Spinal magnetic resonance imaging with reduced specific absorption rate in patients harbouring a spinal cord stimulation device - A single-centre prospective study analysing safety, tolerability and image quality.

BACKGROUND: Spinal cord stimulation (SCS) is an accepted treatment in patients with failed back surgery (FBS), complex regional pain syndrome (CRPS) and persistent radicular pain following surgery. In order to avoid patient hazards or device malfunction manufacturers advise to abstain from magnetic resonance imaging (MRI) in patients with implanted electrodes or pulse generators. METHODS: In a prospective study, 13 patients harbouring an implanted Medtronic Spinal Cord Stimulation (SCS) device underwent MRI (1.5 T) of the lumbar (n=13), the cervical (n=2) or the thoracic spine (n=1) following the development of new spinal symptoms. An adapted MRI protocol was used limiting the transmitted energy and specific absorption rate. Tolerability and safety were assessed by means of a standardized patient evaluation form documenting pain on a visual analogue scale (0-10), neurologic deficit, and discomfort during the scan. In addition, overall satisfaction with the examination procedure was rated on a Likert scale (1-5). Image quality was rated independently and blinded to the presence of a SCS device by the radiologist and the surgeon as equivalent, superior or inferior compared to the standard spine MRI examination. RESULTS: None of the 13 patients investigated by the modified spinal MRI protocol experienced new neurological deficits, worsening of symptoms or a defect/malfunction of the implant device. Three patients (23.1 %) reported transient warm sensation in the location of the electrode and in one case intermittent slight tingling in the lower extremities. Overall satisfaction with the examination was 1.13 ± 0.34 according to Likert scale (1-5). The image quality was rated - not statistically significant - slightly inferior to standard lumbar spine imaging (0.82 ± 0.54) with a kappa value of 0.68 between the two investigators. MRI examinations detected relevant and new lesions in 9 (69.2 %) patients which affected treatment in 8 (61.5 %) individuals. CONCLUSION: Using a protocol with a reduced specific energy absorption rate, spinal MRI examinations in patients with SCS can be considered safe. The current view that neurostimulators are a general contraindication to MR examinations has to be reconsidered in patients with new or progressive spinal symptoms.

Identification of the SPLUNC1 ENaC-inhibitory domain yields novel strategies to treat sodium hyperabsorption in cystic fibrosis airway epithelial cultures.

The epithelial sodium channel (ENaC) is responsible for Na(+) and fluid absorption across colon, kidney, and airway epithelia. Short palate lung and nasal epithelial clone 1 (SPLUNC1) is a secreted, innate defense protein and an autocrine inhibitor of ENaC that is highly expressed in airway epithelia. While SPLUNC1 has a bactericidal permeability-increasing protein (BPI)-type structure, its NH2-terminal region lacks structure. Here we found that an 18 amino acid peptide, S18, which corresponded to residues G22-A39 of the SPLUNC1 NH2 terminus inhibited ENaC activity to a similar degree as full-length SPLUNC1 (∼2.5 fold), while SPLUNC1 protein lacking this region was without effect. S18 did not inhibit the structurally related acid-sensing ion channels, indicating specificity for ENaC. However, S18 preferentially bound to the ßENaC subunit in a glycosylation-dependent manner. ENaC hyperactivity is contributory to cystic fibrosis (CF) lung disease. Unlike control, CF human bronchial epithelial cultures (HBECs) where airway surface liquid (ASL) height was abnormally low (4.2 ± 0.6 µm), addition of S18 prevented ENaC-led ASL hyperabsorption and maintained CF ASL height at 7.9 ± 0.6 µm, even in the presence of neutrophil elastase, which is comparable to heights seen in normal HBECs. Our data also indicate that the ENaC inhibitory domain of SPLUNC1 may be cleaved away from the main molecule by neutrophil elastase, suggesting that it may still be active during inflammation or neutrophilia. Furthermore, the robust inhibition of ENaC by the S18 peptide suggests that this peptide may be suitable for treating CF lung disease.

Importance of lipid microdomains, rafts, in absorption, delivery, and biological effects of resveratrol.

The preventive effects of the phytoalexin trans-resveratrol toward cancer have been largely described at the cellular and molecular levels in both in vivo and in vitro models; however, its primary targets are still poorly identified. In this review, we show the crucial role of cell membrane microdomains, that is, lipid rafts, not solely in the initiation of the early biochemical events triggered by resveratrol leading to cancer cell death, but also in resveratrol absorption and distribution. Resveratrol accumulates in lipid rafts and is then taken up by cells through raft-dependent endocytosis. These events allow early activation of kinase pathways and redistribution of cell death receptors within lipid microdomains, events ultimately leading to apoptotic cell death.

Tubular reabsorption and local production of urine hepcidin-25.

BACKGROUND: Hepcidin is a central regulator of iron metabolism. Serum hepcidin levels are increased in patients with renal insufficiency, which may contribute to anemia. Urine hepcidin was found to be increased in some patients after cardiac surgery, and these patients were less likely to develop acute kidney injury. It has been suggested that urine hepcidin may protect by attenuating heme-mediated injury, but processes involved in urine hepcidin excretion are unknown. METHODS: To assess the role of tubular reabsorption we compared fractional excretion (FE) of hepcidin-25 with FE of ß2-microglobulin (ß(2)m) in 30 patients with various degrees of tubular impairment due to chronic renal disease. To prove that hepcidin is reabsorbed by the tubules in a megalin-dependent manner, we measured urine hepcidin-1 in wild-type and kidney specific megalin-deficient mice. Lastly, we evaluated FE of hepcidin-25 and ß(2)m in 19 patients who underwent cardiopulmonary bypass surgery. Hepcidin was measured by a mass spectrometry assay (MS), whereas ß(2)m was measured by ELISA. RESULTS: In patients with chronic renal disease, FE of hepcidin-25 was strongly correlated with FE of ß(2)m (r = 0.93, P <0.01). In megalin-deficient mice, urine hepcidin-1 was 7-fold increased compared to wild-type mice (p < 0.01) indicating that proximal tubular reabsorption occurs in a megalin- dependent manner. Following cardiac surgery, FE of hepcidin-25 increased despite a decline in FE of ß(2)m, potentially indicating local production at 12-24 hours. CONCLUSIONS: Hepcidin-25 is reabsorbed by the renal tubules and increased urine hepcidin-25 levels may reflect a reduction in tubular uptake. Uncoupling of FE of hepcidin-25 and ß(2)m in cardiac surgery patients suggests local production.

A two-hit mechanism for sepsis-induced impairment of renal tubule function.

Renal insufficiency is a common and severe complication of sepsis, and the development of kidney dysfunction increases morbidity and mortality in septic patients. Sepsis is associated with a variety of defects in renal tubule function, but the underlying mechanisms are incompletely understood. We used a cecal ligation and puncture (CLP) model to examine mechanisms by which sepsis influences the transport function of the medullary thick ascending limb (MTAL). MTALs from sham and CLP mice were studied in vitro 18 h after surgery. The results show that sepsis impairs the ability of the MTAL to absorb HCO(3)(-) through two distinct mechanisms. First, sepsis induces an adaptive decrease in the intrinsic capacity of the tubules to absorb HCO(3)(-). This effect is associated with an increase in ERK phosphorylation in MTAL cells and is prevented by pretreatment of CLP mice with a MEK/ERK inhibitor. The CLP-induced reduction in intrinsic HCO(3)(-) absorption rate appears to involve loss of function of basolateral Na(+)/H(+) exchange. Second, sepsis enhances the ability of LPS to inhibit HCO(3)(-) absorption, mediated through upregulation of Toll-like receptor 4 (TLR4)-ERK signaling in the basolateral membrane. The two inhibitory mechanisms are additive and thus can function in a two-hit capacity to impair renal tubule function in sepsis. Both effects depend on ERK and are eliminated by interventions that prevent ERK activation. Thus the TLR4 and ERK signaling pathways represent potential therapeutic targets to treat or prevent sepsis-induced renal tubule dysfunction.

Kidney-specific WNK1 regulates sodium reabsorption and potassium secretion in mouse cortical collecting duct.

Kidney-specific with-no-lysine kinase 1 (KS-WNK1) is a kinase-deficient variant of WNK1 that is expressed exclusively in the kidney. It is abundantly expressed in the distal convoluted tubule (DCT) and to a lesser extent in the cortical thick ascending limb (cTAL), connecting tubule, and cortical collecting duct (CCD). KS-WNK1 inhibits Na(+)-K(+)-2Cl(-)- and sodium chloride cotransporter-mediated Na(+) reabsorption in cTAL and DCT, respectively. Here, we investigated the role of KS-WNK1 in regulating Na(+) and K(+) transport in CCD using in vitro microperfusion of tubules isolated from KS-WNK1 knockout mice and control wild-type littermates. Because baseline K(+) secretion and Na(+) reabsorption were negligible in mouse CCD, we studied tubules isolated from mice fed a high-K(+) diet for 2 wk. Compared with that in wild-type tubules, K(+) secretion was reduced in KS-WNK1 knockout CCD perfused at a low luminal fluid rate of ~1.5 nl/min. Na(+) reabsorption and the lumen-negative transepithelial potential difference were also lower in the KS-WNK1 knockout CCD compared with control CCD. Increasing the perfusion rate to ~5.5 nl/min stimulated K(+) secretion in the wild-type as well as knockout CCD. The magnitudes of flow-stimulated increase in K(+) secretion were similar in wild-type and knockout CCD. Maxi-K(+) channel inhibitor iberiotoxin had no effect on K(+) secretion when tubules were perfused at ~1.5 nl/min, but completely abrogated the flow-dependent increase in K(+) secretion at ~5.5 nl/min. These findings support the notion that KS-WNK1 stimulates ROMK-mediated K(+) secretion, but not flow-dependent K(+) secretion mediated by maxi-K(+) channels in CCD. In addition, KS-WNK1 plays a role in regulating Na(+) transport in the CCD.

Intranasal drug delivery: an efficient and non-invasive route for systemic administration: focus on opioids.

Intranasal administration is a non-invasive route for drug delivery, which is widely used for the local treatment of rhinitis or nasal polyposis. Since drugs can be absorbed into the systemic circulation through the nasal mucosa, this route may also be used in a range of acute or chronic conditions requiring considerable systemic exposure. Indeed, it offers advantages such as ease of administration, rapid onset of action, and avoidance of first-pass metabolism, which consequently offers for example an interesting alternative to intravenous, subcutaneous, oral transmucosal, oral or rectal administration in the management of pain with opioids. Given these indisputable interests, fentanyl-containing formulations have been recently approved and marketed for the treatment of breakthrough cancer pain. This review will outline the relevant aspects of the therapeutic interest and limits of intranasal delivery of drugs, with a special focus on opioids, together with an in-depth discussion of the physiological characteristics of the nasal cavity as well as physicochemical properties (lipophilicity, molecular weight, ionisation) and pharmaceutical factors (absorption enhancers, devices for application) that should be considered for the development of nasal drugs.

Absorption, distribution, metabolism and excretion of peginesatide, a novel erythropoiesis-stimulating agent, in rats.

The pharmacokinetics (PK) (absorption, distribution, metabolism, excretion) of peginesatide, a synthetic, PEGylated, investigational, peptide-based erythropoiesis-stimulating agent (ESA), was evaluated in rats. The PK profile was evaluated at 0.1-5 mg·kg(-1) IV using unlabeled or [(14)C]-labeled peginesatide. Mass balance, tissue distribution and metabolism were evaluated following IV administration of 5 mg·kg(-1) [(14)C]-peginesatide, with tissue distribution also evaluated by quantitative whole-body autoradiography (QWBA) following an IV dose of 17 mg·kg(-1) [(14)C]-peginesatide. Plasma clearance was slow and elimination was biphasic with unchanged peginesatide representing >90% of the total radioactivity of the total radioactive exposure. Slow uptake of the radiolabeled compound from the vascular compartment into the tissues was observed. Biodistribution to bone marrow and extramedullary hematopoietic sites, and to highly vascularized lymphatic and excretory tissues occurred. A predominant degradation event to occur in vivo was the loss of one PEG chain from the branched PEG moiety to generate mono-PEG. Renal excretion was the primary mechanism (41%) of elimination, with parent molecule (67%) the major moiety excreted. In conclusion, elimination of [(14)C]-peginesatide-derived radioactivity was extended, retention preferentially occurred at sites of erythropoiesis (bone marrow), and urinary excretion was the primary elimination route.

Pharmacokinetics, distribution, and metabolism of [14C]sunitinib in rats, monkeys, and humans.

Sunitinib is an oral multitargeted tyrosine kinase inhibitor approved for the treatment of advanced renal cell carcinoma, imatinib-refractory gastrointestinal stromal tumor, and advanced pancreatic neuroendocrine tumors. The current studies were conducted to characterize the pharmacokinetics, distribution, and metabolism of sunitinib after intravenous and/or oral administrations of [(14)C]sunitinib in rats (5 mg/kg i.v., 15 mg/kg p.o.), monkeys (6 mg/kg p.o.), and humans (50 mg p.o.). After oral administration, plasma concentration of sunitinib and total radioactivity peaked from 3 to 8 h. Plasma terminal elimination half-lives of sunitinib were 8 h in rats, 17 h in monkeys, and 51 h in humans. The majority of radioactivity was excreted to the feces with a smaller fraction of radioactivity excreted to urine in all three species. The bioavailability in female rats was close to 100%, suggesting complete absorption of sunitinib. Whole-body autoradioluminography suggested radioactivity was distributed throughout rat tissues, with the majority of radioactivity cleared within 72 h. Radioactivity was eliminated more slowly from pigmented tissues. Sunitinib was extensively metabolized in all species. Many metabolites were detected both in urine and fecal extracts. The main metabolic pathways were N-de-ethylation and hydroxylation of indolylidene/dimethylpyrrole. N-Oxidation/hydroxylation/desaturation/deamination of N,N'-diethylamine and oxidative defluorination were the minor metabolic pathways. Des-ethyl metabolite M1 was the major circulating metabolite in all three species.

Intestinal phosphate transport.

Phosphate is absorbed in the small intestine by a minimum of 2 distinct mechanisms: paracellular phosphate transport which is dependent on passive diffusion, and active transport which occurs through the sodium-dependent phosphate cotransporters. Despite evidence emerging for other ions, regulation of the phosphate-specific paracellular pathways remains largely unexplored. In contrast, there is a growing body of evidence that active transport through the sodium-dependent phosphate cotransporter, Npt2b, is highly regulated by a diverse set of hormones and dietary conditions. Furthermore, conditional knockout of Npt2b suggests that it plays an important role in maintenance of phosphate homeostasis by coordinating intestinal phosphate absorption with renal phosphate reabsorption. The knockout mouse also suggests that Npt2b is responsible for the majority of sodium-dependent phosphate uptake. The type-III sodium-dependent phosphate transporters, Pit1 and Pit2, contribute to a minor role in total phosphate uptake. Despite coexpression along the apical membrane, differential responses of Pit1 and Npt2b regulation to chronic versus dietary changes illustrates another layer of phosphate transport control. Finally, a major problem in patients with CKD is management of hyperphosphatemia. The present evidence suggests that targeting key regulatory pathways of intestinal phosphate transport may provide novel therapeutic approaches for patients with CKD.

Counteracting vasopressin-mediated water reabsorption by ATP, dopamine, and phorbol esters: mechanisms of action.

Water homeostasis is regulated by a wide variety of hormones. When in need for water conservation, vasopressin, released from the brain, binds renal principal cells and initiates a signaling cascade resulting in the insertion of aquaporin-2 (AQP2) water channels in the apical membrane and water reabsorption. Conversely, hormones, including extracellular purines and dopamine, antagonize AVP-induced water permeability, but their mechanism of action is largely unknown, which was investigated here. Addition of these hormones to mpkCCD cells decreased total and plasma membrane abundance of AVP-induced AQP2, partly by increasing its internalization to vesicles and lysosomal degradation. This internalization was ubiquitin dependent, because the hormones increased AQP2 ubiquitination, and the plasma membrane localization of AQP2-K270R, which cannot be monoubiquitinated, was unaffected by these hormones. Both hormones also increased AQP2 phosphorylation at S261, which followed ubiquitination, but was not essential for hormone-induced AQP2 degradation. A similar process occurs in vivo, as incubation of dDAVP-treated kidney slices with both hormones also resulted in the internalization and S261 phosphorylation of AQP2. Both hormones also reduced cAMP and AQP2 mRNA levels, suggesting an additional effect on AQP2 gene transcription. Interestingly, phorbol esters only reduced AQP2 through the first pathway. Together, our results indicate that ATP and dopamine counteract AVP-induced water permeability by increasing AQP2 degradation in lysosomes, preceded by ubiquitin-dependent internalization, and by decreasing AQP2 gene transcription by reducing the AVP-induced cAMP levels.

Regulation of renal NaCl transport by nitric oxide, endothelin, and ATP: clinical implications.

NaCl absorption along the nephron is regulated not just by humoral factors but also by factors that do not circulate or act on the cells where they are produced. Generally, nitric oxide (NO) inhibits NaCl absorption along the nephron. However, the effects of NO in the proximal tubule are controversial and may be biphasic. Similarly, the effects of endothelin on proximal tubule transport are biphasic. In more distal segments, endothelin inhibits NaCl absorption and may be mediated by NO. Adenosine triphosphate (ATP) inhibits sodium bicarbonate absorption in the proximal tubule, NaCl absorption in thick ascending limbs via NO, and water reabsorption in collecting ducts. Defects in the effects of NO, endothelin, and ATP increase blood pressure, especially in a NaCl-sensitive manner. In diabetes, disruption of NO-induced inhibition of transport may contribute to increased blood pressure and renal damage. However, our understanding of how NO, endothelin, and ATP work, and of their role in pathology, is rudimentary at best.

Dysregulation of epithelial Na+ absorption induced by inhibition of the kinases TORC1 and TORC2.

BACKGROUND AND PURPOSE: Although the serum and glucocorticoid-inducible protein kinase 1 (SGK1) appears to be involved in controlling epithelial Na(+) absorption, its role in this physiologically important ion transport process is undefined. As SGK1 activity is dependent upon target of rapamycin complex 2 (TORC2)-catalysed phosphorylation of SGK1-Ser(422) , we have explored the effects of inhibiting TORC2 and/or TORC1 upon the hormonal control of Na(+) absorption. EXPERIMENTAL APPROACH: Na(+) absorption was quantified electrometrically in mouse cortical collecting duct cells (mpkCCD) grown to confluence on permeable membranes. Kinase activities were assessed by monitoring endogenous protein phosphorylation, with or without TORC1/2 inhibitors (TORIN1 and PP242) and the TORC1 inhibitor: rapamycin. KEY RESULTS: Inhibition of TORC1/2 (TORIN1, PP242) suppressed basal SGK1 activity, prevented insulin- and dexamethasone-induced SGK1 activation, and caused modest (10-20%) inhibition of basal Na(+) absorption and substantial (∼80%) inhibition of insulin/dexamethasone-induced Na(+) transport. Inhibition of TORC1 did not impair SGK1 activation or insulin-induced Na(+) transport, but did inhibit (∼80%) dexamethasone-induced Na(+) absorption. Arginine vasopressin stimulated Na(+) absorption via a TORC1/2-independent mechanism. CONCLUSION AND IMPLICATIONS: Target of rapamycin complex 2, but not TORC1, is important to SGK1 activation. Signalling via phosphoinositide-3-kinase/TORC2/SGK1 can explain insulin-induced Na(+) absorption. TORC2, but not TORC1, is also involved in glucocorticoid-induced SGK1 activation but its role is permissive. Glucocorticoid-induced Na(+) transport displayed a requirement for TORC1 activity. Therefore, TORC1 and TORC2 contribute to the regulation of Na(+) absorption. Pharmacological manipulation of TORC1/2 signalling may provide novel therapies for Na(+)-sensitive hypertension.

Negligible effect of oral garlic oil on the oral absorption of pyridoxine in metadoxine in rats.

Metadoxine [an ion-pair between pyridoxine and pyrrolidone carboxylate (PCA)] plus garlic oil treatment synergistically reduces alcoholic steatosis compared to each agent alone. We evaluated the effect of garlic oil on the pharmacokinetics of pyridoxine. After the oral administration of metadoxine, the total area under the plasma concentration-time curve from time zero to time infinity (AUC) and the peak plasma concentration (C(max)) of pyridoxine were significantly greater (by 40.6%) and higher (by 63.9%), respectively, than after oral administration of pyridoxine plus PCA. Oral metadoxine plus garlic oil also gave larger AUC (31.8%) and higher C(max) (64.9%) than pyridoxine plus PCA. However, garlic oil did not change the AUC or C(max) of pyridoxine in metadoxine. Thus, garlic oil does not enhance the metadoxine activity by affecting the absorption of pyridoxine.

Elevated Na+/K+-ATPase responses and its potential role in triggering ion reabsorption in kidneys for homeostasis of marine euryhaline milkfish (Chanos chanos) when acclimated to hypotonic fresh water.

The milkfish (Chanos chanos) is an economic species in Southeast Asia. In Taiwan, the milkfish are commercially cultured in environments of various salinities. Na(+)/K(+)-ATPase (NKA) is a key enzyme for fish iono- and osmoregulation. When compared with gills, NKA and its potential role were less examined by different approaches in the other osmoregulatory organs (e.g., kidney) of euryhaline teleosts. The objective of this study was to investigate the correlation between osmoregulatory plasticity and renal NKA in this euryhaline species. Muscle water contents (MWC), plasma, and urine osmolality, kidney histology, as well as distribution, expression (mRNA and protein), and specific activity of renal NKA were examined in juvenile milkfish acclimated to fresh water (FW), seawater (SW 35 per thousand), and hypersaline water (HSW 60 per thousand) for at least two weeks before experiments. MWC showed no significant difference among all groups. Plasma osmolality was maintained within the range of physiological homeostasis in milkfish acclimated to different salinities, while, urine osmolality of FW-acclimated fish was evidently lower than SW- and HSW-acclimated individuals. The renal tubules were identified by staining with periodic acid Schiff's reagent and hematoxylin. Moreover, immunohistochemical staining showed that NKA was distributed in the epithelial cells of proximal tubules, distal tubules, and collecting tubules, but not in glomeruli, of milkfish exposed to different ambient salinities. The highest abundance of relative NKA alpha subunit mRNA was found in FW-acclimated milkfish rather than SW- and HSW-acclimated individuals. Furthermore, relative protein amounts of renal NKA alpha and beta subunits as well as NKA-specific activity were also found to be higher in the FW group than SW and the HSW groups. This study integrated diverse levels (i.e., histological distribution, gene, protein, and specific activity) of renal NKA expression and illustrated the potential role of NKA in triggering ion reabsorption in kidneys of the marine euryhaline milkfish when acclimated to a hypotonic FW environment.

P2Y4-mediated regulation of Na+ absorption in the Reissner's membrane of the cochlea.

The epithelial cells of Reissner's membrane (RM) are capable of transporting Na(+) out of endolymph via epithelial Na(+) channel (ENaC). However, much remains to be known as to mechanism of regulation of Na(+) absorption in RM. We investigated P2Y signaling as a possible regulatory mechanism of ENaC in gerbil RM using voltage-sensitive vibrating probe technique and immunohistochemistry. Results showed that UTP induced partial inhibition of the amiloride-sensitive short-circuit current but did not change short-circuit current when applied in the presence of amiloride. The inhibitory effect of UTP was not completely reversible in minutes. The response to UTP was inhibited by reactive blue-2 and 2',3'-O-(4-benzoylbenzoyl)adenosine 5'-triphosphate but not by suramin or pyridoxalphosphate-6-azophenyl-2', 4'-disulfonic acid, which indicates this P2Y receptor as the P2Y(4) subtype. The phospholipase C (PLC) inhibitors 1-[6[[(17beta)-3-methoxyestra-1,3,5(10)-trien-17-yl]amino]hexyl]-1H-pyrrole-2,5-dione and 1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine markedly inhibited the effect of UTP on ENaC. In contrast, neither modulation of protein kinase C nor application of 2-aminoehoxydiphenyl borate affected P2Y(4)-mediated inhibition of ENaC. Immunoreactive staining for P2Y(4) was observed in the RM, apical membrane of stria vascularis, spiral ligament, and organ of Corti, including outer hair cell, inner hair cell, outer pillar cell, Deiters' cell, and Hensen cell. These results suggest that the physiological role of P2Y(4) receptor in RM is likely to regulate Na(+) homeostasis in the endolymph. The acute inhibition of ENaC activity by activation of P2Y(4) receptor is possibly mediated by decrease of phosphatidylinositol 4,5-biphosphate in the plasma membrane through PLC activation.

Computational prediction of local drug effect on carcinogenic acetaldehyde in the mouth based on in vitro/in vivo results of freely soluble L-cysteine.

BACKGROUND: The computational models for predicting oral drug absorption in humans using in vitro and in vivo data have been published. However, only a limited number of studies are available on the prediction of local drug efficacy in the mouth using computational models. AIM: The goal of this study was to develop a simulation model for prediction of drug amount and effect on carcinogenic acetaldehyde in the mouth. METHODS: The model was based partly on our previous studies in which we showed in vivo that l-cysteine-containing tablets can eliminate carcinogenic salivary acetaldehyde in the mouth during smoking. To develop as informative a model as possible, we also investigated whether a lower saliva pH (4.7) can affect the freely soluble l-cysteine dissolution rate and cysteine stability profile in the mouth, compared to the normal saliva pH of 7.4. RESULTS: Stability of the active drug is not pH dependent and thus users with normal, healthy saliva pH and those with lower pH can benefit from cysteine-containing products. The simulated saliva profiles of l-cysteine and acetaldehyde corresponded to the in vivo results. CONCLUSIONS: The model developed can be used as an alternative tool to obtain faster and cheaper answers on how freely soluble drugs affect local conditions in the mouth. Because tobacco smoke contains more than 60 carcinogenic compounds, the model developed can offer a new view in eliminating or reducing not only one toxic compound from smoke but also many others compounds using only one formulation containing various active compounds.

A claudin-4 modulator enhances the mucosal absorption of a biologically active peptide.

Biologics, such as peptides, proteins and nucleic acids, are emerging pharmaceuticals. Passage across the epithelium is the first step in the absorption of biologics. Tight junctions (TJ) function as seals between adjacent epithelial cells, preventing free movement of solutes across the epithelium. We previously found that modulation of a key TJ component, claudin-4, is a potent method to enhance jejunal absorption when we used dextran as a model drug and the C-terminal fragment of Clostridium perfringens enterotoxin (C-CPE) as a claudin-4 modulator. Here, we investigated whether the claudin-4 modulator enhances jejunal, nasal and pulmonary absorption of a biologics human parathyroid hormone derivative, hPTH(1-34). The claudin-4 modulator enhanced nasal but not jejunal and pulmonary absorption of hPTH(1-34). C-CPE is hydrophobic with low solubility of less than 0.3mg/ml, but deletion of 10 amino acids at the N-terminal of C-CPE increased its solubility by 30-fold. Moreover, the N-terminal truncated C-CPE bound to claudin-4, modulated the TJ-barrier and enhanced jejunal absorption of dextran. The N-terminal-truncated C-CPE also enhanced jejunal and pulmonary absorption of hPTH(1-34). This report is the first to indicate that a claudin-4 modulator may be a promising enhancer of the jejunal, pulmonary and nasal absorption of a peptide drug.

A novel administration route of edaravone--II: mucosal absorption of edaravone from edaravone/hydroxypropyl-beta-cyclodextrin complex solution including L-cysteine and sodium hydrogen sulfite.

We examined the pharmacokinetics of edaravone when edaravone/hydroxypropyl-beta-cyclodextrin (HPbetaCD) complex solution, including L-cysteine (L-Cys) and sodium hydrogen sulfite (SHS), was administered intravenously, rectally and via the oral mucosa. In oral mucosal administration, atomized edaravone/HPbetaCD complex solution that contained L-Cys and SHS was sprayed into the mouth of Wistar rats. Oral mucosal and rectal administration of edaravone/HPbetaCD complex solution that contained L-Cys and SHS was compared with that for edaravone/HPbetaCD complex solution without L-Cys and SHS. When edaravone 0.25-1.0 mg was administered intravenously, C(0) and AUC(0-60) were linear. In oral mucosal and rectal administration, C(max) and AUC(0-60) of edaravone/HPbetaCD with L-Cys and SHS were significantly higher than those of edaravone/HPbetaCD without L-Cys and SHS. On the other hand, bioavailability of oral mucosal, rectal and oral administration was about 100, 63.5 and 26.6%, respectively. This study suggested that L-Cys and SHS were useful for the oral mucosal and rectal administration of edaravone.

A stochastic model for transepidermal drug delivery.

BACKGROUND: Topical drug application has been widely used to manage skin diseases as well as to treat a variety of local and systemic disorders. To evaluate the efficiency of transepidermal drug delivery, an efficient model is needed to study the process of percutaneous transport. MODEL DESCRIPTION: A stochastic model based on Monte Carlo methods and Cellular Automata is presented in this work to study the molecular transport through the stratum corneum of the human skin, which is a typical process in transepidermal drug delivery. METHODS: To validate the model, an in vitro experiment on percutaneous absorption of radioactive 17beta-estradiol was performed. RESULTS AND DISCUSSION: The simulation results agree with the experimental data. CONCLUSION: The use and power of the presented approach in studying the process of transepidermal drug delivery were demonstrated.