Exploring high pressure nebulization of Pluronic F127 hydrogels for intraperitoneal drug delivery.

Peritoneal metastasis is an advanced cancer type which can be treated with pressurized intraperitoneal aerosol chemotherapy (PIPAC). Here, chemotherapeutics are nebulized under high pressure in the intraperitoneal (IP) cavity to obtain a better biodistribution and tumor penetration. To prevent the fast leakage of chemotherapeutics from the IP cavity, however, nebulization of controlled release formulations is of interest. In this study, the potential of the thermosensitive hydrogel Pluronic F127 to be applied by high pressure nebulization is evaluated. Therefore, aerosol formation is experimentally examined by laser diffraction and theoretically simulated by computational fluid dynamics (CFD) modelling. Furthermore, Pluronic F127 hydrogels are subjected to rheological characterization after which the release of fluorescent model nanoparticles from the hydrogels is determined. A delicate equilibrium is observed between controlled release properties and suitability for aerosolization, where denser hydrogels (20% and 25% w/v Pluronic F127) are able to sustain nanoparticle release up to 30 h, but cannot effectively be nebulized and vice versa. This is demonstrated by a growing aerosol droplet size and exponentially decreasing aerosol cone angle when Pluronic F127 concentration and viscosity increase. Novel nozzle designs or alternative controlled release formulations could move intraperitoneal drug delivery by high pressure nebulization forward.

Pharmacokinetics, tissue distribution and peritoneal retention of Ag2S quantum dots following intraperitoneal administration to mice.

OBJECTIVES: To investigate the pharmacokinetics, biodistribution and peritoneal retention of Ag2S quantum dots (Qds) after intraperitoneal (IP) injection into mice and to compare the results with those reported for the intravenous (IV) injection of these particles. METHODS: Ag2S Qds was prepared by a simple one-step co-precipitation method and was injected intraperitoneally into mice. Six animals were sacrificed at predetermined time points, and blood, peritoneal content and tissue samples were collected. Ag concentration that represents the concentration of Qds was analysed by atomic absorption spectrophotometry. KEY FINDINGS: Detectability of Qds in the peritoneal sample up to 2 h indicated that, compared with small drug molecules, the absorption of Ag2S Qds from the peritoneal cavity occurred at a slower rate. The AUC tissue/AUC blood ratio in the liver and intestine after IP injection (0.55 and 0.98, respectively) was considerably lower than those for the bolus injection (217 and 94, respectively), while this ratio in the spleen and lungs was markedly higher than the IV route. CONCLUSIONS: Overall, the obtained results suggest that IP injection of Ag2S Qds could be more effective for drug delivery to/imaging of the spleen and lungs, whereas the IV injection for the drug delivery to/imaging of the liver and intestine.

Importance of particle size of oligomannose-coated liposomes for induction of Th1 immunity.

Oligomannose-coated liposomes (OMLs) comprised of dipalmitoylphosphatidylcholine, cholesterol and Man3-DPPE at a molar ratio of 1:1:0.1 and particle diameters of about 1000 nm can induce liposome-encased antigen-specific strong Th1 immunity. In this study, we evaluated the effect of particle sizes of OMLs on induction of Th1 immune responses in mice. Spleen cells obtained from mice immunized with antigen-encapsulating OMLs with 1000- and 800-nm diameters secreted remarkably high levels of IFN-γ upon in vitro stimulation. In addition, sera of mice that received these OMLs had significantly higher titers of antigen-specific IgG2a than those of IgG1, which are commonly associated with Th1 responses. In contrast, treatment with antigen-encapsulating OMLs with 400- and 200-nm diameters failed to induce IFN-γ secretion from spleen cells, although these OMLs did elicit elevation of antigen-specific IgGs. In addition, the titers of serum antigen-specific IgG2a were the same as those of IgG1 in mice that received 400-nm OMLs. Resident peritoneal mononuclear phagocytes (MNPs) treated with OMLs of diameter ≥ 600 nm secreted IL-12, which is essential for induction of Th1 immune responses, while those treated with OMLs of ≤ 400 nm failed to produce this cytokine. However, 400-nm OMLs did induce enhanced expression of MHC class II and costimulatory molecules on MNPs, similarly to OMLs of ≥ 600 nm. Taken together, these results strongly indicate that OMLs of diameter ≥ 600 nm are required to induce Th1 immune responses against OML-encased antigens, although OMLs of diameter ≤ 400 nm can activate MNPs.

MMP-7 affects peritoneal ultrafiltration associated with elevated aquaporin-1 expression via MAPK/ERK pathway in peritoneal mesothelial cells.

Peritoneal membrane dysfunction and the resulting ultrafiltration failure are the major disadvantages of long-term peritoneal dialysis (PD). It becomes increasingly clear that mesothelial cells play a vital role in the pathophysiological changes of the peritoneal membrane. Matrix metalloproteinases (MMPs) function in the extracellular environment of cells and mediate extracellular matrix turnover during peritoneal membrane homeostasis. We showed here that dialysate MMP-7 levels markedly increased in the patients with PD, and the elevated MMP-7 level was negatively associated with peritoneal ultrafiltration volume. Interestingly, MMP-7 could regulate the cell osmotic pressure and volume of human peritoneal mesothelial cells. Moreover, we provided the evidence that MMP-7 activated mitogen-activated protein kinases (MAPKs)-extracellular signal-regulated kinase 1/2 (ERK) pathway and subsequently promoted the expression of aquaporin-1 (AQP-1) resulting in the change of cell osmotic pressure. Using a specific inhibitor of ERK pathway abrogated the MMP-7-mediating AQP-1 up-regulation and cellular homeostasis. In summary, all the findings indicate that MMP-7 could modulate the activity of peritoneal cavity during PD, and dialysate MMP-7 might be a non-invasive biomarker and an alternative therapeutic target for PD patients with ultrafiltration failure.

A Syndrome of Apparent Renal Failure.

Pseudo-azotemia is the syndrome of hypercreatininemia and hyperkaliemia without a change in glomerular filtration rate or structure of the kidney. A 57-year-old vulnerable woman with learning difficulties experienced an intraperitoneal bladder rupture in the absence of a pelvic fracture after a fall. It is suspected that the blunt force compression of a distended bladder situated above the bony protection of the pelvis resulted in delayed intraperitoneal bladder rupture. Urinary ascites resulted in pseudo-azotemia because of urinary creatinine reabsorption across the peritoneum. This "apparent" renal failure is fully reversible when diagnosis and treatment are prompt, with normalization of abnormal laboratory-investigation results often within 24 hours.

Glucose absorption from peritoneal dialysate is associated with a gain in fat mass and a reduction in lean body mass in prevalent peritoneal dialysis patients.

The majority of peritoneal dialysates use glucose to generate an osmotic gradient for the convective removal of water and Na. Although glucose can potentially be absorbed, previous studies have failed to establish whether this leads to increased fat weight gain. We measured body composition using bioimpedance in peritoneal dialysis (PD) patients, electively starting PD, attending for their first assessment of peritoneal membrane function after 2-3 months, and then after 12 months. We studied 143 patients: eighty-nine (62·2 %) males, fifty-three (37·1 %) diabetics, mean age 61·3 (SD 14·9) years, with ninety (62·1 %) patients treated by automated PD cyclers with a daytime icodextrin exchange and thirty-seven (25·9 %) by continuous ambulatory PD. Median fat mass increased by 1·8 (-0·5 to 4·1) kg, whereas fat-free mass fell -1·3 (-2·9 to 1·0) kg, and the increase in fat mass was negatively associated with the fall in soft lean mass (r -0·41, P < 0·001). Increased fat mass was associated with measured peritoneal glucose absorption (r 0·69, P < 0·001), and glucose absorption was associated with the amount of 22·7 g/l glucose dialysate (OR 2·0, 95 % CI 1·5, 2·5, P < 0·001), peritoneal urea clearance (OR 9·5, 95 % CI 2·4, 37·1, P = 0·001) and male sex (OR 4·8, 95 % CI 1·5, 14·9, P = 0·008). We report an observational study in prevalent PD patients following body composition from their first assessment of PD membrane function for approximately 12 months, and despite the majority of patients prescribed icodextrin, we have demonstrated not only an association between intra-peritoneal glucose absorption and fat weight gain but also loss of fat-free mass.

Evaluation of the distribution of nicotine intravenous injection: an adult autopsy case report with a review of literature.

We reported the first comprehensive autopsy case of death due to intravenous injection of nicotine. We examined the distribution of nicotine in the body tissues and fluid and exposed the pathophysiology of nicotine poisoning. A 19-year-old woman was rushed to the hospital in cardiorespiratory arrest and was confirmed dead upon arrival. Liquid nicotine, hydrogen peroxide water, and a syringe were found in the hotel room where she stayed. On autopsy, nicotine concentration was the highest (15,023 µg/mg) in the tissue around the injection mark on the right upper arm. Among the body fluids, the intraperitoneal fluid had the highest, whereas the pericardial fluid had the lowest (0.736 µg/mL) nicotine concentration. Among the organs, the brain had the highest (11.637 µg/mg), whereas the fat tissue had the lowest (1.307 µg/mg) nicotine concentration. The concentration of cotinine, which is the metabolite of nicotine, was the highest in the tissue around the injection mark on the right arm (5.495 µg/mg) and was almost the same among the other body fluids and organs. The respective concentrations of nicotine and cotinine were 1.529 µg/mL and 0.019 µg/mL in the left heart blood and 3.157 µg/mL and 0.002 µg/mL in right heart blood. In this case, the nicotine concentrations in blood reached the lethal level. The distributions of nicotine and cotinine, as indicated by the intravenous injection, were related to the distribution of organs that metabolize nicotine and the distribution of nicotinic acetylcholine receptors.

Free Water Transport and Its Association with Cardiovascular Status in Children on Peritoneal Dialysis.

Background:Volume overload is one of the most important factors associated with left ventricular hypertrophy (LVH) and cardiovascular disease in chronic peritoneal dialysis (PD) patients. MiniPET is a reliable tool to evaluate free water transport (FWT). In a clinical setting, the significance of FWT has not been evaluated in terms of outcome in children on PD. The objective was to define a FWT value of clinical significance in children on PD, fixing its relationship to left ventricular mass index (LVMI) as a well-known outcome parameter.Methods:MiniPET was performed with 3.86% glucose, 1-h long, to measure FWT in PD patients > 6 years old. An echocardiogram (ECG) was performed within 2 months of the MiniPET. Left ventricular hypertrophy was defined as LVMI ≥ 38.6 g/height2.7 (95th percentile). Receiver operating characteristic curve (ROC) analysis was used to determine the cut-off value of FWT searching the highest sensitivity and specificity to differentiate patients with normal/abnormal LVMI. A p < 0.05 was considered significant.Results:Forty-six studies were performed on 32 patients, 16 males; mean age 11.59 ± 3.07 years. Mean normalized FWT (nFWT) was 144.4 ± 84.8 mL/m2, corresponding to 46.7% of total ultrafiltration. Mean LVMI was 42 ± 11.3 g/m2.7 with a negative correlation to nFWT (p < 0.01). Eighteen out of 32 patients had LVH. The ROC analysis (nFWT vs LVMI) showed an area under the curve of 0.71 (95% confidence interval [CI], 0.53 - 0.89; p = 0.04), allowing a cut-off nFWT value of 110 mL/m2 to be defined, dividing the population into 2 groups of patients according to the LVMI cut-off value of 38,6 g/m2.7.Conclusions:The nFWT showed an inverse correlation to LVMI. A nFWT value < 110 mL/m2 was significantly associated with LVH. The negative relationship observed between nFWT and LVMI, and the cut-off level for nFWT according to the 95th percentile of LVMI, suggest that the regular evaluation of nFWT could become a useful tool in assessing the capacity of PD treatment to keep patients' volume status under control, avoiding cardiovascular impairment.

Interleukin-13 and its signaling pathway is associated with obesity-related colorectal tumorigenesis.

The incidence of colorectal cancer (CRC) has been on the rise, which is linked to the increasing prevalence of obesity, based on global epidemiological evidence. Although chronic inflammation is implicated in tumor development, the mechanisms underlying obesity-associated CRC remain unknown. Here, we sought to identify the inflammatory cytokines and their roles in obesity-related colorectal tumorigenesis using cytokine array analyses in a mouse model. Colorectal tumorigenesis was induced through i.p. injection of azoxymethane once a week for 6 weeks in 6-week-old female WT C57Black/6J mice and the obesity diabetes model mouse KK/TaJcl, KK-Ay/TaJcl. The formation of aberrant crypt foci and colorectal tumors were more frequent in obese mice compared with WT mice, and both serum interleukin (IL)-13 and IL-13 receptor (R) expression in the normal intestinal mucosal epithelium were significantly increased in the obese mice. Furthermore, addition of IL-13 to a human CRC cell line and a human colon organoid culture altered the phenotype of intestinal epithelial cells. Knockdown experiments further revealed that IL-13Rα1 dominantly induced mucosal proliferation. Collectively, These results suggest an association between anti-inflammatory cytokines and colorectal carcinogenesis, and provide new research directions for cancer prevention strategies. In particular, inflammation provoked by obesity, notably by increased expression of the cytokine IL-13, could play an important role in the carcinogenesis of obesity-related CRC.

Fluid Tonicity Affects Peritoneal Characteristics Derived by 3-Pore Model.

Background:It is typically assumed that within short time-frames, patient-specific peritoneal membrane characteristics are constant and do not depend on the initial fluid tonicity and dwell duration. The aim of this study was to check whether this assumption holds when membrane properties are estimated using the 3-pore model (3PM).Methods:Thirty-two stable peritoneal dialysis (PD) patients underwent 3 8-hour peritoneal equilibration tests (PETs) with different glucose-based solutions (1.36%, 2.27%, and 3.86%). Temporary drainage was performed at 1 and 4 hours. Glucose, urea, creatinine, sodium, and phosphate concentrations were measured in dialysate and blood samples. Three-pore model parameters were estimated for each patient and each 8-hour PET separately. In addition, model parameters were estimated using data truncated to the initial 4 hours of peritoneal dwell.Results:In all cases, model-estimated parameter values were within previously reported ranges. The peritoneal absorption (PA) and diffusive permeability for all solutes except sodium increased with fluid tonicity, with about 18% increase when switching from glucose 2.27% to 3.86%. Glucose peritoneal reflection coefficient and osmotic conductance (OsmCond), and fraction of hydraulic conductance for ultrasmall pores decreased with fluid tonicity (over 40% when switching from glucose 1.36%). Model fitting to the truncated 4-hour data resulted in little change in the parameters, except for PA, peritoneal hydraulic conductance, and OsmCond, for which higher values for the 4-hour dwell were found.Conclusion:Initial fluid tonicity has a substantial impact on the 3PM-estimated characteristics of the peritoneal membrane, whereas the impact of dwell duration was relatively small and possibly influenced by the change in the patient's activity.

Hyperthermic intraperitoneal chemotherapy with oxaliplatin for peritoneal carcinomatosis: a clinical pharmacological perspective on a surgical procedure.

Cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (HIPEC) has become the standard of care in the treatment of patients with peritoneal carcinomatosis of colorectal origin. The use of oxaliplatin for HIPEC has gained popularity. Although the HIPEC procedure is adopted throughout the world, major differences exist between treatment protocols regarding the carrier solution, perfusate volume, use of an open or closed technique, duration of the perfusion and application of additional flushing. These differences can influence the pharmacokinetics and pharmacodynamics of oxaliplatin and might thereby have an impact on the efficacy and/or safety of the treatment. Clinicians should be aware of the clinical importance of oxaliplatin pharmacology when performing HIPEC surgery. This review adds new insights into the complex field of the pharmacology of HIPEC and highlights an important worldwide problem: the lack of standardization of the HIPEC procedure.

Peritoneal lavage with povidone-iodine solution in colorectal cancer-induced rats.

BACKGROUND: Although peritoneal lavage with povidone-iodine (PVPI) is frequently performed after surgery on the gastrointestinal tract, the effects of PVPI on the intestinal epithelial barrier are unknown. The purpose of this study was to investigate the effects of abdominal irrigation with PVPI on the intestinal epithelial barrier in a colorectal cancer (CRC)-induced rat model. MATERIALS AND METHODS: The CRC model was induced in rats with azoxymethane and dextran sodium sulfate. Next, a total of 24 male CRC-induced rats were randomly divided into three groups (n = 8): (1) a sham-operated group, (2) an NS group (peritoneal lavage 0.9% NaCl), and (3) a PVPI group (peritoneal lavage with 0.45%-0.55% PVPI). The mean arterial pressure was continuously monitored throughout the experiment. The levels of plasma endotoxin and D-lactate, blood gases, and protein concentration were measured. The ultrastructural changes of the epithelial tight junctions were observed by transmission electron microscopy. RESULTS: The mean arterial pressure after peritoneal lavage was lower in the PVPI group than that in the NS group. The protein concentration and levels of endotoxin and D-lactate were higher in the PVPI group than they were in the PVPI group. In addition, PVPI treatment resulted in a markedly severe metabolic acidosis and intestinal mucosal injury compared with NS rats. CONCLUSIONS: Peritoneal lavage with PVPI dramatically compromises the integrity of the intestinal mucosa barrier and causes endotoxin shock in CRC rats. It is unsafe for clinical applications to include peritoneal lavage with PVPI in colorectal operations.

Metabolic map of osthole and its effect on lipids.

1. Osthole, a coumarin compound from plants, is a promising agent for the treatment of metabolic diseases, including hyperglycemia, fatty liver, and cancers. Studies indicate that the peroxisome proliferator-activated receptors (PPAR) α and γ are involved in the pharmacological effects of osthole. The in vitro and in vivo metabolism of osthole and its biological activity are not completely understood. 2. In this study, ultra-performance chromatography electrospray ionization quadrupole time-of-flight mass spectrometry (UPLC-ESI-QTOFMS)-based metabolomics was used to determine the metabolic pathway of osthole and its influence on the levels of endogenous metabolites. Forty-one osthole metabolites, including 23 novel metabolites, were identified and structurally elucidated from its metabolism in vitro and in vivo. Recombinant cytochrome P450s (CYPs) screening showed that CYP3A4 and CYP3A5 were the primary enzymes contributing to osthole metabolism. 3. More importantly, osthole was able to decrease the levels of lysophosphatidylethanolamine (LPE) and lysophosphatidylcholine (LPC) in the plasma, which explains in part its modulatory effects on metabolic diseases. 4. This study gives the insights about the metabolic pathways of osthole in vivo, including hydroxylation, glucuronidation, and sulfation. Furthermore, the levels of the lipids regulated by osthole indicated its potential effects on adipogenesis. These data contribute to the understanding of the disposition and pharmacological activity of osthole in vivo.

P.L.E.A.T.-Preventing Lymphocele Ensuring Absorption Transperitoneally: A Robotic Technique.

OBJECTIVE: To reduce the risk of symptomatic lymphocele after robotic pelvic lymph node dissection (PLND), we present a technique, preventing lymphocele ensuring absorption transperitoneally (P.L.E.A.T.), where the peritoneum is "pleated" along its midline, leaving 2 lateral openings and allowing lymphatic fluid to drain away from the pelvis and into the abdomen. MATERIALS AND METHODS: We analyzed a single-surgeon series of PLNDs during robotic radical prostatectomy, comparing 195 "standard" PLNDs (in which the peritoneum was "re-approximated" or left completely open) with 176 cases in which P.L.E.A.T. was performed. RESULTS: In the group without P.L.E.A.T., 8 cases of symptomatic (grade ≥3, according to the Clavien-Dindo Classification) lymphoceles (4.1%) were recorded. Only 1 patient in the P.L.E.A.T. group complained of symptoms because of a lymphocele (P = .039). No patient reported complications because of the procedure. CONCLUSION: The P.L.E.A.T. technique is a fast, easy-to-perform, and safe method of reducing the risk of symptomatic lymphocele after transperitoneal robotic PLND.

High Mobility Group Box-1 Protein and Outcomes in Critically Ill Surgical Patients Requiring Open Abdominal Management.

Background. Previous studies assessing various cytokines in the critically ill/injured have been uninformative in terms of translating to clinical care management. Animal abdominal sepsis work suggests that enhanced intraperitoneal (IP) clearance of Damage-Associated Molecular Patterns (DAMPs) improves outcome. Thus measuring the responses of DAMPs offers alternate potential insights and a representative DAMP, High Mobility Group Box-1 protein (HMGB-1), was considered. While IP biomediators are being recognized in critical illness/trauma, HMGB-1 behaviour has not been examined in open abdomen (OA) management. Methods. A modified protocol for HMGB-1 detection was used to examine plasma/IP fluid samples from 44 critically ill/injured OA patients enrolled in a randomized controlled trial comparing two negative pressure peritoneal therapies (NPPT): Active NPPT (ANPPT) and Barker's Vacuum Pack NPPT (BVP). Samples were collected and analyzed at the time of laparotomy and at 24 and 48 hours after. Results. There were no statistically significant differences in survivor versus nonsurvivor HMGB-1 plasma or IP concentrations at baseline, 24 hours, or 48 hours. However, plasma HMGB-1 levels tended to increase continuously in the BVP cohort. Conclusions. HMGB-1 appeared to behave differently between NPPT cohorts. Further studies are needed to elucidate the relationship of HMGB-1 and outcomes in septic/injured patients.

High Penetration of Paclitaxel in Abdominal Wall of Rabbits after Hyperthermic Intraperitoneal Administration of Nab-Paclitaxel Compared to Standard Paclitaxel Formulation.

PURPOSE: Paclitaxel (PTX) is currently used in combination with cisplatin for Hyperthermic Intraperitoneal Chemotherapy (HIPEC) for the treatment of peritoneal carcinomatosis. Albumin-bound PTX is a promising new drug for HIPEC because of its easy solubility in aqueous perfusion medium and possibly because of the tendency of albumin to cross physiological barriers and accumulate in tumor tissue. METHODS: We tested the feasibility of using nab-paclitaxel in rabbits treated by HIPEC for 60 min compared with the classical formulation at an equivalent PTX dose. Samples of perfusate and blood were collected at different time points and peritoneal tissues were collected at the end of perfusion. PTX concentrations were determined by HPLC. The depth of paclitaxel penetration through the peritoneal barrier was assessed by mass spectrometry imaging. RESULTS: PTX after nab-paclitaxel treatment penetrated up to 0.63 mm in the peritoneal wall, but after CRE-paclitaxel, it was not detectable in the peritoneum. Moreover, the peritoneal concentration after nab-paclitaxel was five times that after paclitaxel classical formulation. Despite the high levels reached in the peritoneum, systemic exposure of PTX was low. CONCLUSIONS: Our results show that nab-paclitaxel penetrates into the abdominal wall better than CRE-paclitaxel, in terms of effective penetration and peritoneal tissue concentration.

AVN-322 is a Safe Orally Bio-Available Potent and Highly Selective Antagonist of 5-HT6R with Demonstrated Ability to Improve Impaired Memory in Animal Models.

BACKGROUND: In recent years, 5-hydroxytryptamine subtype 6 receptor (5-HT6 receptor, 5- HT6R) has emerged as a promising therapeutic target for the treatment of neuropathological disorders, including Alzheimer's disease (AD) and schizophrenia. 5-HT6 receptors were hypothesized to be implicated in the processes of learning, memory, and cognition with 5-HT6R antagonists being effective in animal models of cognition and memory impairment. Several selective 5-HT6R ligands are currently undergoing clinical trials for treatment of AD. METHODS: We describe results of preclinical development of a novel and highly selective and potent 5- HT6R antagonist, AVN-322, as a clinical candidate for the treatment of AD to improve concurrent debilitation of memory and cognition in the AD patients, and schizophrenia as a substance with antipsychotic effect. In the manuscript, we present its in vitro and vivo efficacy, ADME, pharmacokinetics in animals and in humans, and toxicity. RESULTS: While having high binding affinity in medium picomolar range, the lead compound demonstrates substantially better selectivity index then the reference drug candidates currently being tested in clinical studies. AVN-322 showed high oral bioavailability and favorable blood-brain barrier (BBB) penetration. In vivo testing revealed its clear cognition enhancing effect. AVN-322 significantly restored both scopolamine- and MK-801-induced cognitive dysfunction and demonstrated antipsychotic potential. CONCLUSION: Taking into account its good safety profile and favorable pharmacokinetics, AVN-322 can be reasonably considered as a novel drug candidate for the treatment of neurological disorders such as AD and/or schizophrenia.

In vitro intestinal permeability studies, pharmacokinetics and tissue distribution of 6-methylcoumarin after oral and intraperitoneal administration in Wistar rats

ABSTRACT 6-Methylcoumarin (6MC) is a semisynthetic coumarin with important in vitro and in vivo anti-inflammatory activity. In order to continue the pre-clinical characterization of this molecule, in vitro intestinal permeability, plasma profile and tissue distribution after oral administration in rats were studied. The permeability of 6MC was evaluated by the Caco-2 cellular model in both the apical-basal (A-B) and basal-apical (B-A) directions. The pharmacokinetics and biodistribution were evaluated in rats after oral and intraperitoneal administration at doses of 200 mg/kg. Transport experiments with Caco-2 cells showed that 6MC presented high permeability at all concentrations evaluated. This finding suggested that 6MC could be transported across the gut wall by passive diffusion. The plasma concentration-time curve showed that the maximum concentration (Cmax) was 17.13 ± 2.90 µg/mL at maximum time (Tmax) of 30 min for the oral route and Cmax 26.18 ± 2.47 µg/mL at 6.0 min for the intraperitoneal administration, with elimination constant of (Ke ) 0.0070 min-1 and a short life half time of (T1/2 ) lower that 120 min. The distribution study showed that 6MC has high accumulation in the liver, and widespread distribution in all the organs evaluated.

Concomitant bidirectional transport during peritoneal dialysis can be explained by a structured interstitium.

Clinical and animal studies suggest that peritoneal absorption of fluid and protein from dialysate to peritoneal tissue, and to blood and lymph circulation, occurs concomitantly with opposite flows of fluid and protein, i.e., from blood to dialysate. However, until now a theoretical explanation of this phenomenon has been lacking. A two-phase distributed model is proposed to explain the bidirectional, concomitant transport of fluid, albumin and glucose through the peritoneal transport system (PTS) during peritoneal dialysis. The interstitium of this tissue is described as an expandable two-phase structure with phase F (water-rich, colloid-poor region) and phase C (water-poor, colloid-rich region) with fluid and solute exchange between them. A low fraction of phase F is assumed in the intact tissue, which can be significantly increased under the influence of hydrostatic pressure and tissue hydration. The capillary wall is described using the three-pore model, and the conditions in the peritoneal cavity are assumed commencing 3 min after the infusion of glucose 3.86% dialysis fluid. Computer simulations demonstrate that peritoneal absorption of fluid into the tissue, which occurs via phase F at the rate of 1.8 ml/min, increases substantially the interstitial pressure and tissue hydration in both phases close to the peritoneal cavity, whereas the glucose-induced ultrafiltration from blood occurs via phase C at the rate of 15 ml/min. The proposed model delineating the phenomenon of concomitant bidirectional transport through PTS is based on a two-phase structure of the interstitium and provides results in agreement with clinical and experimental data.

In Vivo Feasibility of Electrostatic Precipitation as an Adjunct to Pressurized Intraperitoneal Aerosol Chemotherapy (ePIPAC).

BACKGROUND: Intraperitoneal chemotherapy is limited by tissue penetration. Pressurized intraperitoneal aerosol chemotherapy (PIPAC) has been shown to improve drug uptake by utilizing the physical properties of gas and pressure. This study investigated the effect of adding electrostatic precipitation to further enhance the pharmacologic properties of this technique. METHODS: A comparative study was performed using an in vivo porcine model. There were 3 cases in each group, PIPAC and electrostatic precipitation pressurized intraperitoneal aerosol chemotherapy (ePIPAC), plus 1 negative control comparing intraperitoneal distribution and tissue uptake of 2 tracer substances (toluidine blue and DT01). Tracer uptake was determined by measuring DT01 in tissue and peritoneal fluid at the end of each procedure. RESULTS: Electrostatic precipitation of the aerosol was technically feasible in all ePIPAC animals. The aerosol was cleared completely from the visual field within 15 s in the ePIPAC group versus 30 min in the PIPAC group. The peritoneal surface was homogeneously stained in both groups. After 30 min, 1.5 % remaining DT01 was measured in samples of ePIPAC-treated peritoneal fluid versus 15 % in PIPAC animals (p = 0.01). Tissue concentration was increased after ePIPAC versus PIPAC (p = 0.06). CONCLUSIONS: ePIPAC is technically feasible and improves tissue uptake of 2 tracer substances compared to PIPAC by up to tenfold. Intraperitoneal distribution was homogeneous in both groups. ePIPAC has the potential to allow more efficient drug uptake, further dose reduction, a significant shortening of the time required for PIPAC application, and improved health and safety measures.