Relative Bioavailability of Two Oral Formulations of Risperidone 2 mg: A Single-Dose, Randomized-Sequence, Open-Label, Two-Period Crossover Comparison in Healthy Brazilian Volunteers

Background: Risperidone (RSP) is a benzisoxazole antipsychotic agent used to treat schizophrenia and other psychiatric illnesses in adults and children (including those with autism). After oral administration, RSP is completely absorbed from the gastrointestinal tract and undergoes hydroxylation to yield 9-hydroxyrisperidone (9-OH-RSP), an active metabolite that has a pharmacologic profile and potency similar to RSP. Objectives: The aims of this study were to compare the relative bioavailability of a pharmaceutical-equivalent (test) formulation with a reference formulation of oral RSP 2 mg, both available commercially on the Brazilian pharmaceutical market, and to generate data regarding the oral bioavailability of the tested drug in healthy Brazilian volunteers. Methods: This single-dose, randomized-sequence, open-label, 2-period crossover study was conducted in healthy Brazilian volunteers from August to December 2008. Subjects were randomly assigned to receive the test formulation followed by the reference formulation or vice versa, with a 30-day washout period between doses. Study drugs were administered after a 12-hour overnight fast. For pharmacokinetic analysis, blood samples were drawn at 0 (baseline), 0.25, 0.5, 1, 1.5, 3, 5, 8, 12, 24, 48, 72, 96, and 120 hours after administration. Plasma concentrations of RSP and 9-OH-RSP were determined using LC-MS/MS. The test and reference formulations were to be considered bioequivalent if the 90% CIs for the geometric mean test/reference ratios were within a predetermined range of 80% to 125%, in accordance with the policies of the Brazilian Sanitary Surveillance Agency and the US Food and Drug Administration. Tolerability was determined using clinical assessments, monitoring of vital signs, analysis of laboratory test results, and subject interviews regarding adverse events. Results: A total of 22 subjects were enrolled (11 men, 11 women; mean [SD] age, 32 [12] years [range, 18-58 years]; weight, 70.4 [11.9] kg [range, 50-103 kg]; height, 1.67 [0.08] m [range, 1.56-1.80 m]; and body mass index, 25 [4] kg/m(2) [range, 18-29 kg/m(2)]). For RSP, mean (SD) C(max) values were 12.6 (2.7) and 16.0 (2.3) ng/mL for the test and reference formulations, respectively. For 9-OH-RSP, mean C(max) values were 17.8 (1.3) and 21.0 (1.7) ng/mL for the test and reference formulations. The 90% CIs for the mean test/reference ratios for RSP C(max), AUC(0-120), and AUC(0-infinity) were 74% to 82%, 75% to 85%, and 76% to 85%, respectively, and 83% to 87%, 75% to 79%, and 75% to 78% for 9-OH-RSP. The related adverse events (headache, low back pain, drowsiness, standing hypotension, local postvenipuncture ecchymoses, insomnia, nausea, and vomiting) were transient and mild. Conclusions: This single-dose study found that the test and reference formulations of oral RSP 2 mg did not meet the Brazilian and US regulatory criteria for bioequivalence in these fasting, healthy volunteers. The study formulations appeared to be well tolerated. (Clin Ther 2010;32:2106-2115) (C) 2010 Elsevier HS Journals, Inc.

Oral lesions in 166 patients with cutaneous psoriasis: A controlled study

Objectives. This study was aimed to test if the frequency of oral lesions bears statistical correlation or not with the condition of cutaneous psoriasis. Study design. Two groups were examined, one made up of 166 patients with skin psoriasis and the other with the same number of individuals with a negative history of skin diseases (control group), matched by age, race, and sex. Patients with psoriasis were grouped according to their having localized or generalized forms of the disease. The oral mucosa was thoroughly examined in both groups. Data were analyzed using chi-square test, Fisher`s test, the odds ratio (OR) with a 95% confidence interval (CI), and the Ryan-Holm step-down Bonferroni procedure. The overall significance was set at P <= 0.05. Results. The oral lesions significantly associated with psoriasis were fissured tongue (FT, OR=2.7; 95% CI: 1.3-5.6), and geographic tongue (GT, OR=5.0; 95% CI: 1.5-16.8). Other factors analyzed, such as topical and/or systemic medication for treatment of psoriasis versus nontreated patients, and localized versus generalized forms of psoriasis presented no statistical association with the frequency of FT or GT lesions (P > 0.05). Conclusions. Patients with psoriasis presented no specific oral lesion different from those seen in the control group. Although further investigation is warranted to establish whether or not either FT or GT can be characterized as an oral expression of psoriasis, the present investigation did find for both these types of lesions that the frequency of each bore a statistically significant relation with the presence of cutaneous psoriasis.

Oral tolerance attenuates changes in in vitro lung tissue mechanics and extracellular matrix remodeling induced by chronic allergic inflammation in guinea pigs

Oral tolerance attenuates changes in in vitro lung tissue mechanics and extracellular matrix remodeling induced by chronic allergic inflammation in guinea pigs. J Appl Physiol 104: 1778-1785, 2008. First published April 3, 2008; doi:10.1152/japplphysiol.00830.2007.-Recent studies emphasize the presence of alveolar tissue inflammation in asthma. Immunotherapy has been considered a possible therapeutic strategy for asthma, and its effect on lung tissue had not been previously investigated. Measurements of lung tissue resistance and elastance were obtained before and after both ovalbumin and acetylcholine challenges. Using morphometry, we assessed eosinophil and smooth muscle cell density, as well as collagen and elastic fiber content, in lung tissue from guinea pigs with chronic pulmonary allergic inflammation. Animals received seven inhalations of ovalbumin (1-5 mg/ml; OVA group) or saline (SAL group) during 4 wk. Oral tolerance (OT) was induced by offering ad libitum ovalbumin 2% in sterile drinking water starting with the 1st inhalation (OT1 group) or after the 4th (OT2 group). The ovalbumin-exposed animals presented an increase in baseline and in postchallenge resistance and elastance related to baseline, eosinophil density, and collagen and elastic fiber content in lung tissue compared with controls. Baseline and post-ovalbumin and acetylcholine elastance and resistance, eosinophil density, and collagen and elastic fiber content were attenuated in OT1 and OT2 groups compared with the OVA group. Our results show that inducing oral tolerance attenuates lung tissue mechanics, as well as eosinophilic inflammation and extracellular matrix remodeling induced by chronic inflammation.

Claudin-7 down-regulation is an important feature in oral squamous cell carcinoma

Aims: Claudins, a large family of essential tight junction (TJ) proteins, are abnormally regulated in human carcinomas, especially claudin-7. The aim of this study was to investigate claudin-7 expression and alterations in oral squamous cell carcinoma (OSCC). Methods and results: Expression of claudin-7 was analysed in 132 cases of OSCC organized in a tissue microarray. Claudin-7 mRNA transcript was evaluated using real-time polymerase chain reaction and the methylation status of the promoter was also assessed. Claudin-7 was negative in 58.3% of the cases. Loss of claudin-7 protein expression was associated with recurrence (P = 0.019), tumour size (P = 0.014), clinical stage of OSCC (P = 0.055) and disease-free survival (P = 0.015). Down-regulation of the claudin-7 mRNA transcripts was observed in 78% of the cases, in accordance with immunoexpression. Analysis of the methylation status of the promoter region of claudin-7 revealed that treatment of O28 cells (that did not express claudin-7 mRNA transcripts) with 5-Aza-2`-Deoxycytidine (5-Aza-dC) led to the re-expression of claudin-7 mRNA transcript. Conclusion: Loss of claudin-7 expression is associated with important subcellular processes in OSCC with impact on clinical parameters.

Oral tolerance reduces Th17 cells as well as the overall inflammation in the central nervous system of EAE mice

Multiple sclerosis (MS) is an autoimmune disease characterized by inflammatory immune response directed against myelin antigens of the central nervous system. In its murine model, EAE, Th17 cells play an important role in disease pathogenesis. These cells can induce blood-brain barrier disruption and CNS immune cells activation, due to the capacity to secrete high levels of IL-17 and IL-22 in an IL-6 + TGF-beta dependent manner. Thus, using the oral tolerance model, by which 200 mu g of MOG 35-55 is given orally to C57BL/6 mice prior to immunization, we showed that the percentage of Th17 cells as well as IL-17 secretion is reduced both in the periphery and also in the CNS of orally tolerated animals. Altogether, our data corroborates with the pathogenic role of IL-17 and IFN-gamma in EAE, as its reduction after oral tolerance, leads to an overall reduction of pro-inflammatory cytokines, such as IL-1 alpha, IL-6, IL-9, IL-12p70 and the chemokines MIP-1 beta, RANTES, Eotaxin and KC in the CNS. It is noteworthy that this was associated to an increase in IL-10 levels. Thus, our data clearly show that disease suppression after oral tolerance induction, correlates with reduction in target organ inflammation, that may be caused by a reduced Th1/Th17 response. Crown Copyright (c) 2010 Published by Elsevier B.V. All rights reserved.

Oral Mucosal Melanoma of the Mandibular Gingiva: A Case Report

Orla mucosal melanoma is rare and is reported to be more aggressive than cutaneous melanoma. The incidence of oral mucosal melanoma peaks at 41 to 60 years of age and the male to female ratio is 2 to 1. Preferred sites in the oral mucosa include the hard palate and maxillary alveolar crests. Risk factors have not been clearly identified, but melanotic pigmentation is present in one-third of patients prior to the diagnosis of melanoma. We report an unusual case of oral mucosal melanoma of the mandibular gingiva with the main characteristics of an in situ lesion and areas of superficial invasion in a 45-year-old woman. The patient was treated with surgical resection of the lesion and a 54-month follow-up shows no evidence of recurrence. Oral mucosal melanomas are aggressive neoplasms that may arise from prior pigmented lesions in the oral mucosa. Classification of these tumors is not well-established and the main prognostic factor appears to be lymph node compromise. The main treatment modality is surgical resection. Cutis. 2010;86:89-93.

Oral lesions in lupus erythematosus-cytokines profiles of inflammatory infiltrate

Background: Lupus erythematosus (LE) is a chronic inflammatory disease. Presence of type 1 cytokines in cutaneous discoid lesions suggests that they may be critical for induction, development and maintenance of these manifestations. Type 2 cytokines in combination with local interferon gamma (INF-gamma) are thought to be related to the physiopathology of cutaneous LE. Cytokines profiles are still unknown in oral LE lesions. Materials and Methods: Expression of Th1 and Th2 cytokines (including IL-4, IL-5, IL-6, IL-10, IL-12, tumor necrosis factor alpha (TNF-alpha) and INF-gamma was investigated and compared in 29 biopsies of intra-oral (sun-protected) and labial lesions (sun-exposed) of LE using immunohistochemistry. Results: Inflammatory infiltrate of LE lesions was strongly positive for IFN-gamma (97%) and TNF-alpha (90%), both Th1 type cytokines. Interleukin-10, a Th2 cytokine was also strongly expressed. Other cytokines were only mildly positive. Cytokines patterns were similar in intra-oral (sun-covered) and labial (sun-exposed) LE lesions. Conclusions: Oral LE lesions are associated with both type 1 and type 2 cytokines, characterized by stronger expression of INF-gamma, TNF-alpha and IL-10. These findings suggest that although ultraviolet (UV) light is involved in the induction of LE lesions, mechanisms of lesions formation may be similar in sun-exposed as well as sun-covered areas.

Oral manifestations of inflammatory bowel disease: a review based on the observation of six cases

Inflammatory bowel disease (IBD) comprises two chronic, tissue-destructive, clinical entities: Crohn`s disease (CD) and ulcerative colitis (UC), both immunologically based. Bowel symptoms are predominant, but extra-intestinal complications may occur, including involvement of the oral cavity. Oral involvement during IBD includes several types of lesions: the most common are aphthae; uncommon lesions include, among others, pyostomatitis vegetans and granulomatous lesions of CD. Starting with a presentation of six patients with oral manifestations, which were crucial for the final diagnosis of IBD, a review on the subject is presented. Oral involvement in IBD may be previous or simultaneous to the gastrointestinal symptoms. However, in the majority of cases, bowel disease precedes the onset of oral lesions by months or years. In many patients, the intestinal symptoms may be minimal and can go undetected; thus, most authors believe that the bowel must be thoroughly examined in all patients with suspected IBD even in the absence of specific symptoms. Usually, the clinical course of oral lesions is parallel to the activity of IBD; therefore, oral manifestations are a good cutaneous marker of IBD.

The frequency of human papillomavirus findings in normal oral mucosa of healthy people by PCR

The human papillomavirus (HPV) is a DNA virus, which belongs to papillomaviridae family, being of low and high risk, which infect the skin and mucous membranes and can induce benign and malign tumor formation. In the oral mucosa they have been associated with oral papilloma, focal epithelial hyperplasia, leucoplakia and oral neoplasia. Aim: to study the frequency of HPV finding in oral mucosa of normal people. Materials and methods: Prospective study, cross-sectional cohort. One hundred volunteers, young adults, healthy, aged between 20 and 31 years, university students with no history, no complains, without oral or oropharyngeal lesions. They were submitted to a questionnaire with questions regarding HPV infection epidemiology. The samples were harvested by brushing and analyzed by PCR. Results: The results were negative for HPV in all samples. Conclusion: It seems we had high social and economical class individuals, with nutrition rich in carotenoyds and vitamin C, low smoking and alcohol consumption and heterosexual habits with predominant monogamy and regular use of condoms.

Primary Oral Mucosal Melanoma: A Series of 35 New Cases From South America

Oral mucosal melanoma is rare and reported to be more aggressive than its cutaneous counterpart. Due to the rarity of this entity, data on epidemiology, tumor behavior, treatment, follow-up, and Survival of patients are mainly based oil single case reports. The few existing series of patients show that oral mucosa melanoma has its peak between 4 1 and 60 years of age, and male to female ratio is 2: 1. Preferred oral sites include hard palate and maxillary alveolar crests. Risk factors have not been clearly identified, and surgical treatment is still the treatment of choice for oral mucosal melanomas. The authors retrospectively studied 35 patients with primary melanoma of the oral cavity to report their clinical and pathological features, Such as age, sex, site of the tumor, metastasis, treatment, response to therapy, and Outcome. We found no significant sex predominance, and the mean age of the patients was 60.6 years, with a range From 9 to 91 years. The majority of the patients (71.42%) had palate commitment, and invasive histopathological aspect was observed in 80% of the specimens (grade 3). Long-distance metastasis was found in 60% of the cases. Fourteen patients were submitted to wide Surgical resections, with local relapse being observed in 11 of them (78.5%). The authors Suggest that improved outcome in oral malignant melanoma requires the development of new therapies and the prevention of distant metastasis.

Efficacy and Tolerability of Lodenafil Carbonate for Oral Therapy in Erectile Dysfunction: A Phase II Clinical Trial

Oral treatment with phosphodiesterase type 5 inhibitor (PDE5) is considered the first-line treatment for patients with erectile dysfunction (ED). Lodenafil carbonate (LC) is a novel PDE5. This is a phase II, prospective, randomized, double-blind, and placebo controlled clinical trial of LC. Efficacy end points were International Index of Sexual Function (IIEF) erectile domain, IIEF questions 3 and 4, and Sexual Encounter Profile (SEP) questions 2 and 3, before and after the use of LC or placebo. Seventy-two men older than 18 years, with ED for at least 6 months with stable sexual relationship were enrolled. Patients were randomized to placebo or LC 80 mg, 40 mg, or 20 mg and followed for 4 weeks. IIEF erectile domain scores before and after the use of medications were (mean +/- standard deviation [SD]): placebo: 11.9 +/- 3.4 and 12.6 +/- 5.5; LC 20 mg: 15.8 +/- 4.1 and 18.9 +/- 6.6; LC 40 mg: 11.9 +/- 4.4 and 15.4 +/- 8.1; LC 80 mg: 14.2 +/- 4.7 and 22.8 +/- 6.0 (anova P < 0.01). The SEP-2 scores before and after the use of medications were (Mean +/- SD): placebo: 71.0 +/- 33.1 and 51.2 +/- 43.1; LC 20 mg 70.3 +/- 34.2 and 75.5 +/- 31.5; LC 40 mg: 48.4 +/- 42.1 and 60.8 +/- 42.5; LC 80 mg: 68.6 +/- 33.5 and 89.6 +/- 26.0. The SEP-3 scores were: placebo 23.3 +/- 27.6 and 33.6 +/- 42.3; LC 20 mg: 32.3 +/- 38.9 and 51.2 +/- 41.7; LC 40 mg: 39.7 +/- 44.7 and 46.7 +/- 41.1; LC 80 mg* 17.2 +/- 29.5 and 74.3 +/- 36.4 (*P < 0.05 for difference to placebo). The drug was well tolerated. Adverse reactions were mild and self-limited and included headache, rhinitis, flushing, color visual disorders, and dyspepsia. This study showed that the dosage of 80 mg of LC was significantly more efficacious than placebo and well tolerated. Glina S, Toscano I, Gomatzky C, de Goes PM, Junior AN, de Almeida Claro JF, and Pagani E. Efficacy and tolerability of lodenafil carbonate for oral therapy in erectile dysfunction: A phase II clinical trial. J Sex Med 2009;6:553-557.

Oral tolerance attenuates airway inflammation and remodeling in a model of chronic pulmonary allergic inflammation

We investigated the effects of oral tolerance (OT) in controlling inflammatory response, hyperresponsiveness and airway remodeling in guinea pigs (GP) with chronic allergic inflammation. Animals received seven inhalations of ovalbumin (1-5 mg/mL-OVA group) or normal saline (NS group). OT was induced by offering ad libitum ovalbumin 2% in sterile drinking water starting with the 1st ovalbumin inhalation (OT1 group) or after the 4th (OT2 group). The induction of OT in sensitized animals decreased the elastance of respiratory system (Ers) response after both antigen and methacholine challenges, peribronchial edema formation, eosinophilic airway infiltration, eosinophilopoiesis, and airways collagen and elastic fiber content compared to OVA group (P < 0.05). The number of mononuclear cells and resistance of respiratory system (Rrs) responses after antigen and methacholine challenges were decreased only in OT2 group compared to OVA group (P < 0.05). Concluding, our results show that inducing OT attenuates airway remodeling as well as eosinophilic inflammation and respiratory system mechanics. (C) 2008 Elsevier B.V. All rights reserved.

Biological markers and prognosis in recurrent oral cancer after salvage surgery

Objective: To analyze the prognostic effect of epidermal growth factor receptor (EGFR), matrix metalloproteinases 2 and 9, and vascular endothelial growth factor expression in patients with locally recurrent oral carcinoma after salvage surgery. Design: Retrospective cohort study. Settings: Tertiary center cancer hospital. Patients: The charts of 111 patients with local recurrence of oral carcinomas were retrospectively analyzed. The previous treatment consisted of surgery in 33 patients (30.0%), radiotherapy with or without chemotherapy in 46 patients (41.0%), and surgery with adjuvant radiotherapy in 32 patients (29.0%). The expression of EGFR, matrix metalloproteinases 2 and 9, and vascular endothelial growth factor was analyzed with a tissue microarray immunohistochemical technique. Main Outcome Measures: Overall survival and cancer-specific survival (CSS). Results: The recurrences were diagnosed in less than 1 year in 69 patients (62.2%) and in more than 1 year in 42 patients (37.8%). The prognosis was worse in the group with the disease-free interval of less than 1 year (P=.01). Patients with more advanced disease (clinical stage of recurrence, III/IV) had worse rates of CSS (P=.04). Cases that were positive for EGFR had a 3-year CSS of 27.2%, while EGFR-negative cases had a 3-year CSS of 64.3% (P=.001). The expression of matrix metalloproteinases 2 (P=.83) and 9 (P=.15) and vascular endothelial growth factor (P=.86) was not significant in this group. In multivariate analysis, only the disease-free interval and the overexpression of EGFR were associated with a higher risk of cancer death. Conclusions: Local recurrence in oral carcinomas carries a poor prognosis. A disease-free interval of more than 1 year and a EGFR-negative expression are the main prognostic factors related to better CSS in patients treated with salvage surgery.

Expression of Mycobacterium leprae HSP65 in tobacco and its effectiveness as an oral treatment in adjuvant-induced arthritis

Transgenic plants are able to express molecules with antigenic properties. In recent years, this has led the pharmaceutical industry to use plants as alternative systems for the production of recombinant proteins. Plant-produced recominant proteins can have important applications in therapeutics, such as in the treatment of rheumatoid arthritis (RA). In this study, the mycobacterial HSP65 protein expressed in tobacco plants was found to be effective as a treatment for adjuvant-induced arthritis (AIA). We cloned the hsp65 gene from Mycobacterium leprae into plasmid pCAMBIA 2301 under the control of the double 35S promoter from cauliflower mosaic virus. Agrobacterium tumefaciens bearing the pChsp65 plasmid was used to transform tobacco plants. Incorporation of the hsp65 gene was confirmed by PCR, reverse transcription-PCR, histochemistry, and western blot analyses in several transgenic lines of tobacco plants. Oral treatment of AIA rats with the HSP65 protein allowed them to recover body weight and joint inflammation was reduced. Our results suggest a synergistic effect between the HSP65 expressed protein and metabolites presents in tobacco plants.

Effectiveness of Oral Rinse with Chlorhexidine in Preventing Nosocomial Respiratory Tract Infections among Intensive Care Unit Patients

OBJECTIVE. To evaluate the effectiveness of the oral application of a 0.12% solution of chlorhexidine for prevention of respiratory tract infections among intensive care unit (ICU) patients. DESIGN. The study design was a double-blind, randomized, placebo-controlled trial. SETTING. The study was performed in an ICU in a tertiary care hospital at a public university. PATIENTS. Study participants comprised 194 patients admitted to the ICU with a prospective length of stay greater than 48 hours, randomized into 2 groups: those who received chlorhexidine (n = 98) and those who received a placebo (n = 96). INTERVENTION. Oral rinses with chlorhexidine or a placebo were performed 3 times a day throughout the duration of the patient`s stay in the ICU. Clinical data were collected prospectively. RESULTS. Both groups displayed similar baseline clinical features. The overall incidence of respiratory tract infections (RR, 1.0 [95% confidence interval [CI], 0.63-1.60]) and the rates of ventilator-associated pneumonia per 1,000 ventilator-days were similar in both experimental and control groups (22.6 vs 22.3; P = .95). Respiratory tract infection-free survival time (7.8 vs 6.9 days; P = .61), duration of mechanical ventilation (11.1 vs 11.0 days; P = .61), and length of stay (9.7 vs 10.4 days; P = .67) did not differ between the chlorhexidine and placebo groups. However, patients in the chlorhexidine group exhibited a larger interval between ICU admission and onset of the first respiratory tract infection (11.3 vs 7.6 days; P = .05). The chances of surviving the ICU stay were similar (RR, 1.08 [95% CI, 0.72-1.63]). CONCLUSION. Oral application of a 0.12% solution of chlorhexidine does not prevent respiratory tract infections among ICU patients, although it may retard their onset.