Curcumin solid dispersion based on three model acrylic polymers: formulation and release properties

Abstract To investigate structure-property relationship of polymer-based curcumin solid dispersion (SD), three acrylic polymers were used to formulate curcumin SD by solvent evaporation method. Curcumin Eudragit EPO SD (cur@EPO), curcumin Eudragit RS PO SD (cur@RSPO) and curcumin Eudragit RL PO SD (cur@RLPO) showed deep red, golden orange and reddish orange color, respectively. Cur@RSPO entrapped 15.42 wt% of curcumin followed by cur@RL PO and cur@EPO. FTIR spectra indicated that in cur@EPO, curcumin may transfer hydrogen to the dimethylaminoethyl methacrylate group and thus change its color to red. In contrast, curcumin may form hydrogen bonding with Eudragit RS PO and Eudragit RL. Curcumin exists in amorphous state in three SDs as proved by differential scanning calorimetry and X-Ray diffraction measurement. In vitro digestion presented that lower pH value in simulated gastric fluid (SGF) stimulates the curcumin release from cur@EPO while permeability influences the release profile in other two SDs. When in simulated intestinal fluid (SIF), first order release model governs the release behaviors of all three SDs which showed sustained release pattern. Our results are helpful to elucidate how structure of polymer may impact on the major properties of curcumin contained SD and will be promising to broaden its therapeutic applications.

Effect of Intrahippocampal Administration of α7 Subtype Nicotinic Receptor Agonist PNU-282987 and Its Solvent Dimethyl Sulfoxide on the Efficiency of Hypoxic Preconditioning in Rats.

We have previously suggested a key role of the hippocampus in the preconditioning action of moderate hypobaric hypoxia (HBH). The preconditioning efficiency of HBH is associated with acoustic startle prepulse inhibition (PPI). In rats with PPI > 40%, HBH activates the cholinergic projections of hippocampus, and PNU-282987, a selective agonist of α7 nicotinic receptors (α7nAChRs), reduces the HBH efficiency and potentiating effect on HBH of its solvent dimethyl sulfoxide (DMSO, anticholinesterase agent) when administered intraperitoneally. In order to validate the hippocampus as a key structure in the mechanism of hypoxic preconditioning and research a significance of α7nAChR activation in the hypoxic preconditioning, we performed an in vivo pharmacological study of intrahippocampal injections of PNU-282987 into the CA1 area on HBH efficiency in rats with PPI ≥ 40%. We found that PNU-282987 (30 µM) reduced HBH efficiency as with intraperitoneal administration, while DMSO (0.05%) still potentiated this effect. Thus, direct evidence of the key role of the hippocampus in the preconditioning effect of HBH and some details of this mechanism were obtained in rats with PPI ≥ 40%. The activation of α7nAChRs is not involved in the cholinergic signaling initiated by HBH or DMSO via any route of administration. Possible ways of the potentiating action of DMSO on HBH efficiency and its dependence on α7nAChRs are discussed.

Analysis of electric cigarette liquid effect on mouse brain tumor growth through EGFR and ERK activation.

INTRODUCTION: Recently, electric cigarettes with liquid (e-liquid) were introduced as an alternative to tobacco smoking. They were promoted as possible cessation aids and were considered to be potentially less harmful than traditional tobacco-based cigarettes. However, there is little information on the toxicants present in e-liquids and their possible carcinogenic effects. METHODS: Western blot analysis was performed to identify the protein levels of cancer progression related signal transducers. Patient-derived brain tumor cells (CSC2) were injected into mouse brains and tumor growth was then observed by performing magnetic resonance imaging (MRI) and hematoxylin and eosin (H&E) staining of the whole brain. Immunohistochemistry (IHC) staining and Immunofluorescence staining were performed to study the expression of pEGFR and pERK. RESULTS: Western blotting revealed that e-liquids increased pEGFR and pERK expression in a dose dependent manner. Animal experiments revealed that the e-liquid treated group had accelerated tumor growth and poor prognosis compared to the vehicle group. Histological staining showed activation of pEGFR and pERK in the e-liquid treated group. CONCLUSION: Our study revealed that e-liquid activates pEGFR and pERK, leading to accelerated brain tumor growth and poor prognosis.

Combination of Phospholipid Complex and Matrix Dispersion.

Phospholipid complexation, despite being a successful, versatile, and burgeoning strategy, stickiness of phospholipids leads to suboptimal dissolution rate of drugs. This work was undertaken to fabricate simvastatin-phospholipid complex (SIM-PLC)-loaded matrix dispersion (SIM-PLC-MD) using Soluplus® as carrier material, to augment dispersibility and dissolution of SIM-PLC without altering complexation between simvastatin (SIM) and phospholipid. SIM-PLC and SIM-PLC-MD were prepared using solvent evaporation and discontinuous solvent evaporation techniques, respectively. The successful complexation was substantiated by FTIR method. Besides, PXRD and SEM studies disclosed the absence of crystallinity of SIM in both SIM-PLC and SIM-PLC-MD. The TEM analysis monitored the self-assembly of SIM-PLC and SIM-PLC-MD into colloidal structures, which could be correlated with redispersion in GIT fluids upon oral administration. The considerable increase in hydrophilicity of SIM-PLC-MD and SIM-PLC as evident from partition coefficient experiment can further be correlated with their remarkably improved solubility profiles in the following pattern: SIM-PLC-MD˃SIM-PLC˃SIM. Correspondingly, improved dispersibility of SIM-PLC-MD in comparison to SIM-PLC can be accountable for accelerated dissolution rate by 2.53-fold and 1.5-fold in pH 1.2 and 6.8 conditions, respectively. The oral pharmacokinetic evaluation in Sprague Dawley (SD) rats revealed 3.19-fold enhancement in oral bioavailability of SIM through SIM-PLC-MD when compared with plain SIM, whereas 1.83-fold increment was observed in the case of SIM-PLC. Finally, the efficacy experimentation in SD rats revealed that SIM-PLC-MD significantly reduced triglycerides and cholesterol levels in comparison to SIM and SIM-PLC. These outcomes suggest that a matrix dispersion strategy improves oral bioavailability and hypolipidemic activity of SIM.

Study of the physicochemical properties of drugs suitable for administration using a lymphatic drug delivery system.

Lymph node (LN) metastasis is thought to account for 20-30% of deaths from head and neck cancer. The lymphatic drug delivery system (LDDS) is a new technology that enables the injection of drugs into a sentinel LN (SLN) during the early stage of tumor metastasis to treat the SLN and secondary metastatic LNs. However, the optimal physicochemical properties of the solvent used to carry the drug have not been determined. Here, we show that the osmotic pressure and viscosity of the solvent influenced the antitumor effect of cisplatin (CDDP) in a mouse model of LN metastasis. Tumor cells were inoculated into the proper axillary LN (PALN), and the LDDS was used to inject CDDP solution into the subiliac LN (SiLN) to treat the tumor cells in the downstream PALN. CDDP dissolved in saline had no therapeutic effects in the PALN after it was injected into the SiLN using the LDDS or into the tail vein (as a control). However, CDDP solution with an osmotic pressure of ~ 1,900 kPa and a viscosity of ~ 12 mPa⋅s suppressed tumor growth in the PALN after it was injected into the SiLN using the LDDS. The high osmotic pressure dilated the lymphatic vessels and sinuses to enhance drug flow in the PALN, and the high viscosity increased the retention of CDDP in the PALN. Our results demonstrate that optimizing the osmotic pressure and viscosity of the solvent can enhance the effects of CDDP, and possibly other anticancer drugs, after administration using the LDDS.

Electrocoagulation for liver metastases.

BACKGROUND: Primary liver tumours and liver metastases from colorectal carcinoma are two of the most common malignant tumours to affect the liver. The liver is second only to the lymph nodes as the most common site for metastatic disease. More than half of the people with metastatic liver disease will die from metastatic complications. Electrocoagulation by diathermy is a method used to destroy tumour tissue, using a high-frequency electric current generating high temperatures, applied locally with an electrode (needle, blade, or ball). The objective of this method is to destroy the tumour completely, if possible, in a single session. With the time, electrocoagulation by diathermy has been replaced by other techniques, but the evidence is unclear. OBJECTIVES: To assess the beneficial and harmful effects of electrocoagulation by diathermy, administered alone or with another intervention, versus no intervention, other ablation methods, or systemic treatments in people with liver metastases. SEARCH METHODS: We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, MEDLINE Ovid, Embase Ovid, LILACS, Science Citation Index Expanded, Conference Proceedings Citation Index - Science, CINAHL, ClinicalTrials.gov, ICTRP, and FDA to October 2020. SELECTION CRITERIA: We considered all randomised trials that assessed beneficial and harmful effects of electrocoagulation by diathermy, administered alone or with another intervention, versus comparators, in people with liver metastases, regardless of the location of the primary tumour. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. We assessed risk of bias of the included trial using predefined risk of bias domains, and presented the review results incorporating the certainty of the evidence using GRADE. MAIN RESULTS: We included one randomised clinical trial with 306 participants (175 males; 131 females) who had undergone resection of the sigmoid colon, and who had five or more visible and palpable hepatic metastases. The diagnosis was confirmed by histological assessment (biopsy) and by carcinoembryonic antigen (CEA) level. The trial was conducted in Iraq. The age of participants ranged between 38 and 79 years. The participants were randomised to four different study groups. The liver metastases were biopsied and treated (only once) in three of the groups: 75 received electrocoagulation by diathermy alone, 76 received electrocoagulation plus allopurinol, 78 received electrocoagulation plus dimethyl sulphoxide. In the fourth intervention group, 77 participants functioning as controls received a vehicle solution of allopurinol 5 mL 4 x a day by mouth; the metastases were left untouched. The status of the liver and lungs was followed by ultrasound investigations, without the use of a contrast agent. Participants were followed for five years. The analyses are based on per-protocol data only analysing 223 participants. We judged the trial to be at high risk of bias. After excluding 'nonevaluable patients', the groups seemed comparable for baseline characteristics. Mortality due to disease spread at five-year follow-up was 98% in the electrocoagulation group (57/58 evaluable people); 87% in the electrocoagulation plus allopurinol group (46/53 evaluable people); 86% in the electrocoagulation plus dimethyl sulphoxide group (49/57 evaluable people); and 100% in the control group (55/55 evaluable people). We observed no difference in mortality between the electrocoagulation alone group versus the control group (risk ratio (RR) 0.98, 95% confidence interval (CI) 0.94 to 1.03; 113 participants; very low-certainty evidence). We observed lower mortality in the electrocoagulation combined with allopurinol or dimethyl sulphoxide group versus the control group (RR 0.87, 95% CI 0.80 to 0.95; 165 participants; low-certainty evidence). We are very uncertain regarding post-operative deaths between the electrocoagulation alone group versus the control group (RR 1.03, 95% CI 0.07 to 16.12; 152 participants; very low-certainty evidence) and between the electrocoagulation combined with allopurinol or dimethyl sulphoxide groups versus the control group (RR 1.00, 95% CI 0.09 to 10.86; 231 participants; very low-certainty evidence). The trial authors did not report data on number of participants with other adverse events and complications, recurrence of liver metastases, time to progression of liver metastases, tumour response measures, and health-related quality of life. Data on failure to clear liver metastases were not provided for the control group. There was no information on funding or conflict of interest. We identified no ongoing trials. AUTHORS' CONCLUSIONS: The evidence on the beneficial and harmful effects of electrocoagulation alone or in combination with allopurinol or dimethyl sulphoxide in people with liver metastases is insufficient, as it is based on one randomised clinical trial at low to very low certainty. It is very uncertain if there is a difference in all-cause mortality and post-operative mortality between electrocoagulation alone versus control. It is also uncertain if electrocoagulation in combination with allopurinol or dimethyl sulphoxide may result in a slight reduction of all-cause mortality in comparison with a vehicle solution of allopurinol (control). It is very uncertain if there is a difference in post-operative mortality between the electrocoagulation combined with allopurinol or dimethyl sulphoxide group versus control. Data on other adverse events and complications, failure to clear liver metastases or recurrence of liver metastases, time to progression of liver metastases, tumour response measures, and health-related quality of life were most lacking or insufficiently reported for analysis. Electrocoagulation by diathermy is no longer used in the described way, and this may explain the lack of further trials.

Effect of early tumor response on the health-related quality of life among patients on second-line chemotherapy for advanced gastric cancer in the ABSOLUTE trial.

BACKGROUND: This study evaluated the association between early tumor response at 8 weeks, previously reported as a positive outcome prognosticator, and health-related quality of life (HRQOL) in advanced gastric cancer (AGC) patients enrolled in the ABSOLUTE trial. METHODS: HRQOL was assessed using the EuroQol-5 Dimension (EQ-5D) utility index score in patients with complete response (CR) + partial response (PR) and progressive disease (PD) at 8 weeks, and time-to-deterioration (TtD) of the EQ-5D score, with the preset minimally important difference (MID) of 0.05, was compared between these populations. Among the enrolled patients, 143 and 160 patients were assessable in weekly solvent-based paclitaxel (Sb-PTX) arm and weekly nanoparticle albumin-bound paclitaxel (nab-PTX) arm, respectively. RESULTS: Changes of the EQ-5D score from baseline to 8 weeks in the nab-PTX arm were 0.0009 and - 0.1229 in CR + PR and PD patients, respectively; the corresponding values for the Sb-PTX arm were - 0.0019 and - 0.1549. For both treatments, changes of the EQ-5D score from baseline at 8 weeks were significantly larger in patients with PD than in those with CR + PR. The median TtD was 3.9 and 2.2 months in patients with CR + PR and PD, respectively, for nab-PTX [hazard ratio (HR) = 0.595, 95% confidence interval (CI) 0.358-0.989]. For Sb-PTX, the corresponding values were 4.7 and 2.0 months (HR = 0.494, 95% CI 0.291-0.841). CONCLUSIONS: Early tumor shrinkage was associated with maintained HRQOL in AGC patients on the second-line chemotherapy with taxanes.

The effect of orally administered glycerol on anterior chamber depth during cataract surgery in eyes with narrow anterior chambers.

PURPOSE: Cataract surgery on eyes with shallow anterior chambers may be demanding. Glycerol intake prior to surgery has been a well-known method in an effort to increase anterior chamber depth. It is used since it is thought that glycerol as an osmotic agent causes the vitreous body to shrink, pulling back the iris and thereby deepening the anterior chamber - making the surgery easier. Our controlled clinical trial tests this hypothesis and investigates the effect of glycerol on anterior chamber depth (ACD), intraocular pressure (IOP), corneal thickness (CCT), pupil diameter change after viscodilation (PD), operating time and perioperative complications. METHODS: We performed a controlled clinical trial. All patients underwent cataract surgery on both eyes with at least 7 days apart. Preoperatively the patient was given glycerol orally when the right eye was operated - when the left eye was operated, nothing was given. In this way, each patient was serving as its own control. Measurements of ACD, IOP and CCT were performed before and after glycerol intake, pupillary diameter was measured before and after viscoelastics during the operation, and operating time and surgical complications were noted. RESULTS: The study included 22 patients with bilateral cataract and anterior chambers depth <2.5 mm. Glycerol caused the anterior chamber to increase by 0.022 mm (p < 0.05), and IOP was lowered by 5.1 mmHg compared to the control group (p < 0.05). However, exposure to glycerol showed no effect on CCT, pupillary dilation of viscoelastics, operating time or surgical complications. CONCLUSION: Glycerol increases anterior chamber depth and lowers intraocular pressure significantly. These changes had no significant impact on operating time nor on the complication rate, suggesting that these changes are too subtle to have a clinical impact on the cataract procedure.

Interventional radiology for treatment of bone metastases.

Therapeutic advances in oncology have led to longer survival in many forms of cancer, including those complicated by bone metastases. When a bone metastasis is painful or when there is a risk of fracture, interventional radiology procedures can be carried out for pain control and/or stabilisation. All of these techniques can be performed under local anaesthesia. Cementoplasty and vertebroplasty are stabilisation procedures consisting in the percutaneous injection of acrylic cement into a lytic bone lesion. The effect on pain can be explained by the consolidation of weakened, fractured or pre-fractured bone, but also to a lesser extent by the toxic, chemical and thermal effect of the cement. Tumour ablation techniques include alcoholisation or thermal ablation (by heat with radiofrequency and microwave or cold by cryoablation). Percutaneous thermal ablation of bone tumours is most often performed as a palliative measure resulting in a significant and lasting reduction in symptoms. Radiofrequency ablation consists in placing needles through which an electrical current passes. Microwave ablation acts by causing very high frequency vibrations of water molecules. Cryoablation releases argon gas at the tip of the needle, forming an "ice ball" effectively destroying tumour cells. Any of these techniques can be combined to radiation therapy, performed before or after radiation. Finally, tumour embolisation can have a goal of pain control, or preparation of surgery to reduce the risk of peroperative haemorrhage.

Comparison of passive-dosed and solvent spiked exposures of pro-carcinogen, benzo[a]pyrene, to human lymphoblastoid cell line, MCL-5.

Genotoxicity testing methods in vitro provide a means to predict the DNA damaging effects of chemicals on human cells. This is hindered in the case of hydrophobic test compounds, however, which will partition to in vitro components such as plastic-ware and medium proteins, in preference to the aqueous phase of the exposure medium. This affects the freely available test chemical concentration, and as this freely dissolved aqueous concentration is that bioavailable to cells, it is important to define and maintain this exposure. Passive dosing promises to have an advantage over traditional 'solvent spiking' exposure methods and involves the establishment and maintenance of known chemical concentrations in the in vitro medium, and therefore aqueous phase. Passive dosing was applied in a novel format to expose the MCL-5 human lymphoblastoid cell line to the pro-carcinogen, benzo[a]pyrene (B[a]P) and was compared to solvent (dimethyl sulphoxide) spiked B[a]P exposures over 48 h. Passive dosing induced greater changes, at lower concentrations, to micronucleus frequency, p21 mRNA expression, cell cycle abnormalities, and cell and nuclear morphology. This was attributed to a maintained, definable, free chemical concentration using passive dosing and the presence or absence of solvent, and highlights the influence of exposure choice on genotoxic outcomes.

Quantitative assessment of required separator fluid volume in multi-infusion settings.

BACKGROUND: Administering a separator fluid between incompatible solutions can optimize the use of intravenous lumens. Factors affecting the required separator fluid volume to safely separate incompatible solutions are unknown. METHODS: An intravenous tube (2-m, 2-mL, 6-French) containing methylene blue dye was flushed with separator fluid until a methylene blue concentration ⩽2% from initial was reached. Independent variables were administration rate, dye solvent (glucose 5% and NaCl 0.9%), and separator fluid. In the second part of the study, methylene blue, separator fluid, and eosin yellow were administered in various administration profiles using 2- and 4-mL (2 × 2 m, 4-mL, 6-French) intravenous tubes. RESULTS: Neither administration rate nor solvent affected the separator fluid volume (p = 0.24 and p = 0.12, respectively). Glucose 5% as separator fluid required a marginally smaller mean ± SD separator fluid volume than NaCl 0.9% (3.64 ± 0.13 mL vs 3.82 ± 0.11 mL, p < 0.001). Using 2-mL tubing required less separator fluid volume than 4-mL tubing for methylene blue (3.89 ± 0.57 mL vs 4.91 ± 0.88 mL, p = 0.01) and eosin yellow (4.41 ± 0.56 mL vs 5.63 ± 0.15 mL, p < 0.001). Extended tubing required less separator fluid volume/mL of tubing than smaller tubing for both methylene blue (2 vs 4 mL, 1.54 ± 0.22 vs 1.10 ± 0.19, p < 0.001) and eosin yellow (2 vs 4 mL, 1.75 ± 0.22 vs 1.25 ± 0.03, p < 0.001). CONCLUSION: The separator fluid volume was neither affected by the administration rate nor by solvent. Glucose 5% required a marginally smaller separator fluid volume than NaCl 0.9%, however its clinical impact is debatable. A larger intravenous tubing volume requires a larger separator fluid volume. However, the ratio of separator fluid volume to the tubing's volume decreases as the tubing volume increases.

Effect of binary combinations of solvent systems on permeability profiling of pure agomelatine across rat skin: a comparative study with statistically optimized polymeric nanoparticles.

Objective: Agomelatine (AGM), an antidepressant drug has low biological half-life coupled with extensive hepatic first-pass metabolism. For effective treatment of depression, daily medication is required but irregular dose intake occurs due to psychological illness which can be overcome by development of transdermal drug delivery system. But for effective transdermal delivery permeation of AGM through stratum corneum is a crucial step. Thus present study was intended to formulate and optimize polymeric nanoparticles of agomelatine and to compare the effect of binary combinations of solvent system on permeability profiling of pure agomelatine with statistically optimized polymeric nanoparticles.Methods: Polymeric agomelatine nanoparticles (AGM-PNPs) were prepared by nano-precipitation method which was further optimized by experimental design and characterized by FTIR, DSC, XRD and SEM study while ex-vivo study was performed on adult male wistar rats.Results: The optimized formulation has particle size in nano range (107.64 nm) with low PDI (0.209), stable zeta potential (-15 mV) and high entrapment efficiency (81.91%). Ex-vivo analysis of optimized nanoparticles suggests that nanoparticles permeate faster compared to plain AGM, while, permeation profile of AGM was enhanced when combination of solvent systems were used. It was observed that among various solvent system 33% PG-ethanol showed maximum flux (148.48 ± 3.24 µg/cm2/h) and least lag time (4.04 ± 0.12 h). The flux was further enhanced (180.98 ± 2.54 µg/cm2/h) when 5%v/v transcutol-HP was added as penetration enhancer.Conclusion: The above observations concluded that binary combination of 33% PG-ethanol with 5 %v/v transcutol-HP can serve as a solvent system of choice for effective transdermal delivery of agomelatine via nanoparticulate system.

Transarterial Ethanol Ablation for Small Hepatocellular Carcinoma (≤ 3 cm): A Comparative Study Versus Radiofrequency Ablation.

PURPOSE: The objective was to evaluate the local treatment efficacy of transarterial ethanol ablation (TEA) as compared to radiofrequency ablation (RFA) for small hepatocellular carcinoma (HCC). MATERIALS AND METHODS: This was a retrospective study between January 2005 and April 2017, in which the treatment outcomes of all patients who received either percutaneous TEA or RFA for HCC tumors of size ≤ 3 cm, of Child-Pugh grade A or B, received no prior treatment other than surgical resection, were compared. For TEA, a mixture of absolute ethanol and ethiodized oil at a proportion of 1:2 by volume was administered superselectively into the tumor via a microcatheter placed at the feeding arteries. The TEA group and the RFA group consisted of 68 consecutive patients (88 treated target tumors) and 129 consecutive patients (129 tumors), respectively. RESULTS: Technical success was achieved in all the target tumors in both groups. Grade 3 complication (CIRSE Classification) of prolonged fever occurred in 3 cases with multi-focal and large tumors in the TEA group. There was no statistically significant difference in complete response rate between the TEA group (84/88 or 95.5%) and the RFA group (188/195 or 96.4%) (p = 0.7). Time to progression in the TEA group [median 11.9 months, interquartile range (IQR) 5.6-18 months] was not statistically different from that in the RFA group (median 9.5 months, IQR 3.5-18.7 months) (p = 0.773). CONCLUSION: TEA could be an effective alternative of RFA for the local treatment of small HCC; it is especially valuable for tumors of unfavorable location.

Deep eutectic solvents for pharmaceutical formulation and drug delivery applications.

Solvents play key roles in designing drug delivery systems (DDSs). They are used as the reaction media in the preparation of DDSs and as vehicles for delivery of problematic drugs. The number of pharmaceutically acceptable solvents is limited and developing new green ones is of a great of interest. A deep eutectic solvent (DES) is a room temperature liquid composed of a mixture of hydrogen bond acceptor and hydrogen bond donor. DESs exhibit interesting physical and chemical characteristics such as low vapor pressure, non-inflammability, chemically tailorable, solvency power for a wide range of solutes, and water non-reactivity. Furthermore, they can be easily prepared from low toxicity, readily available, and inexpensive constituents. Due to these properties, DESs have attracted growing attention as green solvents in different areas of science from chemistry to material engineering and biology. In this review, after a brief introduction about DESs, we provide an overview about current advances made over the last decade in utilizing of DESs for solubilization of water insoluble drugs, transdermal drug delivery, inorganic nanoparticle synthesis, and designing polymeric and self-assembled drug carriers. This paper also discusses main challenges and limitations of DESs that should be considered before using of them.

Examination of the influence of cedar fragrance on cognitive function and behavioral and psychological symptoms of dementia in Alzheimer type dementia.

We examined whether symptoms of dementia are improved by olfactory nerve stimulation in Alzheimer type dementia patients. First, a stick-type olfactory identification ability test was performed in patients with Alzheimer type dementia, to select patients without olfactory dysfunctions. Then, these patients were randomly assigned into the intervention (n = 19) and the control groups (n = 17). To evaluate the effects of olfactory nerve stimulation, we exposed the intervention group to a disinfecting ethanol with added aroma extracts from ceder and the control group to the ethanol without the added aroma extracts. Each group underwent the intervention for 8 weeks, cognitive and behavioral functions were evaluated before and after treatments using the Neuropsychiatric Inventory (NPI), the Japanese version of Zarit Caregiver Burden interview (J-ZBI), and the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog). A significant improvement was observed in the NPI score and J-ZBI in the intervention group compared to the control group at 4 and 8 weeks. On the other hand, there was no significant difference in the score of ADAS-cog. Exposure to cedar fragrance improved behavioral and psychological symptoms of dementia (BPSD) in Alzheimer type dementia and may reduce the burden of nursing care. In addition to its effectiveness, the procedure is simple and minimally invasive and would be a valuable non-pharmaceutical treatment.

Derivation of cancer no significant risk levels and screening safety assessment for 2-nitropropane in spray products.

Two proposition 65 no-significant-risk level (NSRL)-type values were derived for 2-nitropropane (2-NP), in the absence of a Californian published NSRL. In addition, a safety assessment was performed based on estimated typical consumer inhalation and dermal exposure to 2-NP during indoor application of paint from a spray can containing the solvent 1-nitropropane. For the NSRL derivation, benchmark dose (BMD) modeling was performed using hepatocellular carcinoma incidence data from 2-NP single exposure inhalation studies in Sprague-Dawley rats. Several BMD models provided an acceptable fit for the male rat hepatocellular carcinoma incidence data (gamma, log-probit, log-logistic and multistage); therefore, the mean of the BMD lower limits from each model were used as the point of departure to derive the inhalation cancer potency. The oral human cancer potency was derived from the inhalation human cancer potency based on the ratio of the uptake factors for inhalation vs. oral routes. The derived inhalation and oral NSRLs are 67 µg/day and 32 µg/day, respectively. For the inhalation and dermal exposure assessment, three key factors were analyzed: the 2-NP residual concentration in the spray paint product, the mass of spray paint used and the frequency of use. Based on the screening exposure assessment, potential consumer inhalation and dermal exposure to 2-NP from indoor application of paint from a spray can does not exceed our proposed NSRLs, and a warning label is therefore not required for spray can products containing the solvent 1-nitropropane where 2-NP is a minor contaminant.

Efficacy and safety of scheduled early endoscopic ultrasonography-guided ethanol reinjection for patients with pancreatic neuroendocrine tumors: Prospective pilot study.

Endoscopic ultrasonography (EUS)-guided ethanol injection was recently proposed for treatment of patients with small pancreatic neuroendocrine tumors (p-NET); however, tips on how to carry out safe and effective procedures are unclear. We launched a pilot study for scheduled early EUS-guided ethanol reinjection for small p-NET. Major eligibility criteria were presence of pathologically diagnosed grade (G) 1 or G2, tumor size ≤2 cm and being a poor or rejected candidate for surgery. For the treatment, we used a 25-gauge needle and pure ethanol. Contrast-enhanced computed tomography (CE-CT) was carried out on postoperative day 3, and if enhanced areas of the tumor were still apparent, an additional session was scheduled during the same hospitalization period. Primary endpoint was complete ablation rate at 1 month after treatment, and secondary endpoint was procedure-related adverse events. A total of five patients were treated. Median size of the tumor was 10 (range: 7-14) mm. Of the five patients, three underwent an additional session. Median volume of ethanol injection per session was 0.8 (range: 0.3-1.0) mL, and the total was 1.0 (0.9-1.8) mL. Complete ablation was achieved in four of the five tumors (80%) with no adverse events. During 1 year of follow up, none of the patients reported any procedure-related adverse events, and no recurrence of tumor. Scheduled early EUS-guided ethanol reinjection appears to be safe and effective for treating small p-NET (UMIN number: 000018834).

Phase I study of KRP-116D, a 50% w/w dimethyl sulfoxide aqueous solution, on the systemic absorption from bladder by intravesical instillation in healthy Japanese subjects.

OBJECTIVE: This was a single-institution, single-dose, single-arm phase 1 study in healthy adult males to evaluate the safety and absorption of dimethyl sulfoxide (DMSO) from the bladder into the body when KRP-116D (a 50% w/w DMSO solution) was intravesically administered and allowed to remain in the bladder for 15 minutes. METHODS: Six healthy adult males were enrolled in this study. KRP-116D (50 mL) was instilled directly into the bladder via a catheter where it was allowed to remain for 15 minutes under lidocaine anesthesia in accordance with the usage of RIMSO-50 (50% w/w DMSO solution) approved in the USA. The residual DMSO solution in the bladder was collected 15 minutes after instillation. The concentrations of DMSO in the plasma and the recovered solution were analyzed by a validated high-performance liquid chromatography (HPLC) method. The concentration in the residual DMSO solution was multiplied by the solution volume and divided by the dosage to calculate the recovery rate of DMSO. RESULTS: Plasma DMSO was detected in one of six subjects, and in the remaining five subjects DMSO was not detected (<19.6 µg/mL). The recovery rate of DMSO from the bladder was 60.7% to 93.7%. The only drug-related adverse event was breath odor (garlic-like breath) observed in four of six subjects (66.7%). CONCLUSION: Absorption of DMSO from the bladder was low (16.3%), and the systemic exposure was limited. Most of the DMSO was recovered from the bladder. KRP-116D 50 mL was well tolerated and safe.

A cautionary note: Toxicity of polyethylene glycol 200 injected intraperitoneally into mice.

The parenteral administration of hydrophobic substances in vivo requires the use of organic solvents to ensure sufficient solubility and avoid precipitation. Dimethyl sulfoxide is commonly used for this purpose. Based on the common assumption that polyethylene glycol (PEG) is non-toxic, our local regulatory authorities recently recommended the use of PEG instead. However, mice injected intraperitoneally (i.p.) with PEG 200 at a dose of 8 mL/kg (i.e. 9 g/kg) did not tolerate PEG 200 well, and half of the animals had to be euthanized. Our results demonstrate that although PEG 200 is generally considered to be harmless, it can be toxic when injected i.p. and is painful for the recipient mice. Nevertheless, it can be used as a solvent for repeated i.p. injections in mice at a dose of 2 mL/kg (i.e. 2.25 g/kg) without obvious signs of systemic toxicity.