Are herbal mouthwash efficacious over chlorhexidine on the dental plaque?

AIM: To compare the effect of herbal extract mouthwash and chlorhexidine mouthwash on the dental plaque level. MATERIALS AND METHODS: The subjects (60 healthy medical students aged ranges between 20 and 25 years) were randomly divided into two groups, that is, the herbal group and the chlorhexidine gluconate mouthwash group. The data were collected at the baseline and 3 days. The plaque was disclosed using erythrosine disclosing agent and their scores were recorded using the Quigley and Hein plaque index modified by Turesky-Gilmore-Glickman. Statistical analysis was carried out later to compare the effect of all the two groups. RESULTS: Our result showed that the chlorhexidine group shows a greater decrease in plaque score followed by herbal extract, but the result was statistically insignificant. CONCLUSION: The results indicate that herbal mouthwash may prove to be an effective agent owing to its ability to reduce plaque level, especially in low socioeconomic strata.

Tamoxifen nanostructured lipid carriers: enhanced in vivo antitumor efficacy with reduced adverse drug effects.

A novel approach of enhancing the Tamoxifen uptake via Intestinal Lymphatic System is executed by developing long chain lipid and oil based nanostructured lipid carrier system (Tmx-NLC). The aim was to achieve improved systemic bioavailability of Tamoxifen, prevent systemic and hepatotoxicity and enhance antitumor efficacy. Following the proof of concept achieved in cell culture experiments and in vivo pharmacokinetic and biodistribution study, the current work focuses on investigation of antitumor efficacy and treatment associated toxicity in murine mammary tumor mice model. The efficacy study demonstrated greater tumor suppression and 100% survival with 1.5 and 3 mg/kg Tmx-NLC compared to 3 mg/kg Tamoxifen suspension and Mamofen(®) (Khandelwal Pharmaceuticals, Mumbai, India). Tmx-NLC treatment for a month demonstrated improved systemic toxicity profile and no evidences of hepatotoxicity. Thus, developed Tmx-NLC could prove to be a promising delivery strategy to confer superior therapeutic efficacy and ability to address the biopharmaceutical and toxicity associated issues of drug.

Endosomal escape: a bottleneck in intracellular delivery.

With advances in therapeutic science, apart from drugs, newer bioactive moieties like oligonucleotides, proteins, peptides, enzymes and antibodies are constantly being introduced for the betterment of therapeutic efficacy. These moieties have intracellular components of the cells like cytoplasm and nucleus as one of their pharmacological sites for exhibiting therapeutic activity. Despite their promising efficacy, their intracellular bioavailability has been critically hampered leading to failure in the treatment of numerous diseases and disorders. The endosomal uptake pathway is known to be a rate-limiting barrier for such systems. Bioactive molecules get trapped in the endosomal vesicles and degraded in the lysosomal compartment, necessitating the need for effective strategies that facilitate the endosomal escape and enhance the cytosolic bioavailability of bioactives. Microbes like viruses and bacteria have developed their innate mechanistic tactics to translocate their genome and toxins by efficiently penetrating the host cell membrane. Understanding this mechanism and exploring it further for intracellular delivery has opened new avenues to surmount the endosomal barrier. These strategies include membrane fusion, pore formation and proton sponge effects. On the other hand, progress in designing a novel smart polymeric carrier system that triggers endosomal escape by undergoing modulations in the intracellular milieu has further led to an improvement in intracellular delivery. These comprise pH, enzyme and temperature-induced modulators, synthetic cationic lipids and photo-induced physical disruption. Each of the aforementioned strategies has its own unique mechanism to escape the endosome. This review recapitulates the numerous strategies designed to surmount the bottleneck of endosomal escape and thereby achieve successful intracellular uptake of bioactives.

Prevalence of musculoskeletal disorder and alternative medicine therapies among dentists of North India: A descriptive study.

AIM: Health professionals especially the dental professional are the frequent targets of musculoskeletal disorders (MSD). Complementary and alternative medicine (CAM) can be of some help in managing these MSD especially in. The purpose of this study was to determine the prevalence of CAM therapies as a treatment modality for MSD management among dental professionals of north India. MATERIALS AND METHODS: Registered dentist of North Indian origin, India (n = 3598) were included in the study. The questionnaire was sent to all the dentists which consisted of the demographic profile, MSD in the past year, CAM therapies utilization and opinion about CAM therapies. Data analysis was done using SPSS version 21 and data were presented in tabular and graphic form. Test of significance was done using chi-square statistics with P < 0.05 considered as significant. RESULTS: A response rate of 80% (n = 2879) was obtained, and all complained of MDS in some or the other part of their life. The use of CAM was reported among 70% (n = 2015) of the dentist who suffered from MSD. Other dentists either used conventional treatment or did not use anything. CONCLUSION: As the name implies, alternative medical systems is a category that extends beyond a single modality and refers to an entire system of theory and practice that developed separately from conventional medicine. CAM should be subject to rigorous scientific inquiry so that interventions that work are systematically distinguished from those that do not. In addition, the use of CAM treatments should be based on evidence of effectiveness and safety as demonstrated in randomized clinical trials.

Pulmonary multifunctional nano-oncological modules for lung cancer treatment and prevention.

Mortality associated with lung cancer and its metastasis has outnumbered those related to other forms of cancer. Despite being a directly accessible organ, conventional oncological strategies exhibiting prolific outcome in treatment and prevention of lung cancer is far from reality. This is attributed to numerous challenges posed by lung environment. The extracellular aura of lung comprises immensely complicated structures, ciliary escalators, omnipresence of mucus and alveolar fluid, and macrophagial uptake which presents an array of impediments to the arrival of therapeutic moiety at the tumor site. Besides these, intracellular obstacles viz enzymatic degradation, cell membrane translocation, endosomal escape and/or nuclear entry also limit superior therapeutic efficacy. The current review elaborates wide-ranging challenges to lung cancer treatment and its circumvention by latest developments in multifunctional nano-oncological modules delivered via the pulmonary route-which smartly deal with the abovementioned issues and bestow positivity to this complication.

Correlation of myocardial perfusion SPECT with invasive and computed tomography coronary angiogram.

BACKGROUND: The consequences of atherosclerosis can be detected by multislice computed tomography (MSCT), invasive coronary angiogram (CAG) and the resultant myocardial ischaemia by myocardial perfusion single photon emission computed tomography (MPS). In this study an attempt is made to compare MSCT with MPS and also to compare the MSCT findings with that of invasive CAG in patients suspected to have coronary artery disease (CAD). MATERIALS AND METHODS: A total of 99 patients suspected to have CAD underwent both MSCT and MPS with (99m)Tc sestamibi. The MSCT studies were classified as having no CAD, significant CAD (>50% diameter stenosis), and insignificant CAD (<50% diameter stenosis). Myocardial perfusion single photon emission computed tomography was reported as normal and reversible ischaemia. In a subgroup of 33 patient invasive CAG was done. RESULTS: In 99 patients, 396 coronaries were evaluated with MSCT and MPS. Coronary artery calcium scoring (CACS) in these patient ranged from 0 to 2200. No CAD was noted in 128 (32%) coronaries but MPS was found abnormal in 9 (7%) coronaries. Insignificant CAD was noted in 169 (43%) coronaries amongst which reversible ischaemia was noted in 23 (14%). Significant CAD was noted in 99 (25%) coronaries of which only 54 (55%) were MPS positive for reversible ischaemia. The MSCT has a negative predictive value (NPV) of 97%. When MSCT was normal, MPS was almost normal, but the reverse was not true. That is when MPS was normal MSCT was not always normal but showed lesion of insignificant obstruction. In the subset of 33 patients, who underwent invasive angiogram, 132 coronaries were evaluated. Coronary angiogram showed 48 coronaries (36%) to have significant CAD (>50% diameter stenosis). Multislice computed tomography correlated well in 46 (84%) with P value of <0.001 (χ(2)-test) but for 9 (16%) showing overestimation due to increased CACS (>800). Myocardial perfusion single photon emission computed tomography was normal in 15 (27%) coronaries. CONCLUSION: Myocardial perfusion single photon emission computed tomography provides functional information of the anatomical lesions and MSCT provides anatomical information. Both are two different diagnostic modalities. The MSCT has high NPV in patients with less likelihood for CAD. When compared with CAG, the correlation with MSCT was good and is useful where the calcium score is low.

Myocardial perfusion single photon emission computed tomography in asymptomatic diabetics.

BACKGROUND: Coronary artery disease (CAD) is the most important cause of mortality in diabetic patients. Diabetes mellitus (DM) due to autonomic neuropathy leads to asymptomatic CAD. Hence, it is important to screen the patients with DM for CAD. AIM: To study the prevalence of asymptomatic CAD by Myocardial Perfuision SPECT (Single Photon Emission Computed Tomography) (MPS) in diabetics. METHODS: This prospective study included 88 asymptomatic patients (58 males and 30 females) of Type 2 DM of more than 5 years duration in the age group of 40-65 years. Risk factors like hypertension, dyslipidemia, smoking, family history of CAD and Body Mass Index > or = 25 kg/sq.m were assessed. All these patients underwent MPS study as two day standard protocol. Thirty eight patients underwent invasive Coronary Angiography (CAG) and stenosis greater than 50% was considered significant. RESULTS: Abnormal perfusion was detected in 38 (43%) diabetics and 4 (11%) controls. A total of 81 perfusion defects were identified (19 fired and 62 reversible). CAG showed significant coronary stenosis in 26 (68.4%), insignificant in 8 (21%) and no stenosis in 4 (10.6%) patients. A total of 114 coronaries were analysed, significant stenosis in 67 (58.8%) coronaries, 21 (18.4%) had insignificant lesions and 26(22.8%) were normal. In comparison to CAG, MPS had sensitivity of 86.6% and specificity of 51%. CONCLUSION: The Myocardial Perfusion SPECT is a sensitive diagnostic tool to identify ischemia in asymptomatic diabetics. MPS can be used as screening test for risk stratification. It has a prognostic value in predicting the outcome of CAD and can be useful for long-term follow up too.

Correlation among on-call resident study volume, discrepancy rate, and turnaround time.

RATIONALE AND OBJECTIVES: With continued increase in imaging utilization and remote access image viewing technology, many academic radiology departments are presented with the suggestion to supplement on-call resident preliminary reports with an outsourced attending interpretation. This idea is often brought to administrative attention because of the subjective impression that outsourced studies will benefit from significantly faster interpretation times and lower discrepancy rates, especially when study volume is high. We attempt to retrospectively analyze on-call resident studies at a busy Trauma I university hospital and establish whether a statistical correlation exists among study volume, discrepancy rate, and turnaround time. MATERIALS AND METHODS: On-call computed tomography and ultrasound studies between January 2008 and June 2008 were retrospectively reviewed by blinded staff radiologists for discrepancies between preliminary and final reports. A correlation analysis between discrepancy rate and study volume per shift was performed. In addition, correlation analysis between volume per shift and interpretation time was also performed. RESULTS: A total of 1133 studies were reviewed. The major discrepancy rate is 1.85% with average turnaround time of 28.5 minutes. The correlation coefficient between major discrepancy rate and study volume is 0.35. The correlation coefficient between interpretation time and study volume is 0.29. CONCLUSION: Our large retrospective review of preliminary reports from different residents reveals no significant correlation among discrepancy rate, turnaround time, and study volume. The overall discrepancy rate is similar to that reported by other studies. Other institutions can perform this study to analyze whether their volume and resident performance warrants supplemental assistance before depriving residents of the educational benefits the independent on-call experience affords.

Design and synthesis of 6-phenylnicotinamide derivatives as antagonists of TRPV1.

6-Phenylnicotinamide (2) was previously identified as a potent TRPV1 antagonist with activity in an in vivo model of inflammatory pain. Optimization of this lead through modification of both the biaryl and heteroaryl components has resulted in the discovery of 6-(4-fluorophenyl)-2-methyl-N-(2-methylbenzothiazol-5-yl)nicotinamide (32; SB-782443) which possesses an excellent overall profile and has been progressed into pre-clinical development.

Characterization of SB-705498, a potent and selective vanilloid receptor-1 (VR1/TRPV1) antagonist that inhibits the capsaicin-, acid-, and heat-mediated activation of the receptor.

Vanilloid receptor-1 (TRPV1) is a nonselective cation channel, predominantly expressed by sensory neurons, which plays a key role in the detection of noxious painful stimuli such as capsaicin, acid, and heat. TRPV1 antagonists may represent novel therapeutic agents for the treatment of a range of conditions including chronic pain, migraine, and gastrointestinal disorders. Here we describe the in vitro pharmacology of N-(2-bromophenyl)-N'-[((R)-1-(5-trifluoromethyl-2-pyridyl)pyrrolidin-3-yl)]urea (SB-705498), a novel TRPV1 antagonist identified by lead optimization of N-(2-bromophenyl)-N'-[2-[ethyl(3-methylphenyl)amino]ethyl]urea (SB-452533), which has now entered clinical trials. Using a Ca(2+)-based fluorometric imaging plate reader (FLIPR) assay, SB-705498 was shown to be a potent competitive antagonist of the capsaicin-mediated activation of the human TRPV1 receptor (pK(i) = 7.6) with activity at rat (pK(i) = 7.5) and guinea pig (pK(i) = 7.3) orthologs. Whole-cell patch-clamp electrophysiology was used to confirm and extend these findings, demonstrating that SB-705498 can potently inhibit the multiple modes of receptor activation that may be relevant to the pathophysiological role of TRPV1 in vivo: SB-705498 caused rapid and reversible inhibition of the capsaicin (IC(50) = 3 nM)-, acid (pH 5.3)-, or heat (50 degrees C; IC(50) = 6 nM)-mediated activation of human TRPV1 (at -70 mV). Interestingly, SB-705498 also showed a degree of voltage dependence, suggesting an effective enhancement of antagonist action at negative potentials such as those that might be encountered in neurons in vivo. The selectivity of SB-705498 was defined by broad receptor profiling and other cellular assays in which it showed little or no activity versus a wide range of ion channels, receptors, and enzymes. SB-705498 therefore represents a potent and selective multimodal TRPV1 antagonist, a pharmacological profile that has contributed to its definition as a suitable drug candidate for clinical development.

N-Tetrahydroquinolinyl, N-quinolinyl and N-isoquinolinyl biaryl carboxamides as antagonists of TRPV1.

Starting from the high throughput screening hit (3), novel N-tetrahydroquinolinyl, N-quinolinyl and N-isoquinolinyl carboxamides have been identified as potent antagonists of the ion channel TRPV1. The N-quinolinylnicotinamide (46) showed excellent potency at human, guinea pig and rat TRPV1, a favourable in vitro DMPK profile and activity in an in vivo model of inflammatory pain.

Discovery of SB-705498: a potent, selective and orally bioavailable TRPV1 antagonist suitable for clinical development.

Small molecule antagonists of the vanilloid receptor TRPV1 (also known as VR1) are disclosed. Pyrrolidinyl ureas such as 8 and 15 (SB-705498) emerged as lead compounds following optimisation of the previously described urea SB-452533. Pharmacological studies using electrophysiological and FLIPR-Ca2+-based assays showed that compounds such as 8 and 15 were potent antagonists versus the multiple chemical and physical modes of TRPV1 activation (namely capsaicin, acid and noxious heat). Furthermore, 15 possessed suitable developability properties to enable progression of this compound into in vivo studies and subsequently clinical development.

3,4-Dihydro-2H-benzoxazinones are 5-HT(1A) receptor antagonists with potent 5-HT reuptake inhibitory activity.

Starting from a high throughput screening hit, a series of 3,4-dihydro-2H-benzoxazinones has been identified with both high affinity for the 5-HT(1A) receptor and potent 5-HT reuptake inhibitory activity. The 5-(2-methyl)quinolinyloxy derivative combined high 5-HT(1A/1B/1D) receptor affinities with low intrinsic activity and potent inhibition of the 5-HT reuptake site (pK(i)8.2). This compound also had good oral bioavailability and brain penetration in the rat.

Evidence for a molecular mechanism of teratogenicity of SB-236057, a 5-HT1B receptor inverse agonist that alters axial formation.

BACKGROUND: SB-236057 is a potent skeletal teratogen in rodents and rabbits, producing axial and posterior somite malformations in cultured rat embryos. The compound shares some structural similarity to cyclopamine. METHODS: M13 phage display was used to identify amino acid motifs with binding affinity to SB-236057. A 10 microM SB-236057 solution was administered to cultured day 9 postcoitus rat embryos and real-time PCR was conducted at 6 hr posttreatment to evaluate early transcriptional response of axial development genes. Whole-mount in situ hybridization of selected transcripts was conducted on embryos at 48 hr post-compound administration. The rat-enhancer of split protein 1 (r-esp1) expression-functional characterization was done by transcriptional expression and morpholino antisense approaches. RESULTS: We identified several amino acid motifs that had high binding affinity to SB-236057-biotin conjugates, one with 100% sequence homology to a region of r-esp1, one of the Groucho homologs transcribed by the enhancer of split complex (En[spl]C). SB-236057 repressed expression of r-esp1 and members of the Notch-En[spl]C pathway. Goosecoid and HNF3-beta, both suspected to associate with Groucho proteins, were also responsive, although expression of another putative binding protein, engrailed-1 (en-1), and other en-1 pathway members was not affected. R-esp1 mRNA was localized along the axis and antisense inhibition produced similar somite malformations as SB-236057 did. At 48 hr post-SB-236057 or post-r-esp1 antisense administration, affected embryos demonstrated unchanged sonic hedgehog (shh) expression, however HNF3-beta expression was either absent, altered, or reduced. CONCLUSIONS: We present experimental evidence that the mechanism of SB-236057 teratogenicity includes transcriptional alterations to the Notch1-En[spl] pathway. In addition, alterations in HNF3-beta expression were similar to those induced by cyclopamine. The relationships between r-esp1 with Notch1 and shh signaling pathways and potential mechanisms of SB-236057 teratogenicity are also discussed.

Discovery of small molecule antagonists of TRPV1.

Small molecule antagonists of the vanilloid receptor 1 (TRPV1, also known as VR1) are disclosed. Ureas such as 5 (SB-452533) were used to explore the structure activity relationship with several potent analogues identified. Pharmacological studies using electrophysiological and FLIPR Ca(2+) based assays showed compound 5 was an antagonist versus capsaicin, noxious heat and acid mediated activation of TRPV1. Study of a quaternary salt of 5 supports a mode of action in which compounds from this series cause inhibition via an extracellularly accessible binding site on the TRPV1 receptor.