovascular tissues and plasma, attenuates sympathetically-mediated cardiovascular responses and also has salutary effects on renal function. In a canine heart failure model, normalization of transmyocardial norepinephrine balance with nepicastat retards the process of ventricular dilation and prevents progressive worsening of cardiac function. Early short-term clinical studies in CHF patients have shown that nepicastat is well tolerated and produces significant and dose-dependent increases in plasma DA/NE concentrations.

Surgical anesthesia in turkeys with thialbarbital sodium.

Thialbarbital sodium was found to be a reliable and economical general anesthetic for domesticated turkeys. Despite shortness of action of the initial dose, surgical anesthesia was maintained longer than 2 hours by intermittent infusion via a brachial vein cannula. The drug was reconstituted just before use (66 mg/ml) with sterile 1% saline solution. Rapid smooth induction was produced with an initial dosage of 30 mg/kg for hens and 26.5 mg/kg for toms, when administered within a 30- to 60-second interval. Supplemental infusion of the drug in increments of 0.25 to 1.5 ml was used to sustain the desired level of deep narcosis. The occurrence of respiratory failure was considerably less for thialbarbital than with pentobarbital sodium. Recovery was rapid and smooth.