Dose-response relationship between toothpaste soluble fluoride absorbed in the gastrointestinal tract and saliva fluoride secretion

Aim: This study aimed to evaluate if there is a dose-response relationship between toothpaste chemically soluble fluoride absorbed in the gastrointestinal tract and fluoride secreted by saliva, giving support to the use of saliva as surrogate for plasma fluoride. Methods: A 4-phase single blind study was conducted, in which 10 participants were subjected in each phase to one of the assigned treatment groups: group I: fresh sample of a Na2FPO3/CaCO3-based toothpaste with 1,334 µg F/g of total soluble fluoride (TSF) and groups II­IV: aged samples of this toothpaste presenting TSF concentrations of 1,128, 808, and 687 µg F/g, respectively. In all phases, the participants ingested an amount of toothpaste equivalent to 70.0 µg F/Kg body weight, as total fluoride (TF). Saliva and blood samples were collected before (baseline) and up to 180 min after toothpaste ingestion as indicator of fluoride bioavailability. F concentration in saliva and blood plasma was determined with a fluoride ion-specific electrode. The areas under the curve (AUC) of F concentration versus time (AUC = ng F/mL × min) and the peaks of fluoride concentration (Cmax) in saliva and plasma were calculated. Results: A significant correlation between mg of TSF ingested and the AUC (r=0.47; p<0.01), and Cmax (r=0.59; p<0.01) in saliva was found; for TF, the correlation was not significant (p>0.05). In addition, the correlations between plasma and saliva fluoride concentrations were statistically significant for AUC (r=0.55; p<0.01) as for Cmax (r=0.68; p<0.01). Conclusion: The findings support that saliva can be used as a systemic biomarker of bioavailable fluoride present in Na2FPO3/CaCO3-based toothpaste

Therapeutic Drug Monitoring of Vancomycin in Jordanian Patients. Development of Physiologically-Based Pharmacokinetic (PBPK) Model and Validation of Class II Drugs of Salivary Excretion Classification System (SECS).

Vancomycin is a commonly used antibiotic for multi-drug resistant gram-positive infections treatment, especially methicillin-resistant Staphylococcus aureus (MRSA). Despite that, it has wide individual pharmacokinetic variability and nephrotoxic effect. Vancomycin trough concentrations for 57 Jordanian patients were measured in plasma and saliva through immunoassay and liquid chromatography-mass spectrometry (LC-MS/MS), respectively. Plasma levels were within accepted normal range, with exception of 6 patients who showed trough levels of more than 20 µg/ml and vancomycin was discontinued. Bayesian dose-optimizing software was used for patient-specific pharmacokinetics prediction and AUC/MIC calculation. Physiological-based pharmacokinetic (PBPK) vancomycin model was built and validated through GastroPlus™ 9.8 using in-house plasma data. A weak correlation coefficient of 0.2478 (P=0.1049) was found between plasma and saliva concentrations. The suggested normal saliva trough range of vancomycin is 0.01906 to 0.028589 (µg/ml). Analysis of variance showed significant statistical effects of creatinine clearance and albumin concentration on dose-normalized Cmin plasma and saliva levels respectively, which is in agreement with PBPKmodeling. It can be concluded that saliva is not a suitable matrix for TDM of vancomycin. Trough levels in plasma matrix should always be monitored for the safety of patients.

Saliva versus Plasma Therapeutic Drug Monitoring of Gentamicin in Jordanian Preterm Infants. Development of a Physiologically-Based Pharmacokinetic (PBPK) Model and Validation of Class II Drugs of Salivary Excretion Classification System.

Gentamicin has proven to be a very successful treatment for bacterial infection, but it also can cause adverse effects, especially ototoxicity, which is irreversible. Therapeutic drug monitoring (TDM) in saliva is a more convenient non-invasive alternative compared to plasma. A physiologically-based pharmacokinetic (PBPK) model of gentamicin was built and validated using previously-published plasma and saliva data. The validated model was then used to predict experimentally-observed plasma and saliva gentamicin TDM data in Jordanian pediatric preterm infant patients measured using sensitive LCMS/MS method. A correlation was established between plasma and saliva exposures. The developed PBPK model predicted previously reported gentamicin levels in plasma, saliva and those observed in the current study. A good correlation was found between plasma and saliva exposures. The PBPK model predicted that gentamicin in saliva is 5-7 times that in plasma, which is in agreement with observed results. Saliva can be used as an alternative for TDM of gentamicin in preterm infant patients. Exposure to gentamicin in plasma and saliva can reliably be predicted using the developed PBPK model in patients.

Salivary Excretion of Renal-Clearable Silver Nanoparticles.

Salivary elimination is an important pathway for the body to excrete small molecules with digestive enzymes. However, very few engineered nanoparticles can be excreted through salivary glands, which often host bacteria or viruses during infection and involve in disease transmission. Herein, we report that renal clearable glutathione coated AgNPs (GS-AgNPs) can selectively accumulate in the submandibular salivary gland, followed by being excreted in its excretory duct. By conducting head-to-head comparison on in vivo transport and interactions of both GS-AgNPs and glutathione coated gold nanoparticles (GS-AuNPs) with the same sizes, we found that low-density GS-AgNPs showed much higher vascular permeability than GS-AuNPs and can rapidly penetrate into submandibular salivary glands, be efficiently taken up by striated and excretory duct cells, and eventually secreted into saliva.

Treatment with a CD40 Antagonist Antibody Reverses Severe Proteinuria and Loss of Saliva Production and Restores Glomerular Morphology in Murine Systemic Lupus Erythematosus.

CD40 is a costimulatory receptor on APCs that is critical for the induction and maintenance of humoral and cell-mediated immunity. Accordingly, CD40 and its ligand, CD40L, have long been considered targets for the treatment of autoimmune diseases. We developed a rat/mouse chimeric anti-mouse CD40 antagonist mAb, 201A3, and evaluated its ability to alleviate murine lupus. Treatment of NZB/W-F1 mice with 201A3 after the onset of severe proteinuria rapidly reversed established severe proteinuria and nephritis and largely restored normal glomerular and tubular morphology. This coincided with a normalization of the expression of genes associated with proteinuria and injury by kidney parenchymal cells. Anti-CD40 treatment also prevented and reversed loss of saliva production and sialadenitis. These effects on kidney and salivary gland function were confirmed using mice of a second strain, MRL/Mp-lpr/lpr, and extended to alleviating joint inflammation. Immunologically, anti-CD40 treatment disrupted multiple processes that contribute to the pathogenesis of systemic lupus erythematosus (SLE), including autoreactive B cell activation, T effector cell function in target tissues, and type I IFN production. This ability to disrupt disease-critical immunological mechanisms, to reverse glomerular and tubular injury at the cellular and gene expression levels, and to confer exceptional therapeutic efficacy suggests that CD40 is a central disease pathway in murine SLE. Thus, a CD40 antagonist Ab could be an effective therapeutic in the treatment of SLE.

Effectiveness of a spray containing 1% malic acid in patients with xerostomia induced by graft-versus-host disease

Background: To evaluate the clinical effectiveness of a topical sialogogue spray (malic acid, 1%) in the treatment of xerostomia in patients with chronic Graft versus Host Disease (cGVHD). Material and Methods: This study was designed as a randomized double-blind clinical study. Twenty-eight patients with cGVHD suffering from xerostomia were divided into 2 groups: the first group (14 patients) received a topical sialagogue spray containing malic acid 1% (SalivAktive(R)) whereas the second group (14 patients) received a placebo. Both groups received treatment for 2 weeks. Dry Mouth Questionnaire (DMQ) scores and unstimulated salivary flows rate were collected before and after treatment. Results: DMQ scores increased significantly from 1.3 ± 0.4 to 3.5 ± 0.4 points (p<0.05) after two weeks of treat-ment with malic acid, whereas in the control group DMQ scores increased from 1.2 ± 0.7 points to 1.4 ± 0.6 (p>0.05). The unstimulated salivary flow rate in patients treated with malic acid increased significantly from 0.15 ± 0.06 mL/min to 0.24± 0.08 mL/min, while that of the patients treated with placebo went from 0.16 ± 0.07 mL/ min to 0.17 ± 0.09 mL/min (p>0.05). Conclusions: Malic acid 1% spray can be considered effective in the treatment of GVHD induced xerostomia

No disponible

The efficacy and safety of total glucosides of peony in the treatment of primary Sjögren's syndrome: a multi-center, randomized, double-blinded, placebo-controlled clinical trial.

To evaluate the efficacy and safety of total glucosides of peony (TGP) in adults with primary Sjögren's syndrome (pSS). A multi-center, randomized, double-blinded, placebo-controlled study was conducted between March 2012 and July 2014 at ten Chinese hospitals. In total, 320 pSS patients-classified according to the 2002 American-European Consensus Group Criteria-were randomized (2:1 ratio) to receive TGP(600 mg, tid) in the TGP group or placebo for 24 weeks in the placebo group. Study personnel, investigators, and patients were blinded to the treatment grouping. The primary endpoint was the improvement of EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI) at week 24. The secondary endpoints were dry eyes/mouth/skin/nose/throat/vagina visual analogue scale (VAS), pain and discomfort VAS, fatigue VAS, mental discomfort VAS, patient global assessment (PGA), EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI), Schirmer's test, basal/stimulated salivary flow-rate values, and erythrocyte sedimentation rate (ESR). All adverse events were recorded during the trial period. ESSPRI improved more in the TGP than the placebo group (p < 0.001). Dry eyes/throat/vagina VAS, fatigue VAS, mental discomfort VAS, PGA, Schirmer's test, and ESR also improved more in the TGP group than in the placebo group (all p < 0.05). Stimulated salivary flow-rate values increased in the TGP group at week 12 but not at week 24. Adverse events in TGP group were 10.9%. TGP can alleviate some dryness symptoms as well as disease activity in pSS patients over 24 weeks. TGP was well tolerated by study subjects. TGP seems to be an effective and safe treatment for pSS.

Effect of lactoferrin on taste and smell abnormalities induced by chemotherapy: a proteome analysis.

Cancer patients receiving chemotherapy often experience taste and smell abnormalities (TSA). To date, the underlying molecular mechanisms of this frequent side-effect have not been determined and effective treatments are not available. This study assessed the feasibility of lactoferrin (LF) supplementation as a treatment for TSA and investigate the related mechanisms through salivary proteome analysis. Nineteen cancer patients with established TSA following chemotherapy administration were enrolled in this study. Cancer patients and additional 12 healthy subjects took LF supplements, 3 tablets per day (250 mg per tablet), for 30 days. Saliva was collected at three timepoints: baseline, 30-day LF supplementation, and 30-day post-LF supplementation. Patient's TSA level, salivary proteome, and salivary minerals at each LF treatment stage were analyzed. High TSA level was associated with high concentration of salivary Fe and loss of critical salivary immune proteins. LF supplementation significantly decreased the concentration of salivary Fe (P = 0.025), increased the abundance (P < 0.05) of salivary α-amylase and Zn-α-2-GP, and led to an overall increase of expression (≥2-fold changes) of immune proteins including immunoglobulin heavy chain, annexin A1, and proteinase inhibitor. Abundance of α-amylase and SPLUNC2 were further increased (P < 0.05) at 30-day post-LF supplementation in cancer patients. At the same time, total TSA score was significantly reduced (P < 0.001) in chemotherapy patients. This study demonstrated the feasibility of developing lactoferrin supplementation as a treatment to reduce TSA caused by chemotherapy and improve cancer patient's oral immunity.

Sialometric and Sialochemical Changes in Morbidly Obese Patients before and after Bariatric Surgery.

AIM: To evaluate the sialometric and sialochemical changes in morbidly obese patients before and after bariatric surgery. MATERIALS AND METHODS: A total of 74 participants were divided into three groups paired by sex and age: (a) Experimental 1 (E1)-morbid obesity (n = 40)-according to the Fobi-Capella technique, corresponding to the individuals with a body mass index (BMI) of greater than 40 kg/m2 prior to bariatric surgery; (b) Experimental 2 (E2)-the same individuals after surgery; and (c) control (C) (n = 34)-individuals with a BMI of nearly 23 kg/m2. The measure of salivary flow was carried out by collecting stimulated saliva. The pH was evaluated using the pocket pH meter, while the salivary buffer capacity (SBC) was determined by the titration method. Analyses of the salivary concentration of total proteins (TPs), amylase activity, urea, calcium (Ca++), and glucose were evaluated using the calorimetric method. RESULTS: Group E1, as compared with group C, presented the highest pH levels (p = 0.03), amylase activity (p = 0.00), and calcium (p = 0.00). The opposite was observed for glucose (p = 0.00), TP (p = 0.04), and urea (p = 0.04). Group E2, as compared with group C, revealed higher levels of amylase (p = 0.00) and calcium (p = 0.00). The opposite was observed for SBC (p = 0.01), PT (p = 0.00), and glucose (p = 0.00). Group E1, as compared with group E2, presented higher values of SBC (p = 0.00) and urea (p = 0.00). The lowest values were found for calcium and urea (p = 0.03). CONCLUSION: Both weight gain and bariatric surgery are risk factors for the oral condition, causing change in some important salivary components, such as TP, amylase, calcium, and glucose. CLINICAL SIGNIFICANCE: This article is a valuable addition to the scientific literature, due to its novelty. There are no papers that show salivary alterations related to bariatric surgeries.

Saliva versus Plasma Therapeutic Drug Monitoring of Pregabalin in Jordanian Patients.

The objective is using saliva instead of plasma for pregabalin therapeutic drug monitoring (TDM) since saliva reflects the free non-protein bound drug concentration, simple and noninvasive sampling, cheaper and does not require the expertise of drawing blood. Forty four patients participated in this study, two samples of saliva and another two of blood were taken from each patient; first sample of both saliva and blood is the trough sample and was taken just before the first dose of the day and second sample is the peak sample and was taken 1 h after taking the first dose of the day. Descriptive statistics and t-testing after log transformation were done using Excel, p-value=0.05 was adopted for significant difference. Optimized effective intestinal permeability of pregabalin was estimated by PK-Sim program version 7. This study for the first time revealed that pregabalin is excreted in saliva and classified as class 1 based on Salivary Excretion Classification System (SECS). A good correlation of 0.71-0.83 between Cmin and Cmax of plasma and saliva pregabalin was observed respectively which indicate that saliva sampling is a good alternative matrix for pregabalin TDM. C/D-ratios were calculated to demonstrate pharmacokinetic variability of Pregabalin; the results showed that C/D-ratio was higher in women, elderly and in those patients who had Scr.≥0.9 mg/dl. Proposed pregabalin therapeutic ranges are 0.7 to 1.84 µg/ml in plasma and 0.055 to 0.145 µg/ml in saliva, for neuropathic pain, diabetic neuropathy and disc prolapse patients.

Saliva versus Plasma Bioequivalence of Valsartan/Hydrochlorothiazide in Humans: Validation of Classes II and IV Drugs of the Salivary Excretion Classification System.

AIM: The aim of this study is to investigate the robustness of using non-invasive saliva instead of plasma for bioequivalence of valsartan and hydrochlorothiazide (HCT) in humans based on Salivary Excretion Classification System (SECS). METHODS: Plasma and resting saliva samples were collected over 24 h after oral administration of single dose 160 mg valsartan and 12.5 mg HCT to 12 healthy male volunteers after 10 h overnight fasting. Plasma and saliva concentrations were determined by validated liquid chromatography-mass spectrometry. WinNonlin program V5.2 was used to determine pharmacokinetic parameters and bioequivalence metrics. Moreover, optimized effective intestinal permeability was estimated using PK-Sim/Mobi program V5.6. RESULTS AND DISCUSSION: Valsartan is SECS class IV drug due of low permeability and high protein binding and hence didn't appear in saliva. However, HCT is SECS class II drug due to low permeability and low protein binding. No significant differences were observed in the pharmacokinetic parameters in both plasma matrix and saliva matrix (P˃0.05). The 90% confidence intervals did not pass in all parameters due to the high intra-subject variability and small sample size used in this study. Saliva to plasma ratios of HCT were low, yet with high correlation coefficient of 0.96-0.98. So saliva can be used as alternative to plasma sample in pharmacokinetic studies and in bioequivalence when adequate sample size is used.

Saliva Versus Plasma Bioequivalence of Azithromycin in Humans: Validation of Class I Drugs of the Salivary Excretion Classification System.

AIM: The aim of this study was to compare human pharmacokinetics and bioequivalence metrics in saliva versus plasma for azithromycin as a model class I drug of the Salivary Excretion Classification System (SECS). METHODS: A pilot, open-label, two-way crossover bioequivalence study was done, and involved a single 500-mg oral dose of azithromycin given to eight healthy subjects under fasting conditions, followed by a 3-week washout period. Blood and unstimulated saliva samples were collected over 72 h and deep frozen until analysis by a validated liquid chromatography with mass spectroscopy method. The pharmacokinetic parameters and bioequivalence metrics of azithromycin were calculated by non-compartment analysis using WinNonlin V5.2. Descriptive statistics and dimensional analysis of the pharmacokinetic parameters of azithromycin were performed using Microsoft Excel. PK-Sim V5.6 was used to estimate the effective intestinal permeability of azithromycin. RESULTS AND DISCUSSION: No statistical differences were shown in area under the concentration curves to 72 h (AUC0-72), maximum measured concentration (C max) and time to maximum concentration (T max) between test and reference azithromycin products (P > 0.05) in the saliva matrix and in the plasma matrix. Due to the high intra-subject variability and low sample size of this pilot study, the 90% confidence intervals of AUC0-72 and C max did not fall within the acceptance range (80-125%). However, saliva levels were higher than that of plasma, with a longer salivary T max. The mean saliva/plasma concentration of test and reference were 2.29 and 2.33, respectively. The mean ± standard deviation ratios of saliva/plasma of AUC0-72, C max and T max for test were 2.65 ± 1.59, 1.51 ± 0.49 and 1.85 ± 1.4, while for the reference product they were 3.37 ± 2.20, 1.57 ± 0.77 and 2.6 ± 1.27, respectively. A good correlation of R = 0.87 between plasma and saliva concentrations for both test and reference products was also observed. Azithromycin is considered a class I drug based on the SECS, since it has a high permeability and high fraction unbound, and saliva sampling could be used as an alternative to plasma sampling to characterize its pharmacokinetics and bioequivalence in humans when adequate sample size is used.

Rabbit submandibular salivary gland replantation

OBJECTIVES: To test the feasibility of submandibular salivary gland (SMG) replantation techniques and the survival of the replanted glands. Such a study can provide a rationale for later allotransplantation procedures, along with implementation of conventional and advanced immunosuppression therapy. MATERIALS AND METHODS: Six SMG replantations were performed in New Zealand white rabbits. One week postoperatively, (99m)Tc scintigraphy was performed and the uptake ratio and salivary excretion fraction were calculated. Two to four weeks later, submandibular glands were excised, fixed, and stained with H&E for histomorphometric evaluation. RESULTS: Intraoperatively, all glands showed patent blood perfusion except gland 5. Positive tracer uptake and saliva excretion were documented by scintigraphy. On excision, all of the glands except glands 4 and 5 looked viable, with a red color and patent pedicles. Gland 4 was infected and filled with creamy pus, while gland 5 looked pale and necrotic. Histologically, glands 1, 2, 3, and 6 had preserved normal glandular tissue with slight variations from the contralateral normal glands, as their parenchyma was composed of mildly atrophic acini. CONCLUSION: Four out of six replanted SMGs successfully survived. The glands maintained good viability and function. Such success depends on safe harvesting, short anastomosis time, and strict control of infection.

Rabbit submandibular salivary gland replantation

OBJECTIVES: To test the feasibility of submandibular salivary gland (SMG) replantation techniques and the survival of the replanted glands. Such a study can provide a rationale for later allotransplantation procedures, along with implementation of conventional and advanced immunosuppression therapy. MATERIALS AND METHODS: Six SMG replantations were performed in New Zealand white rabbits. One week postoperatively, (99m)Tc scintigraphy was performed and the uptake ratio and salivary excretion fraction were calculated. Two to four weeks later, submandibular glands were excised, fixed, and stained with H&E for histomorphometric evaluation. RESULTS: Intraoperatively, all glands showed patent blood perfusion except gland 5. Positive tracer uptake and saliva excretion were documented by scintigraphy. On excision, all of the glands except glands 4 and 5 looked viable, with a red color and patent pedicles. Gland 4 was infected and filled with creamy pus, while gland 5 looked pale and necrotic. Histologically, glands 1, 2, 3, and 6 had preserved normal glandular tissue with slight variations from the contralateral normal glands, as their parenchyma was composed of mildly atrophic acini. CONCLUSION: Four out of six replanted SMGs successfully survived. The glands maintained good viability and function. Such success depends on safe harvesting, short anastomosis time, and strict control of infection.

Salivary cortisol level and uncooperative behavior in pediatric dental practice

Aim: To investigate the relation between uncooperative behavior and salivary cortisol level in childrenwho underwent preventive dental care. Methods: The sample was composed by 10 children of bothsexes aged 40 to 52 months, presenting uncooperative behavior during dental preventive treatments.The saliva collection was performed using a cotton wheel and an Eppendorf tube (Sarstedt Salivete®)in 3 different moments: a) at home, on a day without dental treatment and at the same time on theday of the sessions treatment; b) 30 min after the end of the session, when there was manifestationof uncooperative behavior; c) 30 min after the end of the session, when there was a cooperativebehavior of the child. A sample of saliva was centrifuged for 5 minutes at 2400 rpm, 1 of mL of salivawas pipetted in an Eppendorf tube and stored in a freezer at -20 ° C. For the determination of thelevels of salivary cortisol was used an Active® kit for cortisol enzyme immunoassay (EIA) DSL-10-67100, composed of specific rabbit antibody anti-cortisol. Data were analyzed statistically for theuncooperative behavior issued in the beginning and at the end of sessions, using the paired t test(p<0.05) and for cortisol levels in saliva samples at home, after the beginning and at the end ofsessions, using repeated-measures ANOVA and Tukey’s test (p<0.05). Results: During expression ofuncooperative behavior in preventive dental care sessions the salivary cortisol level was significantlyhigher (0.65 ± 0.25 µg/dL) compared with expression of collaborative behavior (0.24 ± 0.10 µg/dL).Conclusions: It is possible to conclude that, even under preventive intervention, the stress must becontrolled in order to reduce dental anxiety and fear.

Saliva versus Plasma Relative Bioavailability of Tolterodine in Humans: Validation of Class III Drugs of the Salivary Excretion Classification System.

Relative bioavailability study of tolterodine in healthy human volunteers was done using saliva and plasma matrices in order to investigate the robustness of using saliva instead of plasma as a surrogate for bioavailability and bioequivalence of class III drugs according to the salivary excretion classification system (SECS). Saliva and plasma samples were collected up to 16 h after 2 mg oral dose. Saliva and plasma pharmacokinetic parameters were calculated by non compartmental analysis using Kinetica program V5. Human effective intestinal permeability was optimized by SimCYP program V13. Tolterodine falls into class III (High permeability/Low fraction unbound to plasma proteins) and hence was subjected to salivary excretion. A high pearsons correlation coefficient of 0.97 between mean saliva and plasma concentrations, and saliva/plasma concentrations ratio of 0.33 were observed. In addition, correlation coefficients and saliva/plasma ratios of area under curve and maximum concentration were 0.98, 0.95 and 0.42, 0.34 respectively. On the other hand, time to reach maximum concentration was higher in saliva by 2.37 fold. In addition, inter subject variability values in saliva were slightly higher than plasma leading to need for slightly higher number of subjects to be used in saliva studies (55 vs. 48 subjects). Non-invasive saliva sampling instead of invasive plasma sampling method can be used as a surrogate for bioavailability and bioequivalence of SECS class I drugs when adequate sample size is used.

Role of saliva in esophageal defense: implications in patients with nonerosive reflux disease.

BACKGROUND: It has been previously demonstrated that patients with reflux esophagitis exhibit a significant impairment in the secretion of salivary protective components versus controls. However, the secretion of salivary protective factors in patients with nonerosive reflux disease (NERD) is not explored. The authors therefore studied the secretion of salivary volume, pH, bicarbonate, nonbicarbonate glycoconjugate, protein, epidermal growth factor (EGF), transforming growth factor alpha (TGF-α) and prostaglandin E2 in patients with NERD and compared with the corresponding values in controls (CTRL). METHODS: Salivary secretion was collected during basal condition, mastication and intraesophageal mechanical (tubing, balloon) and chemical (initial saline, acid, acid/pepsin, final saline) stimulations, respectively, mimicking the natural gastroesophageal reflux. RESULTS: Salivary volume, protein and TGF-α outputs in patients with NERD were significantly higher than CTRL during intraesophageal mechanical (P < 0.05) and chemical stimulations (P < 0.05). Salivary bicarbonate was significantly higher in NERD than CTRL group during intraesophageal stimulation with both acid/pepsin (P < 0.05) and saline (P < 0.01). Salivary glycoconjugate secretion was significantly higher in the NERD group than the CTRL group during chewing (P < 0.05), mechanical (P < 0.05) and chemical stimulation (P < 0.01). Salivary EGF secretion was higher in patients with NERD during mechanical stimulation (P < 0.05). CONCLUSIONS: Patients with NERD demonstrated a significantly stronger salivary secretory response in terms of volume, bicarbonate, glycoconjugate, protein, EGF and TGF-α than asymptomatic controls. This enhanced salivary esophagoprotection is potentially mediating resistance to the development of endoscopic mucosal changes by gastroesophageal reflux.

Saliva versus plasma bioequivalence of rusovastatin in humans: validation of class III drugs of the salivary excretion classification system.

Bioequivalence of rusovastatin in healthy human volunteers was done using saliva and plasma matrices in order to investigate the robustness of using saliva instead of plasma as a surrogate for bioequivalence of class III drugs according to the salivary excretion classification system (SECS). Saliva and plasma samples were collected for 72 h after oral administration of rusovastatin 40 mg to 12 healthy humans. Saliva and plasma pharmacokinetic parameters were calculated by non-compartmental analysis. Analysis of variance, 90 % confidence intervals, and intra-subject and inter-subject variability values of pharmacokinetic parameters were calculated using Kinetica program V5. Human effective intestinal permeability was also calculated by SimCYP program V13. Rusovastatin falls into class III (high permeability/low fraction unbound to plasma proteins) and hence was subjected to salivary excretion. A correlation coefficient of 0.99 between saliva and plasma concentrations, and a saliva/plasma concentration ratio of 0.175 were observed. The 90 % confidence limits of area under the curve (AUClast) and maximum concentration (C max) showed similar trends in both saliva and plasma. On the other hand, inter- and intra-subject variability values in saliva were higher than in plasma, leading to the need for a slightly higher number of subjects to be used in saliva studies. Non-invasive saliva sampling instead of the invasive plasma sampling method can be used as a surrogate for bioequivalence of SECS class III drugs when an adequate sample size is used.

Saliva vs. plasma bioequivalence of metformin in humans: validation of class II drugs of the salivary excretion classification system.

To study saliva and plasma bioequivalence of metformin in humans, and to investigate the robustness of using saliva instead of plasma as surrogate for bioequivalence of class II drugs according to the salivary excretion classification system (SECS).Plasma and saliva samples were collected for 12 h after 500 mg oral dosing of metformin to 16 healthy humans. Plasma and saliva pharmacokinetic parameters, 90% confidence intervals and intra-subject variability values were calculated using Kinetica V5. Descriptive statistics and dimensional analysis were calculated by Excel. SimCYP program V13 was used for estimation of effective intestinal permeability.Metformin was subjected to salivary excretion since it falls into class II (Low permeability/High fraction unbound to plasma proteins), with correlation coefficients of 0.95-0.99 between plasma and saliva concentrations. Saliva/plasma concentration ratios were 0.29-0.39. The 90% confidence limits of all parameters failed in both saliva and plasma. Intra-subject variability values in saliva were higher than plasma leading to need for higher number of subjects to be used in saliva.Saliva instead of plasma can be used as surrogate for bioequivalence of class II drugs according to SECS when adequate sample size is used. Future work is planned to demonstrate SECS robustness in drugs that fall into class III.

Saliva vs. plasma bioequivalence of paracetamol in humans: validation of class I drugs of the salivary excretion classification system.

AIMS: To study saliva and plasma bioequivalence of paracetamol in healthy human volunteers, and to investigate the robustness of using saliva instead of plasma as surrogate for bioequivalence of class I drugs according to the salivary excretion classification system (SECS). METHODS: Saliva and plasma pharmacokinetic parameters were calculated by non compartmental analysis. Analysis of variance, 90% confidence intervals, intra-subject and inter-subject variability values of pharmacokinetic parameters were calculated after logarithmic transformation. Calculations were done using Kinetica program V5. Descriptive and comparative statistics were also calculated by Excel. RESULTS AND DISCUSSION: Paracetamol falls into class I (High permeability/High fraction unbound to plasma proteins) and was subjected to salivary excretion, with correlation coefficient of 0.99 between saliva and plasma concentrations and saliva/plasma concentrations ratios of 1.45-1.50. The 90% confidence limits of areas under curve (AUC(last) and AUC(∞)) showed similar trend and passed the 80-125% acceptance criteria in both saliva and plasma. On the other hand for maximum concentration (C(max)), the 90% confidence limits passed the acceptance criteria in plasma and failed in saliva. Inter and intra subject variability values in saliva were higher than plasma leading to need for higher number of subjects to be used in saliva. Saliva and plasma parameter ratios were not significantly different (P>0.05). CONCLUSIONS: Saliva instead of plasma can be used as surrogate for bioequivalence of class I drugs according to SECS when adequate sample size is used. Future work is planned to demonstrate SECS robustness in drugs that fall into classes II or III.