Cost-effectiveness analysis of pressurized intraperitoneal aerosol chemotherapy (PIPAC) in patients with gastric cancer and peritoneal metastasis.

OBJECTIVE: The aim of this study was to assess the cost-effectiveness of pressurized intraperitoneal aerosol chemotherapy with low-dose cisplatin and doxorubicin (PIPAC C/D) for the treatment of advanced gastric cancer. METHODS: A Partitioned Survival Model followed by state transition Markov model was developed to estimate the costs and effectiveness of the use of PIPAC C/D versus palliative chemotherapy in the UK. The intervention was assessed at two different levels of care, including upfront therapy (PIPAC C/D plus Oxaliplatin in combination with Capecitabine (XELOX) chemotherapy versus first-line chemotherapy alone) and second-line therapy (PIPAC C/D alone versus second-line chemotherapy (ramucirumab monotherapy)). Data from multiple sources, including published literature and UK-based databases, were used to inform the economic model. RESULTS: For the upfront therapy analysis, the estimated total costs in the intervention and comparator arms were £32,606 (SD: £3877) and £17,844 (SD: £920), respectively. PIPAC C/D plus XELOX led to an increase of 0.46 in quality-adjusted life-years (QALYs) gained. The incremental cost per QALY gained was £31,868. For the second-line therapy analysis, the use of PIPAC C/D led to an increase of 0.19 in QALYs and a £21,474 reduction in costs, meaning the intervention was a dominant strategy. CONCLUSIONS: The cost-effectiveness results for the upfront therapy analysis indicate that PIPAC C/D plus chemotherapy is a cost-effective strategy. Additionally, PIPAC C/D alone as a second-line therapy has the potential to reduce costs and improve clinical outcomes for patients with advanced gastric cancer with peritoneal metastasis.

Lead (Pb) exposure induces physiological alterations in the serotoninergic and vasopressin systems causing anxiogenic-like behavior in Meriones shawi: Assessment of BDMC as a neuroprotective compound for Pb-neurotoxicity and kidney damages.

BACKGROUND: Studies have shown that lead (Pb) is one of hazardous heavy metals with various adverse effects on human health including mental health; Pb can induce psychiatric disorders like anxiety. In the present work, we examined the potential of bisdemethoxycurcumin (BDMC) as a neuroprotective agent against lead induced anxiety inMeriones shawi (M. shawi). METHODS: We asses, the potential of three consecutive day exposure to Pb (25 mg/kg body weight) in inducing anxiogenic effect, serotoninergic and vasopressinergic disruptions inM. shawi. This was done using neurobehavioral tests (open field, elevated plus maze), immunohistochemestry by anti-serotonin (5-HT), and anti-vasopressin (AVP) antibodies. We also measured the possible restorative potential of BDMC (30 mg/kg body weight), delivered by oral gavage. After that, a biochemical and histopathological studies were done. RESULTS: Our results showed that lead exposure for three consecutive days increases significantly the 5-HT-immunoreactivity in dorsal raphe nucleus (DRN) accompanied with a significant enhancement of AVP-immunoreactivity in the cell bodies and fibers in the supraoptic (SON) and paraventricular (PVN) nuclei of the hypothalamus. In the collecting tube, AVP binds to the V2 receptor of the epithelial cells and increases the water permeability. Our results showed clearly the epithelial cells degeneration after lead exposure, then we suggest that the increased AVP could be a response to the hydric balance disrupted after degenerative effect of lead exposure on epithelial cells. BDMC produced an anxiolytic effect in meriones. Moreover, it restored 5-HT and AVP immunoreactivity within studying nuclei. The biochemical and histopathological studies showed that Pb induced renal damages. In addition, BDMC restored the renal alterations. CONCLUSION: According to the obtained results, we suggest new pharmacological effects of BDMC; while it has an anxiolytic effect against Pb-induced anxiety by working on serotoninergic and vasopressinergic systems with an obvious restoration of the renal injuries induced by lead exposure.

Next-generation sequencing and histological response assessment in peritoneal metastasis from pancreatic cancer treated with PIPAC.

BACKGROUND: Peritoneal metastasis from pancreatic cancer (PM-PC) may be treated with repeated pressurised intraperitoneal aerosol chemotherapy (PIPAC). Utility of next-generation sequencing (NGS) to detect cancer-related mutations in peritoneal quadrant biopsies (QBs) and peritoneal fluid (PF) after systemic and PIPAC treatment has not been evaluated. Around 90% of pancreatic cancers (PCs) harbour a KRAS mutation, making PC ideal for the evaluation of this aspect. AIMS: Evaluation of PM-PC in terms of (1) histological response to PIPAC using Peritoneal Regression Grading Score (PRGS), (2) clinical characteristics and (3) frequency of mutations in QBs and PF before and after PIPAC. METHODS: Peritoneal QBs and PF were obtained prior to each PIPAC. NGS for 22 cancer-related genes was performed on primary tumours, QBs and PFs. Response was assessed by the four-tiered PRGS. RESULTS: Sixteen patients treated with a median of three PIPAC procedures were included. The mean PRGS was reduced from 1.91 to 1.58 (p=0.02). Fifty-seven specimens (13 primary tumours, 2 metastatic lymph nodes, 16 PFs and 26 QB sets) were analysed with NGS. KRAS mutation was found in 14/16 patients (87.50%) and in QBs, primary tumours and PF in 8/12 (66.67%), 8/13 (61.53%) and 6/9 (66.67%). The median overall survival was 9.9 months (SE 1.5, 95% CI 4.9 to 13.9). CONCLUSION: PIPAC induces histological response in the majority of patients with PM-PC. KRAS mutation can be found in PM-PC after PIPAC at a frequency similar to the primaries. NGS may be used to detect predictive mutations in PM-PC of various origins, also when only post-PIPAC QBs or PFs are available.

Pharmaco-molecular assessment of the effects of anandamide and its antagonists on hippocampal tissue in Wistar albino rats.

OBJECTIVE: The members of the matrix metalloproteinase (MMP) family and cannabinoids (CBs) are reportedly associated with hippocampus-dependent memory functions. However, the effects of endogenously formed CBs on hippocampal long-term potentiation remain unknown. The present study aimed to investigate the changes in the gene and protein expression levels of matrix metallopeptidase 9 (MMP-9), phosphatase and tensin homolog (PTEN), and NOTCH receptor 1 (NOTCH1) in rat hippocampal tissues treated with anandamide (AEA), AM251, 6-iodopravadolin (AM630), and N-[4-{[(3,4-Dimethyl-5-isoxazolyl)amino]sulfonyl}phenyl] (ML193). MATERIALS AND METHODS: The subjects were divided into 10 groups (n = five per group). The pharmaceuticals were administered via intraperitoneal injection once a day for seven days, except for the control group. The resected hippocampal tissues were then evaluated using a quantitative real-time polymerase chain reaction (RT-qPCR) and Western blot analysis. The data obtained were statistically analyzed, and p < 0.01 was considered statistically significant. RESULTS: Contrary to the literature, the changes in MMP-9 expression were not statistically significant, but the changes in PTEN and NOTCH1 were. The findings of this in vivo experimental study revealed that the agonists and antagonists acting on the CB system have significant molecular effects on hippocampal tissue. CONCLUSIONS: The changes in gene and protein expressions may be one of the reasons for the neurodegenerative processes observed in patients using these agonists and antagonists, whose effects on the CB system have not been fully explained yet. Our study can contribute to the literature as it is the first study investigating the MMP-9, PTEN and NOTCH1 gene and protein expression.

Severity assessment in mice subjected to carbon tetrachloride.

The Directive 2010/63 EU requires classifying burden and severity in all procedures using laboratory animals. This study evaluated the severity of liver fibrosis induction by intraperitoneal carbon tetrachloride (CCl4) injections in mice. 29 male C57BL/6N mice were treated three times per week for 4 weeks with an intraperitoneal injection (50 µl) of either 0.6 ml/kg body weight CCl4-vehicle solution, germ oil (vehicle-control) or handling only. Severity assessment was performed using serum analysis, behavioral tests (open field test, rotarod, burrowing and nesting behavior), fecal corticosterone metabolite (FCM) measurement, and survival. The most significant group differences were noticed in the second week of treatment when the highest AST (1463 ± 1404 vs. 123.8 ± 93 U/L, p < 0.0001) and nesting values were measured. In addition, respective animals showed lower moving distances (4622 ± 1577 vs. 6157 ± 2060 cm, p < 0.01) and velocity in the Open field, identified as main factors in principal component analysis (PCA). Overall, a 50% survival rate was observed within the treatment group, in which the open field performance was a good tracer parameter for survival. In summary, this study demonstrates the feasibility of assessing severity in mice using behavioral tests and highlight the open field test as a possible threshold parameter for risk assessment of mortality.

[The optimization and assessment of the method for inducing hyperuricemia in rats].

Objective: To explore an effective method for inducing a rat model with hyperuricemia in a short period and assess the effects of the model. Methods: Sprague-Dawley rats were adopted as donors and randomly divided into control group (CT group, n=6) and 5 model groups (M1-M5 groups, n=8 in each group). M1 group (gavage with 10 g/kg yeast extracts and 100 mg/kg adenine, twice per day, 300 mg/kg oxonic acid potassium by intraperitoneal injection, in the 7th day of model inducing), M2 group (gavage with 10 g/kg yeast extracts and 100 mg/kg adenine, twice per day, 300 mg/kg oxonic acid potassium by intraperitoneal injection, in the 1st, 3rd and 7th day of model inducing),M3 group (gavage with 10 g/kg yeast extracts and 100 mg/kg adenine, twice per day, 300 mg/kg oxonic acid potassium by intraperitoneal injection, once per day during the model inducing), M4 group (gavage with 20 g/kg yeast extracts and 100 mg/kg adenine, twice per day, 300 mg/kg oxonic acid potassium by intraperitoneal injection, once per day during the model inducing), M5 group (gavage with 30 g/kg yeast extracts and 100 mg/kg adenine, twice per day, 300 mg/kg oxonic acid potassium by intraperitoneal injection, once per day during the model inducing), and group CT (gavaged with equal volume sterilized water and intraperitoneal injected with normal saline according to the weight and at the same frequency as the model groups). The model inducing lasted for 7 days. After the inducing was finished, blood and 24-hour urine were sampled for uric acid and creatinine determination. Then rats were maintained for 2 weeks and blood and 24-hour urine samples were collected, the concentration of uric acid and creatinine were detected. The kidney and stomach were weighed,morphological changes in kidney were observed. Results: After model inducing, the body weight of rats in all model groups was lower than that of the control group (P＜0.01). Deaths occurred in all the rats with model treatments except M2. M4 and M5 groups were failed to be analyzed because of the high mortality, model 1 and 3 groups had 4 and 2 deaths, respectively. The uric acid levels in blood and urine of the model groups were significantly elevated (P＜ 0.01) at the end of model inducing. The model 2 group's blood uric acid was highest among the model groups (P＜0.05). It sustained a higher concentration than CT group in the three model groups after 2 weeks feeding (P＜0.05). The kidneys in model groups obviously swelling and were heavier than CT group (P＜0.01). The inflammation and structural damages were observed in kidneys of all model groups.Conclusion: The yeast extract (10 g/kg), adenine (100 mg/kg) gavage combined with intraperitoneal injections(the 1st, 3rd, 7th day during inducing) of potassium oxonate can be an rapid and effective method for inducing the rat model with hyperuricemia, which can be suggested to the related research.

Restricted access to innovative surgical technique related to a specific training, is it ethical? Example of the PIPAC procedure. A systematic review and an experts survey.

OBJECTIVE: Using the example of Pressurized Intra Peritoneal Aerosol Chemotherapy (PIPAC), we analyse the development model of this procedure and provide an ethical analysis of the involvement of the industry in a new development. SUMMARY BACKGROUND DATA: In the case of breakthrough innovation, medical training is essential for safe use of the new procedure. In some cases, pharmaceutical companies decide to organise this training. But when it becomes the only training opportunity to use the device, scientists and clinicians could be exposed to a conflict of interest? METHODS: We performed a literature review of PIPAC publications using the STROBE criteria. Then, we conducted interviews with an expert panel to analyse the ethical impact of involvement of the industry in the development of the PIPAC procedure. RESULTS: The number of publications has increased every year since the first publication in Germany, where the technology was developed in 2013. The scientific production was of good quality, with a mean STROBE score of 18.2 ± 2.4 out of 22 points. Ten of the 33 included studies declared a conflict of interest. From the interviews, the main axe concerning the implication of the industry was the training model. The company had decided that only trained and approval surgeon could perform the PIPAC procedure. All four interviewed practitioners agreed that it was initially a good way to implement the procedure safely, but later they felt uncomfortable about the control and validation by the industry. CONCLUSION: Based on the growing number of published papers from a growing number of international centres, the controlled training model is not limiting. However, the different levels of conflict of interest complicate transparency, and we postulated that this development model is limited to the beginning of the procedure diffusion. CLINICALTRIAL. GOV REGISTRATION: NCT04341337.

Efficacy Assessment of an Uncharged Reactivator of NOP-Inhibited Acetylcholinesterase Based on Tetrahydroacridine Pyridine-Aldoxime Hybrid in Mouse Compared to Pralidoxime.

(1) Background: Human exposure to organophosphorus compounds employed as pesticides or as chemical warfare agents induces deleterious effects due to cholinesterase inhibition. One therapeutic approach is the reactivation of inhibited acetylcholinesterase by oximes. While currently available oximes are unable to reach the central nervous system to reactivate cholinesterases or to display a wide spectrum of action against the variety of organophosphorus compounds, we aim to identify new reactivators without such drawbacks. (2) Methods: This study gathers an exhaustive work to assess in vitro and in vivo efficacy, and toxicity of a hybrid tetrahydroacridine pyridinaldoxime reactivator, KM297, compared to pralidoxime. (3) Results: Blood-brain barrier crossing assay carried out on a human in vitro model established that KM297 has an endothelial permeability coefficient twice that of pralidoxime. It also presents higher cytotoxicity, particularly on bone marrow-derived cells. Its strong cholinesterase inhibition potency seems to be correlated to its low protective efficacy in mice exposed to paraoxon. Ventilatory monitoring of KM297-treated mice by double-chamber plethysmography shows toxic effects at the selected therapeutic dose. This breathing assessment could help define the No Observed Adverse Effect Level (NOAEL) dose of new oximes which would have a maximum therapeutic effect without any toxic side effects.

Sedative and Anxiolytic Activities of Opuntia ficus indica (L.) Mill.: An Experimental Assessment in Mice.

Ethnobotanical field surveys revealed the use of fruits of Opuntia ficus indica (L.) Mill. for treating diabetes, burns, bronchial asthma, constipation, kidney stones, and rheumatic pains and as a sedative in Turkish folk medicine. This study aimed to verify the efficacy of the fruits of O. ficus indica experimentally and to define components responsible for the activity using bioassay-guided procedures. The crude methanolic extract of the fruits was sequentially fractionated into five subextracts: n-hexane, dichloromethane, ethyl acetate, n-butanol, and water. Further experiments were carried out on the most active subextract, that is, the ethyl acetate (EtOAc) subextract, which was further subjected to fractionation through successive column chromatographic applications on Sephadex LH-20. For activity assessment, each extract or fraction was submitted to bioassay systems; traction test, fireplace test, hole-board test, elevated plus-maze test, and open-field test were used for sedative and anxiolytic effects, and a thiopental-induced sleeping test was used for the hypnotic effect. Among the subextracts obtained from the methanolic extract, the EtOAc subextract showed significant sedative and anxiolytic effects in the bioassay systems. From the EtOAc subextract, major components were isolated, and their structures were determined as isorhamnetin, isorhamnetin 3-O-glucoside, isorhamnetin 3-O-rutinoside, and kaempferol 3-O-rutinoside using spectral techniques. In conclusion, this study confirmed the claimed use of the plant against anxiety in Turkish folk medicine.

Assessment of Insulin Tolerance In Vivo in Mice.

Insulin resistance in humans and mice is an important hallmark of metabolic diseases. Therefore, assessment of insulin sensitivity/resistance in animal models provides valuable information in the pathophysiology of diabetes and obesity. Depending on the nature of the information required, we can choose between direct and indirect techniques available for the determination of insulin sensitivity. Thus, the complex hyperinsulinemic-euglycemic glucose clamps and the insulin suppression test assess insulin-mediated glucose utilization under steady-state conditions, whereas less complex methods, such as the insulin tolerance test (ITT), rely on measurements of blood glucose levels in animals subjected to intraperitoneal insulin loading. Finally, surrogated indexes derived from blood glucose and plasma insulin levels are also available for assessment of insulin sensitivity/resistance in vivo. In this chapter, we focus on the intraperitoneal insulin tolerance test (IPITT) protocol for measuring insulin resistance in mice.

Assessment of mesenchymal stem cell effect on foreign body response induced by intraperitoneally implanted alginate spheres.

Foreign body response to implanted hydrogels and consequently fibrotic overgrowth on implanted spheres will decrease in vivo performance of these biomaterials. Considering the previous reports related to the immune-privileged properties of mesenchymal stem cells (MSCs), we hypothesized that encapsulated human placenta-derived MSCs (HP-MSCs) will mitigate the foreign body response against alginate hydrogels. The HP-MSC-laden alginate hydrogel was cross-linked with a CaCl2 solution. Morphological and mechanical properties of alginate spheres were determined by scanning electron microscopy imaging, degradation, and swelling tests. The HP-MSC-laden alginate spheres or cell-free spheres were implanted into the peritoneal cavity of BALB/c mice. After intraperitoneal implantation of spheres into BALB/c mice over a period of 14 days, capsules were recovered and precapsular fibrotic tissue on their surfaces was investigated. Assessment of encapsulated HP-MSC viability using acridine orange/propidium iodide staining revealed that foreign body response against cell-laden hydrogel results in fibrous overgrowth on spheres and consequently leads to the HP-MSC necrosis. In spite of immunomodulatory effects of MSCs, the introduction of spheres into the body induces foreign body response that affects the viability of immuno-isolated HP-MSCs during 14-day posttransplant period. The presence of HP-MSCs within alginate hydrogel could not reduce the fibrotic overgrowth on spheres compared with cell-free spheres. Therefore, there is an essential need for hydrogels that mitigate the foreign body response as a key challenge in the development of tissue engineering and drug delivery technologies.

Electrophysiological and Neurochemical Assessment of Selenium Alone or Combined with Carbamazepine in an Animal Model of Epilepsy.

The present study aims to evaluate the efficacy of selenium (Se) alone or combined with carbamazepine (CBZ) against the adverse effects induced by the chemoconvulsant pentylenetetrazole (PTZ) in the cortex of adult male rats. Electrocorticogram (ECoG) and oxidative stress markers were implemented to evaluate the differences between treated and untreated animals. Animals were divided into five groups: control group that received i.p. saline injection, PTZ-treated group that received a single i.p. injection of PTZ (60 mg/kg) for induction of seizures followed by a daily i.p. injection of saline, Se-treated group that received an i.p. injection of sodium selenite (0.3 mg/kg/day) after PTZ administration, CBZ-treated group that received orally CBZ (80 mg/kg/day) after PTZ administration, and combination (Se plus CBZ)-treated group that received an oral administration of CBZ (80 mg/kg/day) followed by an i.p. injection of sodium selenite (0.3 mg/kg/day) after PTZ administration. Quantitative analyses of the ECoG indices and the neurochemical parameters revealed that Se and CBZ have mitigated the adverse effects induced by PTZ. The main results were decrease in the number of epileptic spikes, restoring the normal distribution of slow and fast ECoG frequencies and attenuation of most of the oxidative stress markers. However, there was an increase in lipid perioxidation marker in combined treatment of CBZ and Se. The electrophysiological and neurochemical data proved the potential of these techniques in evaluating the treatment's efficiency and suggest that supplementation of Se with antiepileptic drugs (AEDs) may be beneficial in ameliorating most of the alterations induced in the brain as a result of seizure insults and could be recommended as an adjunct therapy with AEDs.

The impact of nandrolone decanoate abuse on experimental animal model: Hormonal and biochemical assessment.

Nandrolone decanoate (ND) is one of the most commonly abused anabolic androgenic steroids compounds in the world owing to its ability to improve physical performance but its abuse is associated with several adverse effects. The current study was performed to evaluate the effect of recommended and overdose of nandrolone decanoate (ND) for short and long term on the alterations of biochemical markers related to kidney, liver, adrenal, thyroid gland functions and oxidant and antioxidant activities. Sixty male rats were randomly assigned into two major groups. The first was treated with ND for 6 weeks and the second was treated with same drug for 12 weeks. Each of these groups was further subdivided into three sub groups: 1-Control (untreated rats), 2- Rats intraperitoneally injected with ND 3 mg/kg weekly, 3- Rats intraperitoneally injected with ND 15 mg/kg weekly. Administration of high ND dose for either short or long term significantly elevated kidney function biomarkers, liver enzymes both in serum, cytosol and mitochondria, insignificantly increased thyroid function, significantly increased adrenal function while, decreased ACTH. Moreover, oxidative stress biomarkers were significantly upregulated associated with depression in antioxidants activities. Administration of high ND dose for either short or long term as well as the repeated use of recommended ND dose for long term proved to have harmful effects manifested in impairing the functions of kidneys, liver, thyroid and adrenal glands as well as oxidant antioxidant balance.

Intraperitoneal Treatment of Kisspeptin Suppresses Appetite and Energy Expenditure and Alters Gastrointestinal Hormones in Mice.

BACKGROUND: Kisspeptin is a neuropeptide that plays an integral role in the regulation of energy intake and reproduction by acting centrally on the hypothalamus-pituitary-gonadal axis. Our current study explores for the first time the effects of a pharmacological treatment of intraperitoneal kisspeptin-10 on murine feeding behavior, respirometry parameters, energy balance, and metabolic hormones. METHODS: Two groups (n = 16) of age- and sex-matched C57BL/6 wild-type adult mice were individually housed in metabolic cages and intraperitoneally injected with either kisspeptin-10 (2 nmol in 200 µl of saline) (10 µM) or vehicle before the beginning of a dark-phase cycle. Microstructure of feeding and drinking behavior, respirometry gases, respiratory quotient (RQ), total energy expenditure (TEE), metabolic hormones, oral glucose tolerance, and lipid profiles were measured. RESULTS: Intraperitoneal treatment with kisspeptin-10 caused a significant reduction in food intake, meal frequency, meal size, and eating rate. Kisspeptin-10 significantly decreased TEE during both the dark and light phase cycles, while also increasing the RQ during the dark-phase cycle. In addition, mice injected with kisspeptin-10 had significantly higher plasma levels of insulin (343.8 pg/ml vs. 106.4 pg/ml; p = 0.005), leptin (855.5 pg/ml vs. 173.1 pg/ml; p = 0.02), resistin (9411.1 pg/ml vs. 4116.5 pg/ml; p = 0.001), and HDL (147.6 mg/dl vs 97.1 mg/dl; p = 0.04). CONCLUSION: A pharmacological dose of kisspeptin-10 significantly altered metabolism by suppressing food intake, meal size, eating rate, and TEE while increasing the RQ. These changes were linked to increased levels of insulin, leptin, resistin, and HDL. The current results suggest that a peripheral kisspeptin treatment could alter metabolism and energy homeostasis by suppressing appetite, food intake, and fat accumulation.

Assessment Of Spanlastic Vesicles Of Zolmitriptan For Treating Migraine In Rats.

OBJECTIVE: To develop and evaluate zolmitriptan spanlastics (Zol SLs) as a brain-targeted antimigraine delivery system. Spanlastics (SLs) prepared using span 60: tween 80 (70:30%, respectively) gave the highest percentage of entrapment efficiency (EE%). MATERIALS AND METHODS: A total of 60 adult male Wistar albino rats were divided into six groups (n=10 rats/group). Group 1 (Control) comprised rats serving as a negative control. Group 2 was treated with glyceryl trinitrate (NTG) and served as the positive control. Groups 3 (NTG+Zol com), Group 4 (NTG+Zol sol) and Group 5 (NTG+Zol SLs) received commercial zolmitriptan orally, zolmitriptan solution intranasally and Zol SLs F5 intranasally, respectively, 30 min before NTG. Group 6 (Zol SLs) comprised normal rats that received only Zol SLs intranasally. RESULTS: We found decreased Tmax, increased Cmax, AUC0-6, AUC0-∞ and ameliorated behaviour in rats (head scratching) treated with intranasal SLs compared to oral commercial zolmitriptan. CONCLUSION: Our study substantiates the enhanced efficacy of Zol SLs in brain targeting for migraine treatment.

In vivo toxicity assessment of Clinopodium vulgare L. water extract characterized by UHPLC-HRMS.

Clinopodium vulgare L. (Lamiaceae) was used in the traditional Bulgarian medicine for treatment of wounds, diabetes and gastric ulcers. In this study we aimed at safety assessment of C. vulgare lyophilized water extract (CVE) characterized by ultra high-performance liquid chromatography-Orbitrap high resolution mass spectrometry (UHPLC-HRMS). The acute and sub-acute toxicity of CVE was determined in two rodent species (mice and rats), and two routes of administration - intraperitoneal (i.p.) and oral (p.o.). LD50 (i.p.), were found to be 675 mg/kg (mice) and 500 mg/kg (rats). An acute i. p. administration resulted in central nervous system toxic effects. LD50 (p.o.) was higher than 2000 mg/kg for both species. In sub-acute oral administration, CVE did not exert any toxic effect on hematology, blood and urine biochemistry, and histomorphology in pancreas, liver, spleen and kidney. In addition, based on accurate masses, MS/MS and comparison with standards, a variety of flavonoids, caffeic acid oligomers and saponins were tentatively elucidated in CVE. Rosmarinic acid was the major compound. In conclusion, CVE did not cause hematological, biochemical and histopathological changes after oral administration and it is safe for internal use. The obtained UHPLC-HRMS profile revealed CVE as a new rich source of water soluble caffeic acid oligomers.

Assessment of the aerosol distribution pattern of a single-port device for intraperitoneal administration of therapeutic substances.

BACKGROUND: In the last 20 years, intraperitoneal chemotherapy (IPC) has been explored as a modality for the management of peritoneal metastases of gynecologic, gastrointestinal, and primary peritoneal tumors. Direct delivery of chemotherapeutic agents to the peritoneal cavity space has proved superior to systemic chemotherapy when evaluating characteristics such as drug concentration reached in the peritoneal space, penetration into peritoneal metastases, and chemotherapy-related toxicity. Traditionally, IPC is delivered by peritoneal lavage with a liquid solution. This form of delivery has limitations, including inhomogeneous intraperitoneal distribution and limited ability to penetrate tissues and metastatic nodules. An alternative mode of delivery is so-called pressurized intraperitoneal aerosol chemotherapy (PIPAC). Within this context, the present study sought to identify the pattern of spatial distribution of therapeutic solutions aerosolized into the peritoneal space using a single-port PIPAC device and ascertain whether the aerosolized method is superior to the traditional (liquid) mode of IPC delivery. METHODS: Analysis of the rate of intra-abdominal staining with aerosolized 2% silver nitrate in five porcine models. RESULTS: Assessment of differences in stain impregnation between the upper, middle, and lower abdomen did not reveal significant differences (p = 0.42). The median sum scores were 1 for the upper abdomen and 3 for the middle and lower abdomen. CONCLUSIONS: Aerosolization does not reach all regions of the abdomen homogeneously. However, adequate exposure of the upper abdomen, mid-abdomen, and lower abdomen to chemotherapeutic agents can be achieved with PIPAC.

Intraperitoneal administration of follistatin promotes adipocyte browning in high-fat diet-induced obese mice.

With rapid economic development, the prevalence of obesity has increased remarkably worldwide. Obesity can induce a variety of metabolic diseases, such as atherosclerosis, diabetes, hypertension and coronary heart disease, which significantly endanger the health and welfare of individuals. Brown and beige fat tissues play an important role in thermogenesis in mammals. Recent studies have shown that follistatin (FST) can potentially induce the browning of white adipose tissue (WAT). In this study, high-fat diet-induced obese mice were injected with follistatin for one week to explore the effects of follistatin on browning and metabolism and to determine the mechanism. The results showed that follistatin suppressed obesity caused by a high-fat diet and increased insulin sensitivity, energy expenditure, and subcutaneous fat browning. The beneficial effects remained even after a period of withdrawal. Follistatin promoted secretion of irisin from subcutaneous fat via the AMPK-PGC1α-irisin signal pathway, which induces browning of WAT, and activated the insulin pathway in beige fat thereby promoting metabolism.

Assessment of the protective effect of KN-93 drug in systemic epilepsy disorders induced by pilocarpine in male rat.

BACKGROUND AND AIMS: Epileptic seizures occur as a consequence of a sudden imbalance between the stimuli and inhibitors within the network of cortical neurons in favor of the stimulus. One of the drugs that induce epilepsy is pilocarpine. Systemic injection of pilocarpine affects on muscarinic receptors. Increasing evidence has addressed the implication of KN-93 by blocking Ca2+ /calmodulin-dependent protein kinase II (CaMKII), suppressing oxidative stress and inflammation, and also reducing neuron decay. So, we aimed to evaluate the potential preventive effects of KN-93 in systemic epilepsy disorders induced by pilocarpine. MATERIALS AND METHODS: In this animal study, male rats were divided into five groups including treatment group (KN-93 with the dose of 5 mM/10 µL dimethyl sulfoxide (DMSO) before inducing epilepsy by 380 mg/kg pilocarpine) KN-93 group (received 5 mM KN-93), control group, epilepsy group (received 380 mg/kg pilocarpine Intraperitoneal), and sham group (received 10 µL DMSO). Oxidative stress was assessed by measuring its indicators including the concentration of malondialdehyde (MDA), nitrite, glutathione (GSH), as well as the antioxidant activity of catalase. In addition, serum levels of proinflammatory mediators including tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß) were determined. RESULTS: Pretreatment with KN-93 significantly reduced oxidative stress index by reducing the concentration of MDA, nitrite, and increasing the level of GSH. In addition, low concentrations of TNF-α and IL-1ß were observed in hippocampus supernatant of KN-93 pretreated rats in comparison with the pilocarpine groups. Moreover, administration of KN-93 improved neuronal density and attenuated the seizure activity and behavior. CONCLUSIONS: Overall, our findings suggest that KN-93 can effectively suppress oxidative stress and inflammation. Furthermore, KN-93 is able to attenuate seizure behaviors by preventing its effects on neuron loss, so, it is valuable for the treatment of epileptic seizures.

Comparative Assessment of the Effectiveness of Noncompetitive NMDA Receptor Antagonists Amantadine and Hemantane in Morphine Withdrawal Syndrome Model.

Activities of noncompetitive NMDA receptor antagonists (aminoadamantane derivatives) were assessed in random-bred rats with modeled morphine withdrawal syndrome. A single intraperitoneal injection of hemantane (10 or 20 mg/kg) significantly and dose-dependently moderated some behavioral symptoms (teeth-chattering, ptosis, and vocalization) and reduced total score of morphine withdrawal syndrome. In morphine-abstinent rats, hemantane partially prevented the decrease in the thresholds of tactile sensitivity, but had no effect on locomotor activity and body weight loss. Under conditions of morphine withdrawal, intraperitoneal injection of amantadine (10 or 20 mg/kg) decreased motor activity and promoted body weight loss in parallel with the development of mechanical allodynia, but had no effect on the total withdrawal score. Comparison of aminoadamantane derivatives by behavioral and physiological parameters demonstrated the advantage of hemantane during morphine abstinence indicating the need of its study as a promising anti-addiction remedy.