Effect of Chemical Denture Disinfectants and Tree Extracts on Biofilm-forming Staphylococcus aureus and Viridans Streptococcus Species Isolated from Complete Denture.

AIMS: The present study aims at recording the antibacterial efficacy of various disinfectants used at different time periods against Staphylococcus aureus and viridans streptococcal species of bacteria isolated from complete dentures. MATERIALS AND METHODS: Fifty complete denture patients were selected for the study and swabs were collected from their complete denture surfaces. The isolated bacteria were subjected to six experimental groups which includes four groups of chemical denture disinfectants and two tree extracts groups. Isolation of the bacteria S. aureus and viridians streptococcal species was done by means of selective media and confirmed by means of biochemical tests. The bacteria were subjected to biofilm assays. The biofilm-forming bacteria with optical density (O.D.) values of more than 1.5 were selected for the study. About 150 acrylic specimens were fabricated and were contaminated by the 2 isolated bacteria mentioned above. The contaminated samples were disinfected by immersion for 10, 20, and 30 minutes in six disinfectants, namely: (1) 1% sodium hypochlorite, (2) 2% chlorhexidine, (3) 2% glutaraldehyde, (4) 3.8% sodium perborate, (5) 2% aalam extract, and (6) 2% neem extract. RESULTS: ANOVA test was performed for both S. aureus and viridans streptococcal species with regard to various synthetic and tree extracts as well as time duration of disinfection. F values for disinfection vs S. aureus is 205.4 (p < 0.001) and the relevant Scheffe post hoc test values is in the following order: 3 < 1, 4 < 6, 2 < 5. F values for disinfection vs viridans streptococcal species is 364.7 (p < 0.001) and the relevant Scheffe post hoc test values is in the following order: 3 < 4 < 1, 6, 2 < 5. CONCLUSION: For biofilm-forming S. aureus, 2% glutaraldehyde showed best antibacterial efficacy which was followed by 1% sodium hypochlorite and 3.8% sodium perborate. When it comes to biofilm-forming viridans streptococcal species, 2% glutaraldehyde showed best antibacterial efficacy. Next to 2% glutaraldehyde, 3.8% sodium perborate exhibited good disinfection potential. CLINICAL SIGNIFICANCE: Complete denture patients have a plethora of microorganisms habitating their complete dentures. Some bacteria are capable of causing systemic illness such as aspiration pneumonia and endocarditis. Hence, constant removal and disinfection of biofilms from the denture surface is vital to the local and systemic wellness of the patient. The most common bacteria capable of causing pneumonia and endocarditis that are isolated from complete dentures include S. aureus and viridans streptococcal species. The present study evaluates antibacterial efficacy of different disinfection agents especially against these biofilm-forming bacteria for different time periods. How to cite this article: Andonissamy L, Karthigeyan S, Ali SA, et al. Effect of Chemical Denture Disinfectants and Tree Extracts on Biofilm-forming Staphylococcus aureus and Viridans Streptococcus Species Isolated from Complete Denture. J Contemp Dent Pract 2019;20(11):1307-1314.

The design and synthesis of novel spirocyclic heterocyclic sulfone ROMK inhibitors as diuretics.

A spirocyclic class of ROMK inhibitors was developed containing a structurally diverse heterocyclic sulfone moiety and spirocyclic core starting from lead 1. These compounds not only displayed exquisite ROMK potency but significantly improved selectivity over hERG. The lead compounds were found to have favorable pharmacokinetic properties and displayed robust diuretic, natriuretic and blood pressure lowering effects in spontaneously hypertensive rats.

The Renal Outer Medullary Potassium Channel Inhibitor, MK-7145, Lowers Blood Pressure, and Manifests Features of Bartter's Syndrome Type II Phenotype.

The renal outer medullary potassium (ROMK) channel, located at the apical surface of epithelial cells in the thick ascending loop of Henle and cortical collecting duct, contributes to salt reabsorption and potassium secretion, and represents a target for the development of new mechanism of action diuretics. This idea is supported by the phenotype of antenatal Bartter's syndrome type II associated with loss-of-function mutations in the human ROMK channel, as well as, by cardiovascular studies of heterozygous carriers of channel mutations associated with type II Bartter's syndrome. Although the pharmacology of ROMK channels is still being developed, channel inhibitors have been identified and shown to cause natriuresis and diuresis, in the absence of any significant kaliuresis, on acute oral dosing to rats or dogs. Improvements in potency and selectivity have led to the discovery of MK-7145 [5,5'-((1R,1'R)-piperazine-1,4-diylbis(1-hydroxyethane-2,1-diyl))bis(4-methylisobenzofuran-1(3H)-one)], a potential clinical development candidate. In spontaneously hypertensive rats, oral dosing of MK-7145 causes dose-dependent lowering of blood pressure that is maintained during the entire treatment period, and that displays additive/synergistic effects when administered in combination with hydrochlorothiazide or candesartan, respectively. Acute or chronic oral administration of MK-7145 to normotensive dogs led to dose-dependent diuresis and natriuresis, without any significant urinary potassium losses or changes in plasma electrolyte levels. Elevations in bicarbonate and aldosterone were found after 6 days of dosing. These data indicate that pharmacological inhibition of ROMK has potential as a new mechanism for the treatment of hypertension and/or congestive heart failure. In addition, Bartter's syndrome type II features are manifested on exposure to ROMK inhibitors.

Differentiation of ROMK potency from hERG potency in the phenacetyl piperazine series through heterocycle incorporation.

Following the discovery of small molecule acyl piperazine ROMK inhibitors and their initial preclinical validation as a novel diuretic agent, our group set out to discover new ROMK inhibitors with reduced risk for QT effects, suitable for further pharmacological experiments in additional species. Several strategies for decreasing hERG affinity while maintaining ROMK inhibition were investigated and are described herein. The most promising candidate, derived from the newly discovered 4-N-heteroaryl acetyl series, improved functional hERG/ROMK ratio by >10× over the previous lead. In vivo evaluation demonstrated comparable diuretic effects in rat with no detectable QT effects at the doses evaluated in an in vivo dog model.

Discovery of a potent and selective ROMK inhibitor with improved pharmacokinetic properties based on an octahydropyrazino[2,1-c][1,4]oxazine scaffold.

Following the discovery of small molecule acyl piperazine ROMK inhibitors, the acyl octahydropyrazino[2,1-c][1,4]oxazine series was identified. This series displays improved ROMK/hERG selectivity, and as a consequence, the resulting ROMK inhibitors do not evoke QTc prolongation in an in vivo cardiovascular dog model. Further efforts in this series led to the discovery of analogs with improved pharmacokinetic profiles. This new series also retained comparable ROMK potency compared to earlier leads.

Pharmacologic inhibition of the renal outer medullary potassium channel causes diuresis and natriuresis in the absence of kaliuresis.

The renal outer medullary potassium (ROMK) channel, which is located at the apical membrane of epithelial cells lining the thick ascending loop of Henle and cortical collecting duct, plays an important role in kidney physiology by regulating salt reabsorption. Loss-of-function mutations in the human ROMK channel are associated with antenatal type II Bartter's syndrome, an autosomal recessive life-threatening salt-wasting disorder with mild hypokalemia. Similar observations have been reported from studies with ROMK knockout mice and rats. It is noteworthy that heterozygous carriers of Kir1.1 mutations associated with antenatal Bartter's syndrome have reduced blood pressure and a decreased risk of developing hypertension by age 60. Although selective ROMK inhibitors would be expected to represent a new class of diuretics, this hypothesis has not been pharmacologically tested. Compound A [5-(2-(4-(2-(4-(1H-tetrazol-1-yl)phenyl)acetyl)piperazin-1-yl)ethyl)isobenzofuran-1(3H)-one)], a potent ROMK inhibitor with appropriate selectivity and characteristics for in vivo testing, has been identified. Compound A accesses the channel through the cytoplasmic side and binds to residues lining the pore within the transmembrane region below the selectivity filter. In normotensive rats and dogs, short-term oral administration of compound A caused concentration-dependent diuresis and natriuresis that were comparable to hydrochlorothiazide. Unlike hydrochlorothiazide, however, compound A did not cause any significant urinary potassium losses or changes in plasma electrolyte levels. These data indicate that pharmacologic inhibition of ROMK has the potential for affording diuretic/natriuretic efficacy similar to that of clinically used diuretics but without the dose-limiting hypokalemia associated with the use of loop and thiazide-like diuretics.

A novel benzazepinone sodium channel blocker with oral efficacy in a rat model of neuropathic pain.

A series of benzazepinones were synthesized and evaluated for block of Nav1.7 sodium channels. Compound 30 from this series displayed potent channel block, good selectivity versus other targets, and dose-dependent oral efficacy in a rat model of neuropathic pain.

Discovery of a novel sub-class of ROMK channel inhibitors typified by 5-(2-(4-(2-(4-(1H-Tetrazol-1-yl)phenyl)acetyl)piperazin-1-yl)ethyl)isobenzofuran-1(3H)-one.

A sub-class of distinct small molecule ROMK inhibitors were developed from the original lead 1. Medicinal chemistry endeavors led to novel ROMK inhibitors with good ROMK functional potency and improved hERG selectivity. Two of the described ROMK inhibitors were characterized for the first in vivo proof-of-concept biology studies, and results from an acute rat diuresis model confirmed the hypothesis that ROMK inhibitors represent new mechanism diuretic and natriuretic agents.

Protective effect of glutathione against isoproterenol induced myocardial injury in rats.

Though there are studies to show protective effect of glutathione against neurotoxicity and nephrotoxicity, the present study was designed to investigate the cardio protective effect of glutathione against isoproterenol induced myocardial infarction in rats by demonstrating the changes in serum cardiac markers, antioxidant enzymes and ECG changes. Wistar male rats were randomly divided into four groups namely control (GI), glutathione (GII), isoproterenol (GIII) and glutathione + isoproterenol treated (GIV). Glutathione treated group-received glutathione (200 mg/kg body wt) orally for 30 days. Myocardial infarction was induced in rats by isoproterenol administration (100 mg/kg) subcutaneously (sc) at an interval of 24 hrs on 31st and 32nd day cardiac marker enzymes, ECG, lipid peroxidation and antioxidant enzymes were assessed 24 hrs after the last dose of isoproterenol. Isoproterenol showed changes in ECG pattern, increase in serum level of cardiac marker, increased lipid per oxidation and decreased antioxidant defense system in heart. Glutathione pretreatment brings almost all the parameters to near normal level in isoproterenol-induced myocardial infarction in rats. The present study revealed that glutathione ameliorates cardiac damage in isoproterenol induced myocardial infarction in rats due to potent antioxidant, free radical scavenging effect, myocardial adaptation at cellular and organ levels.

Substituted biaryl pyrazoles as sodium channel blockers.

Voltage-gated sodium channels have been shown to play a critical role in neuropathic pain. A series of low molecular weight biaryl substituted pyrazole carboxamides were identified with good in-vitro potency and in-vivo efficacy. Compound 26, a Nav1.7 blocker has excellent efficacy in the Chung model of neuropathic pain.

Substituted biaryl oxazoles, imidazoles, and thiazoles as sodium channel blockers.

Voltage-gated sodium channels have been shown to play a critical role in neuropathic pain. With a goal to develop potent peripherally active sodium channel blockers, a series of low molecular weight biaryl substituted imidazoles, oxazoles, and thiazole carboxamides were identified with good in vitro and in vivo potency.

Discovery of a novel class of biphenyl pyrazole sodium channel blockers for treatment of neuropathic pain.

A series of novel biphenyl pyrazole dicarboxamides were identified as potential sodium channel blockers for treatment of neuropathic pain. Compound 20 had outstanding efficacy in the Chung rat spinal nerve ligation (SNL) model of neuropathic pain.

Discovery of isoxazole voltage gated sodium channel blockers for treatment of chronic pain.

A series of novel isoxazole voltage gated sodium channel blockers have been synthesized and evaluated. Substitutions on the benzylic position of benzamide were investigated to determine their effect on Na(v)1.7 inhibitory potency. The spirocyclobutyl substitution had the most significant enhancement on Na(v)1.7 inhibitory activity.

Discovery of a novel class of isoxazoline voltage gated sodium channel blockers.

Analogs of the previously reported voltage gated sodium channel blocker CDA54 were prepared in which one of the amide functions was replaced with aromatic and non-aromatic heterocycles. Replacement of the amide with an aromatic heterocycle resulted in significant loss of sodium channel blocking activity, while non-aromatic heterocycle replacements were well tolerated.

Miniaturization and HTS of a FRET-based membrane potential assay for K(ir) channel inhibitors.

The K(ir) family of potassium-selective ion channels is characterized by their inward (anomalous) rectifying current-voltage relationship. K(ir) channels are widely expressed in mammalian cells and through their role in regulation of the cell membrane potential have been implicated in diverse physiological functions. To enable the identification of novel K(ir) channel inhibitors, a fluorescence resonance energy transfer (FRET)-based membrane potential assay was developed using a Chinese hamster ovary cell line stably expressing a human K(ir) channel. The FRET-based assay incorporates the use of two dyes {N-(6-chloro-7-hydroxycoumarin-3-carbonyl)-dimyristoylphosphatidylethanolamine (CC2-DMPE) and bis(1,3-diethylthiobarbiturate)trimethine oxonol [DiSBAC(2)(3)]} to track changes in membrane potential, thus enabling all of the advantages of ratiometric readout: reduced inaccuracies arising from well-to-well variation in cell number, dye loading, signal intensities, and plate inconsistencies. The assay was miniaturized to a 1,536-well microtiter plate format and read on a fluorometric imaging plate reader (FLIPR(Tetra), Molecular Devices, Sunnyvale, CA). The assay was automated and utilized to perform a primary high-throughput screening campaign to identify novel inhibitors of the K(ir) channel.

Imidazopyridines: a novel class of hNav1.7 channel blockers.

A series of imidazopyridines were evaluated as potential sodium channel blockers for the treatment of neuropathic pain. Several members were identified with good hNa(v)1.7 potency and excellent rat pharmacokinetic profiles. Compound 4 had good efficacy (52% and 41% reversal of allodynia at 2 and 4h post-dose, respectively) in the Chung rat spinal nerve ligation (SNL) model of neuropathic pain when dosed orally at 10mg/kg.

3-Amino-1,5-benzodiazepinones: potent, state-dependent sodium channel blockers with anti-epileptic activity.

A series of 3-amino-1,5-benzodiazepinones were synthesized and evaluated as potential sodium channel blockers in a functional, membrane potential-based assay. One member of this series displayed subnanomolar, state-dependent sodium channel block, and was orally efficacious in a mouse model of epilepsy.

A high-capacity membrane potential FRET-based assay for NaV1.8 channels.

Clinical treatment of neuropathic pain can be achieved with a number of different drugs, some of which interact with all members of the voltage-gated sodium channel (NaV1) family. However, block of central nervous system and cardiac NaV1 channels can cause dose-limiting side effects, preventing many patients from achieving adequate pain relief. Expression of the tetrodotoxin-resistant NaV1.8 subtype is restricted to small-diameter sensory neurons, and several lines of evidence indicate a role for NaV1.8 in pain processing. Given these features, NaV1.8 subtype-selective blockers are predicted to be efficacious in the treatment of neuropathic pain and to be associated with fewer adverse effects than currently available therapies. To facilitate the identification of NaV1.8-specific inhibitors, we stably expressed the human NaV1.8 channel together with the auxiliary human beta1 subunit (NaV beta1) in human embryonic kidney 293 cells. Heterologously expressed human NaV1.8/NaV beta1 channels display biophysical properties that are similar to those of tetrodotoxin-resistant channels present in mouse dorsal root ganglion neurons. A membrane potential, fluorescence resonance energy transfer-based functional assay on a fluorometric imaging plate reader (FLIPR-Tetra, Molecular Devices, Sunnyvale, CA) platform has been established. This highcapacity assay is sensitive to known state-dependent NaV1 modulators and can be used to identify novel and selective NaV1.8 inhibitors.

Discovery of MK-7145, an Oral Small Molecule ROMK Inhibitor for the Treatment of Hypertension and Heart Failure.

ROMK, the renal outer medullary potassium channel, is involved in potassium recycling at the thick ascending loop of Henle and potassium secretion at the cortical collecting duct in the kidney nephron. Because of this dual site of action, selective inhibitors of ROMK are expected to represent a new class of diuretics/natriuretics with superior efficacy and reduced urinary loss of potassium compared to standard-of-care loop and thiazide diuretics. Following our earlier work, this communication will detail subsequent medicinal chemistry endeavors to further improve lead selectivity against the hERG channel and preclinical pharmacokinetic properties. Pharmacological assessment of highlighted inhibitors will be described, including pharmacodynamic studies in both an acute rat diuresis/natriuresis model and a subchronic blood pressure model in spontaneous hypertensive rats. These proof-of-biology studies established for the first time that the human and rodent genetics accurately predict the in vivo pharmacology of ROMK inhibitors and supported identification of the first small molecule ROMK inhibitor clinical candidate, MK-7145.

El COVID-19 también Afecta el Sistema Nervioso por una de sus Compuertas: El Órgano Vascular de la Lámina Terminal y el Nervio Olfatorio. Alerta Neurológica, Prueba de Disosmia o Anosmia Puede Ayudar a Un Diagnóstico Rápido / COVID-19 also Affects the Nervous System by One of its Gates: The Vascular Organ of Lamina Terminalis and the Olfactory Nerve. Neurological Alert, Dysosmia or Anosmia Test Can Help to A Quick Diagnosis

Se presenta una breve revisión de órgano vascular de la lámina terminal (organum vasculosum laminae terminalis) y el nervio olfatorio, el primero un elemento neuroanatómico hipotalámico relacionado con la producción de hormona antidiurética y su asociación como una vía potencial de invasión del COVID-19 al sistema nervioso central, afectando la regulación fisiológica de liberación de hormonas relacionadas con la homeostásis del sodio. También se vincula el neurotropismo de este virus al asociarse con el nervio olfatorio, una evaginación del cerebro en la que se altera su funcionalidad por generación de disosmia entre otras características neurosemiológicas. Se plantea la necesidad de advertir a los profesionales de la salud en general y a los neurólogos en especial, sobre las potenciales alteraciones neurológicas relacionadas con esta pandemia antes y después del contagio de este virus e implementar una prueba olfatoria rápida con ácido acético, incluso antes de otras valoraciones como hipertérmia, tos y cefalalgia.