In vitro trypanocidal potency and in vivo treatment efficacy of oligomeric ethylene glycol-tethered nitrofurantoin derivatives.

African trypanosomiasis is a significant vector-borne disease of humans and animals in the tsetse fly belt of Africa, particularly affecting production animals such as cattle, and thus, hindering food security. Trypanosoma congolense (T. congolense), the causative agent of nagana, is livestock's most virulent trypanosome species. There is currently no vaccine against trypanosomiasis; its treatment relies solely on chemotherapy. However, pathogenic resistance has been established against trypanocidal agents in clinical use. This underscores the need to develop new therapeutics to curb trypanosomiasis. Many nitroheterocyclic drugs or compounds, including nitrofurantoin, possess antiparasitic activities in addition to their clinical use as antibiotics. The current study evaluated the in vitro trypanocidal potency and in vivo treatment efficacy of previously synthesized antileishmanial active oligomeric ethylene glycol derivatives of nitrofurantoin. The trypanocidal potency of analogues 2a-o varied among the trypanosome species; however, T. congolense strain IL3000 was more susceptible to these drug candidates than the other human and animal trypanosomes. The arylated analogues 2k (IC50 0.04 µM; SI >6365) and 2l (IC50 0.06 µM; SI 4133) featuring 4-chlorophenoxy and 4-nitrophenoxy moieties, respectively, were revealed as the most promising antitrypanosomal agents of all analogues against T. congolense strain IL3000 trypomastigotes with nanomolar activities. In a preliminary in vivo study involving T. congolense strain IL3000 infected BALB/c mice, the oral administration of 100 mg/kg/day of 2k caused prolonged survival up to 18 days post-infection relative to the infected but untreated control mice which survived 9 days post-infection. However, no cure was achieved due to its poor solubility in the in vivo testing medium, assumably leading to low oral bioavailability. These results confirm the importance of the physicochemical properties lipophilicity and water solubility in attaining not only in vitro trypanocidal potency but also in vivo treatment efficacy. Future work will focus on the chemical optimization of 2k through the investigation of analogues containing solubilizing groups at certain positions on the core structure to improve solubility in the in vivo testing medium which, in the current investigation, is the biggest stumbling block in successfully treating either animal or human Trypanosoma infections.

Thiophene Carboxamide Analogs with Long Alkyl Chains Comprising Ethylene Glycol Units Inhibit Glioblastoma Cell Proliferation by Activating AMPK.

Glioblastoma is a refractory malignant tumor that requires novel therapeutic strategies for effective treatment. We have previously reported that JCI-20679 (1), an analog of annonaceous acetogenins, shows potent antitumor activity against glioblastomas. However, the synthesis of 1 requires 23 steps, including 16 steps for the preparation of a tetrahydrofuran (THF) moiety. This study reports the design and synthesis of 11 analogs with a triethylene glycol moiety in place of the THF moiety in 1. Among these, the analog 2k with an n-decyl chain exhibited potent inhibitory activity against the growth of glioblastoma stem cells by inhibiting mitochondrial function and synergistically enhancing the effect of temozolomide (TMZ). Furthermore, 2k significantly suppressed tumor growth without critical toxicity in vivo. Hence, this study presents novel potential anticancer agents and a strategy for the development of these agents that can be produced easily.

Wound cleansing for treating venous leg ulcers.

BACKGROUND: Leg ulcers are open skin wounds that occur below the knee but above the foot. The majority of leg ulcers are venous in origin, occurring as a result of venous insufficiency, where the flow of blood through the veins is impaired; they commonly arise due to blood clots and varicose veins. Compression therapy, using bandages or stockings, is the primary treatment for venous leg ulcers. Wound cleansing can be used to remove surface contaminants, bacteria, dead tissue and excess wound fluid from the wound bed and surrounding skin, however, there is uncertainty regarding the effectiveness of cleansing and the best method or solution to use. OBJECTIVES: To assess the effects of wound cleansing, wound cleansing solutions and wound cleansing techniques for treating venous leg ulcers. SEARCH METHODS: In September 2019 we searched the Cochrane Wounds Specialised Register; the Cochrane Central Register of Controlled Trials (CENTRAL); Ovid MEDLINE (including In-Process & Other Non-Indexed Citations); Ovid Embase and EBSCO CINAHL Plus. We also searched clinical trials registries for ongoing and unpublished studies, and scanned reference lists of relevant included studies as well as reviews, meta-analyses and health technology reports to identify additional studies. There were no restrictions with respect to language, date of publication or study setting. SELECTION CRITERIA: We considered randomised controlled trials (RCTs) comparing wound cleansing with no wound cleansing, or RCTs comparing different wound cleansing solutions, or different wound cleansing techniques. DATA COLLECTION AND ANALYSIS: We screened studies for their appropriateness for inclusion, assessed their risk of bias using the Cochrane 'Risk of bias' tool, and used GRADE methodology to determine the certainty of evidence. Two review authors undertook these tasks independently, using predetermined criteria. We contacted study authors for missing data where possible. MAIN RESULTS: We included four studies with a total of 254 participants. All studies included comparisons between different types of cleansing solutions, and three of these reported our primary outcomes of complete wound healing or change in ulcer size over time, or both. Two studies reported the secondary outcome, pain. One study (27 participants), which compared polyhexamethylene biguanide (PHMB) solution with saline solution for cleansing venous leg ulcers, did not report any of the review's primary or secondary outcomes. We did not identify any studies that compared cleansing with no cleansing, or that explored comparisons between different cleansing techniques. One study (61 participants) compared aqueous oxygen peroxide with sterile water. We are uncertain whether aqueous oxygen peroxide makes any difference to the number of wounds completely healed after 12 months of follow-up (risk ratio (RR) 1.88, 95% confidence interval (CI) 1.10 to 3.20). Similarly, we are uncertain whether aqueous oxygen peroxide makes any difference to change in ulcer size after eight weeks of follow-up (mean difference (MD) -1.38 cm2, 95% CI -4.35 to 1.59 cm2). Finally, we are uncertain whether aqueous oxygen peroxide makes any difference to pain reduction, assessed after eight weeks of follow-up using a 0 to 100 pain rating, (MD 3.80, 95% CI -10.83 to 18.43). The evidence for these outcomes is of very low certainty (we downgraded for study limitations and imprecision; for the pain outcome we also downgraded for indirectness). Another study (40 participants) compared propyl betaine and polihexanide with a saline solution. The authors did not present the raw data in the study report so we were unable to conduct independent statistical analysis of the data. We are uncertain whether propyl betaine and polihexanide make any difference to the number of wounds completely healed, change in ulcer size over time, or wound pain reduction. The evidence is of very low certainty (we downgraded for study limitations and imprecision). The final study (126 participants) compared octenidine dihydrochloride/phenoxyethanol (OHP) with Ringer's solution. We are uncertain whether OHP makes any difference to the number of wounds healed (RR 0.96, 95% CI 0.53 to 1.72) or to the change in ulcer size over time (we were unable to conduct independent statistical analysis of available data). The evidence is of very low certainty (we downgraded for study limitations and imprecision). None of the studies reported patient preference, ease of use of the method of cleansing, cost or health-related quality of life. In one study comparing propyl betaine and polihexanide with saline solution the authors do not report any adverse events occurring. We are uncertain whether OHP makes any difference to the number of adverse events compared with Ringer's solution (RR 0.58, 95% CI 0.29 to 1.14). The evidence is of very low certainty (we downgraded for study limitations and imprecision). AUTHORS' CONCLUSIONS: There is currently a lack of RCT evidence to guide decision making about the effectiveness of wound cleansing compared with no cleansing and the optimal approaches to cleansing of venous leg ulcers. From the four studies identified, there is insufficient evidence to demonstrate whether the use of PHMB solution compared with saline solution; aqueous oxygen peroxide compared with sterile water; propyl betaine and polihexanide compared with a saline solution; or OHP compared with Ringer's solution makes any difference in the treatment of venous leg ulcers. Evidence from three of the studies is of very low certainty, due to study limitations and imprecision. One study did not present data for the primary or secondary outcomes. Further well-designed studies that address important clinical, quality of life and economic outcomes may be important, based on the clinical and patient priority of this uncertainty.

ANTECEDENTES: Las úlceras de la pierna son heridas cutáneas abiertas que se producen por debajo de la rodilla, pero por encima del pie. La mayoría de las úlceras de la pierna son de origen venoso, y se producen como resultado de la insuficiencia venosa, en la que el flujo de sangre a través de las venas se ve afectado; suelen surgir debido a coágulos de sangre y venas varicosas. El tratamiento de compresión (vendas o medias) es el tratamiento principal para las úlceras venosas de la pierna. La limpieza de la herida se puede utilizar para eliminar los contaminantes superficiales, las bacterias, el tejido muerto y el exceso de líquido de la base de la úlcera y de la piel circundante; sin embargo, no se sabe con certeza cuál es la efectividad de la limpieza ni cuál es el mejor método o solución a utilizar. OBJETIVOS: Evaluar los efectos de la limpieza de heridas, las soluciones de limpieza de heridas y las técnicas de limpieza de heridas para el tratamiento de las úlceras venosas de la pierna. MÉTODOS DE BÚSQUEDA: En septiembre de 2019 se hicieron búsquedas en el Registro especializado del Grupo Cochrane de Heridas (Cochrane Wounds Group), en el Registro Cochrane central de ensayos controlados (CENTRAL); Ovid MEDLINE (incluido In­Process & Other Non­Indexed Citations); Ovid Embase y EBSCO CINAHL Plus. También se buscaron estudios en curso y no publicados en los registros de ensayos clínicos, y se examinaron las listas de referencias de los estudios incluidos pertinentes, así como de las revisiones, los metanálisis y los informes de tecnología sanitaria para identificar estudios adicionales. No hubo restricciones en cuanto al idioma, la fecha de publicación ni el contexto de los estudios. CRITERIOS DE SELECCIÓN: Se consideraron los ensayos controlados aleatorizados (ECA) que compararon la limpieza de heridas con ninguna limpieza de heridas, o ECA que compararon diferentes soluciones de limpieza de heridas o diferentes técnicas de limpieza de heridas. OBTENCIÓN Y ANÁLISIS DE LOS DATOS: Se examinaron los estudios para determinar si eran adecuados para inclusión, el riesgo de sesgo se evaluó mediante la herramienta Cochrane "Risk of bias" y se utilizó el método GRADE para determinar la certeza de la evidencia. Dos autores de la revisión realizaron estas tareas de forma independiente, utilizando criterios predeterminados. Cuando fue posible, se estableció contacto con los autores de los estudios para obtener los datos faltantes. RESULTADOS PRINCIPALES: Se incluyeron cuatro estudios con un total de 254 participantes. Todos los estudios incluyeron comparaciones entre diferentes tipos de soluciones de limpieza, y tres de ellos informaron sobre los desenlaces principales de esta revisión, cicatrización completa de la herida o cambio en el tamaño de la úlcera con el tiempo, o ambos. Dos estudios informaron sobre el desenlace secundario de dolor. Un estudio (27 participantes), que comparó la solución de polihexametileno biguanida (PHMB) con el suero fisiológico para la limpieza de las úlceras venosas de la pierna, no informó sobre ninguno de los desenlaces principales ni secundarios de la revisión. No se identificaron estudios que compararan la limpieza con ninguna limpieza, o que explorara comparaciones entre diferentes técnicas de limpieza. Un estudio (61 participantes) comparó el peróxido de oxígeno acuoso con el agua estéril. No hay certeza de que el peróxido de oxígeno acuoso suponga alguna diferencia en el número de heridas completamente cicatrizadas tras 12 meses de seguimiento (razón de riesgos [RR] 1,88; intervalo de confianza [IC] del 95%: 1,10 a 3,20). Del mismo modo, no hay certeza de que el peróxido de oxígeno acuoso suponga alguna diferencia en el cambio del tamaño de la úlcera tras ocho semanas de seguimiento (diferencia de medias [DM] ­1,38 cm2; IC del 95%: ­4,35 a 1,59 cm2). Por último, no hay certeza de que el peróxido de oxígeno acuoso suponga alguna diferencia en la reducción del dolor, evaluada tras ocho semanas de seguimiento mediante una calificación del dolor de 0 a 100 (DM 3,80; IC del 95%: ­10,83 a 18,43). La evidencia para estos desenlaces es de certeza muy baja (se disminuyó la calificación por las limitaciones del estudio y la imprecisión; para el desenlace dolor también se disminuyó la calificación por medidas indirectas). Otro estudio (40 participantes) comparó la propil betaína y la polihexanida con una solución salina. Los autores no presentaron los datos brutos en el informe del estudio, por lo que no fue posible realizar un análisis estadístico independiente de los datos. No se sabe si la propil betaína y la polihexanida suponen alguna diferencia en el número de heridas completamente cicatrizadas, en el cambio del tamaño de la úlcera con el tiempo o en la reducción del dolor de la herida. La evidencia es de certeza muy baja (se disminuyó por las limitaciones del estudio y la imprecisión). El último estudio (126 participantes) comparó el dihidrocloruro de octenidina/fenoxietanol (OHP) con la solución de Ringer. No hay certeza de que el OHP suponga alguna diferencia en el número de heridas cicatrizadas (RR 0,96; IC del 95%: 0,53 a 1,72) ni en el cambio del tamaño de la úlcera con el tiempo (no fue posible realizar un análisis estadístico independiente de los datos disponibles). La evidencia es de certeza muy baja (se disminuyó por las limitaciones del estudio y la imprecisión). Ninguno de los estudios informó sobre la preferencia de los pacientes, la facilidad de uso del método de limpieza, el coste o la calidad de vida relacionada con la salud. En un estudio en el que se compara la propil betaína y la polihexanida con la solución salina, los autores no informaron la aparición de eventos adversos. No hay certeza de que el OHP suponga alguna diferencia en el número de eventos adversos en comparación con la solución de Ringer (RR 0,58; IC del 95%: 0,29 a 1,14). La evidencia es de certeza muy baja (se disminuyó por las limitaciones del estudio y la imprecisión). CONCLUSIONES DE LOS AUTORES: En la actualidad se carece de evidencia de ECA para guiar la toma de decisiones sobre la efectividad de la limpieza de heridas en comparación con ninguna limpieza y los enfoques óptimos para la limpieza de las úlceras venosas de la pierna. A partir de los cuatro estudios identificados, no hay evidencia suficiente para demostrar si el uso de la solución PHMB en comparación con el suero fisiológico; el peróxido de oxígeno acuoso en comparación con el agua estéril; la betaína propil y la polihexanida en comparación con un suero fisiológico; o el OHP en comparación con la solución de Ringer supone alguna diferencia en el tratamiento de las úlceras venosas de la pierna. La evidencia de tres de los estudios es de certeza muy baja, debido a las limitaciones de los estudios y a la imprecisión. Un estudio no presentó datos para los desenlaces principales ni secundarios. Podría ser importante realizar más estudios bien diseñados que aborden desenlaces clínicos, de calidad de vida y económicos importantes, sobre la base de la prioridad clínica y para el paciente de esta falta de certeza.

Amyloid and APOE Status of Screened Subjects in the Elenbecestat MissionAD Phase 3 Program.

BACKGROUND/OBJECTIVES: Elenbecestat, an oral BACE-1 inhibitor that has been shown to reduce Aß levels in cerebrospinal fluid, was investigated in two global phase 3 studies in early AD. Here we report on differences observed in characteristics of APOE ε4 and amyloid positive subjects in the large screening cohort. DESIGN: Screening was performed in 5 sequential tiers over a maximum of 80 days, as part of placebo controlled, double blind phase 3 studies. SETTING: Subjects were evaluated at sites in 7 regions (29 countries). PARTICIPANTS: Overall, 9758 subjects were screened. INTERVENTION: All screened subjects that were eligible received either placebo or 50 mg QID elenbecestat post randomisation. MEASUREMENTS: Gender, disease staging, APOE ε4 status, amyloid status, amyloid positron emission tomography (PET) standard uptake value ratio (SUVr) and amyloid PET Centiloid (CL) values were determined for screened subjects; by country and region. RESULTS: In this program, 44% of subjects were APOE ε4 positive. Frequency of females was similar in both APOE ε4 positive and negative groups. However, early mild AD subjects were slightly higher in the APOE ε4 positive group compared with the APOE ε4 negative group. 56% of subjects were amyloid positive. The mean age in the amyloid positive group was slightly higher than the amyloid negative group. The gender distribution was similar between amyloid groups. A lower number of mild cognitive impairment was observed in the amyloid positive group along with a higher number of early mild AD. APOE ε4 positive subjects were higher in amyloid positive group compared to the amyloid negative group. China had the lowest APOE ε4 and amyloid positivity rates with Western Europe and Oceania performing best. Subjects received florbetapir, florbetaben or flutemetamol amyloid PET tracer. Amyloid negative and positive subjects CL values were normally distributed around their respective means of 1.5 CL and 83 CL. However, there was an appreciable overlap in the 20-40 CL range. CONCLUSIONS: In this large cohort of cognitively impaired subjects, subject demographics characteristics were comparable regardless of APOE genotype or amyloid positivity. APOE ε4 positivity and amyloid positivity varied by country and by geographical region.

Solid self-nanoemulsifying drug delivery systems for oral delivery of polypeptide-k: Formulation, optimization, in-vitro and in-vivo antidiabetic evaluation.

Development of self-nanoemulsifying drug delivery systems (SNEDDS) of polypeptide-k (PPK) is reported with the aim to achieve its oral delivery. Box-Behnken design (BBD) was adopted to develop and optimize the composition of SNEDDS. Oleoyl polyoxyl-6 glycerides (A), Tween 80 (B), and diethylene glycol monoethyl ether (C) were used as oil, surfactant and co-surfactant, respectively as independent variables. The effect of variation in their composition was observed on the mean droplet size (y1), polydispersity index (PDI) (y2), % drug loading (y3) and zeta potential (y4). As per the optimal design, seventeen SNEDDS prototypes were prepared. The optimized composition of SNEDDS formulation was 25% v/v Oleoyl polyoxyl-6 glycerides, 37% v/v Tween 80, 38% v/v diethylene glycol monoethyl ether, and 3% w/v PPK. The optimized formulation revealed values of y1, y2, y3, and y4 as 31.89nm, 0.16, 73.15%, and -15.65mV, respectively. Further the optimized liquid SNEDDS were solidified through spray drying using various hydrophilic and hydrophobic carriers. Among the various carriers, Aerosil 200 was found to provide desirable flow, compression, disintegration and dissolution properties. Both, liquid and solid-SNEDDS have shown release of >90% within 10min. The formulation was found stable with change in pH, dilution, temperature variation and freeze thaw cycles in terms of droplet size, zeta potential, drug precipitation and phase separation. Crystalline PPK was observed in amorphous state in solid SNEDDS when characterized through DSC and PXRD studies. The biochemical, hematological and histopathological results of streptozotocin induced diabetic rats shown promising antidiabetic potential of PPK loaded in SNEDDS at its both the doses (i.e. 400mg/kg and 800mg/kg) as compared to its naïve form at both the doses. The study revealed successful formulation of SNEDDS for oral delivery of PPK.

Efficacy of an emollient containing diethylene glycol/dilinoleic acid copolymer for the treatment of dry skin and pruritus in patients with senile xerosis.

BACKGROUND AND AIMS: Pruritus frequently reduces quality of life (QOL) in patients with senile xerosis. This study investigated the moisturizing and antipruritic effects of a topical emollient containing a diethylene glycol/dilinoleic acid copolymer (D/DC) in patients with pruritic senile xerosis. METHODS: This single-blind study involved 50 subjects, aged 50-75 years. Patients were randomized to self-applied treatment of the lower legs with 10% (n = 20) or 20% (n = 20) D/DC-containing cream, white petrolatum (n = 5), or no treatment (n = 5) thrice daily for four weeks. Clinical scores of skin dryness and scratch marks, skin conductance, and Skindex-16 were evaluated before and after treatment. The degree of pruritus was evaluated by visual analog scale (VAS) score once a week. RESULTS: Patients treated with 10% and 20% D/DC showed significant improvements in skin dryness and scratch mark scores, as well as increased skin conductance, compared with the untreated group, whereas white petrolatum treatment improved only skin dryness scores. Moreover, patients treated with 20% D/DC showed significant improvements in skin dryness scores and skin conductance compared with white petrolatum treatment. The VAS scores in the D/DC-treated and white petrolatum-treated groups were significantly lower than in the untreated group, being particularly lower after one week of treatment with 20% D/DC. CONCLUSION: Topical application of an emollient containing D/DC is effective in improving skin dryness and pruritus in patients with senile xerosis.

Clinical and cost implications of amyloid beta detection with amyloid beta positron emission tomography imaging in early Alzheimer's disease - the case of florbetapir.

OBJECTIVE: Amyloid beta (Aß) positron emission tomography (PET) imaging helps estimate Aß neuritic plaque density in patients with cognitive impairment who are under evaluation for Alzheimer's disease (AD). This study aims to evaluate the cost-effectiveness of the Aß-PET scan as an adjunct to standard diagnostic assessment for diagnosis of AD in France, using florbetapir as an example. METHODS: A state-transition probability analysis was developed adopting the French Health Technology Assessment (HTA) perspective per guidance. Parameters included test characteristics, rate of cognitive decline, treatment effect, costs, and quality of life. Additional scenarios assessed the validity of the analytical framework, including: (1) earlier evaluation/treatment; (2) cerebrospinal fluid (CSF) as a comparator; and (3) use of other diagnostic procedures. Outputs included differences in quality-adjusted life years (QALYs), costs, and incremental cost-effectiveness ratios (ICERs). All benefits and costs were discounted for time preferences. Sensitivity analyses were performed to assess the robustness of findings and key influencers of outcomes. RESULTS: Aß-PET used as an adjunct to standard diagnostic assessment increased QALYs by 0.021 years and 10 year costs by €470 per patient. The ICER was €21,888 per QALY gained compared to standard diagnostic assessment alone. When compared with CSF, Aß-PET costs €24,084 per QALY gained. In other scenarios, Aß-PET was consistently cost-effective relative to the commonly used affordability threshold (€40,000 per QALY). Over 95% of simulations in the sensitivity analysis were cost-effective. CONCLUSION: Aß-PET is projected to affordably increase QALYs from the French HTA perspective per guidance over a range of clinical scenarios, comparators, and input parameters.

Effect of Polyethylene Glycol on Properties and Drug Encapsulation-Release Performance of Biodegradable/Cytocompatible Agarose-Polyethylene Glycol-Polycaprolactone Amphiphilic Co-Network Gels.

We synthesized agarose-polycaprolactone (Agr-PCL) bicomponent and Agr-polyethylene glycol-PCL (Agr-PEG-PCL) tricomponent amphiphilic co-network (APCN) gels by the sequential nucleophilic substitution reaction between amine-functionalized Agr and activated halide terminated PCL or PCL-b-PEG-b-PCL copolymer for the sustained and localized delivery of hydrophilic and hydrophobic drugs. The biodegradability of the APCNs was confirmed using lipase and by hydrolytic degradation. These APCN gels displayed good cytocompatibility and blood compatibility. Importantly, these APCN gels exhibited remarkably high drug loading capacity coupled with sustained and triggered release of both hydrophilic and hydrophobic drugs. PEG in the APCNs lowered the degree of phase separation and enhanced the mechanical property of the APCN gels. The drug loading capacity and the release kinetics were also strongly influenced by the presence of PEG, the nature of release medium, and the nature of the drug. Particularly, PEG in the APCN gels significantly enhanced the 5-fluorouracil loading capacity and lowered its release rate and burst release. Release kinetics of highly water-soluble gemcitabine hydrochloride and hydrophobic prednisolone acetate depended on the extent of water swelling of the APCN gels. Cytocompatibility/blood compatibility and pH and enzyme-triggered degradation together with sustained release of drugs show great promise for the use of these APCN gels in localized drug delivery and tissue engineering applications.

Effects of sulpiride and ethylene glycol monomethyl ether on endometrial carcinogenicity in Donryu rats.

Sulpiride and ethylene glycol monomethyl ether (EGME) are known ovarian toxicants that stimulate prolactin (PRL) secretion, resulting in hypertrophy of the corpora lutea and increased progesterone (P4) production. The purpose of the present study was to investigate how the PRL stimulatory agents affected uterine carcinogenesis and to clarify the effects of PRL on endometrial adenocarcinoma progression in rats. Ten-week-old female Donryu rats were treated once with N-ethyl-N'-nitro-N-nitrosoguanidine (20 mg kg(-1) ), followed by treatment with sulpiride (200 ppm) or EGME (1250 ppm) from 11 weeks of age to 12 months of age. Sulpiride treatment inhibited the incidence of uterine adenocarcinoma and precancerous lesions of atypical endometrial hyperplasia, whereas EGME had no effect on uterine carcinogenesis. Sulpiride markedly prevented the onset of persistent estrus throughout the study period, and EGME delayed and inhibited the onset of persistent estrus. Moreover, sulpiride-treated animals showed high PRL and P4 serum levels without changes in the levels of estradiol-17ß, low uterine weights and histological luteal cell hypertrophy. EGME did not affect serum PRL and P4 levels. These results suggest that the prolonged low estradiol-17ß to P4 ratio accompanied by persistent estrous cycle abnormalities secondary to the luteal stimulatory effects of PRL may explain the inhibitory effects of sulpiride on uterine carcinogenesis in rats. Copyright © 2015 John Wiley & Sons, Ltd.

Study results on the use of different therapies for the treatment of vaginitis in hospitalised pregnant women.

PURPOSE: During pregnancy, many women experience vaginal infections due to a weakened immune system and changes in hormonal status. Treating these infections is of crucial importance, because women are at high risk for serious complications such as preterm birth and late miscarriage. For this reason, the present study was conducted to investigate the effectiveness of octenidine dihydrochloride/phenoxyethanol (OHP) in comparison to antimicrobial therapies in pregnant women in hospital suffering from different types of vaginitis. METHODS: A total of 1,000 patients were divided into 4 different groups according to their type of vaginal infection after smear analyses. Each group was again divided into two subgroups receiving treatment with OHP or antimicrobial therapies with neomycin/polymyxin B/nystatin, metronidazole or miconazole vaginal tablets. RESULTS: The most frequent causes of vaginitis were unspecific bacterial infections (42.4 %) and vaginal candidiasis (44.8 %). The average time needed to obtain negative results from smear analyses was significantly shorter when treated with OHP, both in patients with bacterial vaginosis (BV) or vaginal candidiasis (VC) compared to antimicrobial therapy (1.7 ± 0.8 vs. 2.3 ± 1.1 days; 2.3 ± 1.4 vs. 3.4 ± 1.6 days; both p < 0.001). Equally, the maximum number of days until negative results were detected was significantly lower with OHP compared to antimicrobial therapy (BV: 3 vs. 5 days; VC: 5 vs. 7 days). CONCLUSIONS: OHP has a great effect in the treatment of vaginitis during pregnancy and thus should be an integral part of standard therapy regimens.

Amyloid imaging in Alzheimer's disease: a literature review.

Therapies targeting amyloid-ß peptide currently represent approximately 50% of drugs now being developed for Alzheimer's disease. Some, including active and passive anti-Aß immunotherapy, directly target the amyloid plaques. The new amyloid tracers are increasingly being included in the proposed updated diagnostic criteria, and may allow earlier diagnosis. Those targeting amyloid-ß peptide allow identification of amyloid plaques in vivo. We need to gain insight into all aspects of their application. As florbetapir (Amyvid™) and flutemetamol (Vizamyl™) have received marketing authorization, clinicians require deeper knowledge to be rationally used in diagnosis. In this paper, we review both completed and ongoing observational, longitudinal and interventional studies of these tracers, our main objective being to show the performance of the four most commonly used tracers and their validation.

Differential white matter connectivity in early mild cognitive impairment according to CSF biomarkers.

Mild cognitive impairment (MCI) is a heterogeneous group and certain MCI subsets eventually convert to dementia. Cerebrospinal fluid (CSF) biomarkers are known to predict this conversion. We sought evidence for the differences in white matter connectivity between early amnestic MCI (EMCI) subgroups according to a CSF phosphorylated tau181p/amyloid beta1-42 ratio of 0.10. From the Alzheimer's Disease Neuroimaging Initiative database, 16 high-ratio, 25 low-ratio EMCI patients, and 20 normal controls with diffusion tensor images and CSF profiles were included. Compared to the high-ratio group, radial diffusivity significantly increased in both sides of the corpus callosum and the superior and inferior longitudinal fasciculus in the low-ratio group. In widespread white matter skeleton regions, the low-ratio group showed significantly increased mean, axial, and radial diffusivity compared to normal controls. However, the high-ratio group showed no differences when compared to the normal group. In conclusion, our study revealed that there were significant differences in white matter connectivity between EMCI subgroups according to CSF phosphorylated tau181p/amyloid beta1-42 ratios.

[The study of quality characteristics of the hydrogel ointments and films based on copolymers divinyl esters of diethylene glycol].

The possibility of using a hydrogel based on divinyl ether co- and terpolymer of diethylene glycol as the backbone polymer for incorporating water-soluble medicinal substances was examined. The character of the influence of emulsifiers, plasticizers, high-boiling liquids and bioactive substances is defined within the changes of physical-chemical properties of obtained hydrogels. The obtained polyelectrolyte hydrogels by their homogeneity, dehydration and rheological characteristics may be of concern in function of matrices to create external prolonged-action dosage forms.

Efficacy and tolerability of a local acting antiseptic agent in the treatment of vaginal dysbiosis during pregnancy.

OBJECTIVE: In the present study, the efficacy and tolerability of the local acting antiseptic octenidine hydrochloride/phenoxyethanol (OHP) for the treatment of vaginal dysbiosis (VD) and/or bacterial vaginosis (BV) in pregnancy and its potential influence on preterm births and low-weight newborns were examined. METHODS: One-hundred nine pregnant women with increased pH values (>4.5) and BV characteristic symptoms were treated with OHP for 7 days and a second time in case of a recurrent pH increase. pH values were continuously controlled by women's self-measurements. RESULTS: pH decreased to ≤ 4.5 in 67.9% of patients. Seven of 12 women (58.3%) treated again with OHP due to a recurrent pH increase finally reached the pH target (pH ≤ 4.5). No preterm birth occurred in the OHP group; no newborn had a birth weight <2,000 g. Rates of preterm births and low-weight newborns were comparable between OHP group and pregnant women without VD/BV. CONCLUSIONS: OHP is effective and well tolerated in the treatment of VD/BV also in pregnancy without side effects and the occurrence of resistances. It could be an additional therapeutic option in the prevention of the multifactorial disease pattern 'preterm birth' with all their consequences.

Comparison of local metronidazole and a local antiseptic in the treatment of bacterial vaginosis.

OBJECTIVE: Bacterial vaginosis (BV) is characterized by a mixed flora of pathogenic anaerobic bacteria and associated with risks of pathologic conditions. In the present study, therapy with a local antiseptic spray (octenidine hydrochloride/phenoxyethanol, OHP) for 7 or 14 days is compared against the standard local therapy of BV (metronidazole) in a Serbian patient population. METHODS: As much as 450 women were treated in groups with either 7 days metronidazole vaginal tablets, 7 days OHP, or 14 days OHP. Control smears were taken after each treatment period. RESULTS: In total, 63.2% of the women were without indications of BV after therapy (metronidazole: 61.0%, OHP 7 days: 57.6%, and OHP 14 days: 71.0%). Significantly fewer women were affected from infections after treatment with 14 days OHP compared to OHP for 7 days. CONCLUSIONS: Octenidine hydrochloride/phenoxyethanol spray was as effective as the standard therapy with metronidazole. Patients stated that OHP was more comfortable, easier to apply, and side effects were lesser.

Self-assembled star-shaped chlorin-core poly(epsilon-caprolactone)-poly(ethylene glycol) diblock copolymer micelles for dual chemo-photodynamic therapies.

Amphiphilic 4-armed star-shaped chlorin-core diblock copolymers based on methoxy poly(ethylene glycol) (mPEG) and poly (epsilon-caprolactone) (PCL) were synthesized and characterized in this study. The synthesized photosensitizer-centered amphiphilic star block copolymer that forms assembled micelle-like structures can be used in a photodynamic therapy (PDT)-functionalized drug delivery system. Moreover, the hydrophobic chemotherapeutic agent, paclitaxel, can be trapped in the hydrophobic inner core of micelles. In our results, the star-polymer-formed micelle exhibited efficient singlet oxygen generation, whereas the hydrophobic photosensitizer failed due to aggregation in aqueous solution. The chlorin-core micelle without paclitaxel loading exhibited obvious phototoxicity in MCF-7 breast cancer cells with 7J/cm2 or 14J/cm2 light irradiation at a chlorin concentration of 125microg/ml. After paclitaxel loading, the size of micelle increased from 71.4nm to 103.2nm. Surprisingly, these micelles were found to improve the cytotoxicity of paclitaxel significantly in MCF-7 cells after irradiation through a synergistic effect evaluated by median effect analysis. This functionalized micellar delivery system is a potential dual carrier for the synergistic combination of photodynamic therapy and chemotherapy for the treatment of cancer.

Effect of Octenisept antiseptic on bioburden of neoplastic ulcers in patients with advanced cancer.

OBJECTIVE: To assess the effect of octenidine dihydrochloride (Octenisept, Schülke & Mayr) on the clinical condition and bacterial flora in neoplastic ulcers. METHOD: Twenty-one patients with advanced cancer and neoplastic ulcers were included in the study. Octenisept-moistened gauze dressings were applied to the ulcers three times daily. The clinical and bacteriological status of the wounds were assessed at baseline and after three weeks of treatment. RESULTS: Thirty-three bacterial strains were cultured at baseline. After three weeks of treatment, the tests were repeated on 16 patients. Clinical observations confirmed an improvement in the clinical condition of the ulcers, characterised by a reduction in necrosis, exudate levels, erythema and oedema. According to the bacteriological assessment, Staphylococcus aureus, Staphylococcus epidermidis and Proteus mirabilis were eradicated from the wounds. Enterococcus faecalis persisted in two patients, Escherichia coli in one patient and Pseudomonas aeruginosa in another patient. CONCLUSION: Octenispet was an effective antimicrobial: Staphylococcus aureus and Proteus mirabilis were eradicated in all ulcers. After three weeks of treatment, none of the ulcers developed an infection and there was an improvement in their clinical condition.

Intraperitoneal octenidindihydro-chloride - phenoxyethanol solution to prevent peritoneal adhesion formation in a rat peritonitis model.

BACKGROUND: Peritoneal adhesion is a common complication following abdominal surgery. Despite recent advances in diagnosis and treatment, it still presents a problem for the patients and surgeons. In the present study, we investigated the effects of octenidindihydro-chloride - phenoxyethanol (OCP) on peritoneal adhesions. METHOD: Rats were divided into four groups: Group 1 (saline), Group 2 (peritonitis plus saline), Group 3 (OCP), and Group 4 (peritonitis plus OCP). Peritonitis was induced in the rats of Groups 2 and 4. The abdominal cavities of the rats in Groups 1 and 2 were washed with saline, while those of the rats in Groups 3 and 4 were irrigated with 1:10 OCP solution. Adhesion and fibrotic scores were determined by re-laparotomy after 21 days. RESULTS: The adhesion scores in Groups 1 (saline), 2 (peritonitis plus saline), 3 (OCP) and 4 (peritonitis plus OCP) were 3.30+/-0.94, 5.25+/-1.03, 1.12+/-0.83 and 0.28+/-0.48, respectively. Statistical analysis of adhesion scores revealed significant differences between groups, except between Groups 3 and 4 (p=0.265). Statistical analyses of grades of histopathological signs showed that Group 1 differed from Groups 2 and 4 (p=0.004, p=0.003, respectively); Group 2 differed from Groups 3 and 4 (p=0.001, p=0.001, respectively). On the other hand, differences between Group 3 and Groups 1 and 4 were not significant (p=0.06, p=0.08, respectively). CONCLUSION: OCP decreased the peritoneal adhesion formation macroscopically and microscopically in the presence or absence of peritonitis. Peritoneal defects due to trauma are to be left open and OCP diluted 1:1 should not be used intraperitoneally.

Use of 2% 2-phenoxyethanol and 0.1% octenidine as antiseptic in premature newborn infants of 23-26 weeks gestation.

In preterm newborn infants, topical iodine-containing antiseptics disturb thyroid hormone regulation while alcohol-based disinfectants may cause local burns. We therefore investigated the use of an aqueous solution containing 0.1% octenidine and 2% 2-phenoxyethanol for skin disinfection during the first seven days of life in premature newborns with a gestational age <27 weeks who were consecutively admitted to our level III neonatal intensive care unit between November 1, 2000 and December 31, 2001 (N=24). In boys. (N=13) the renal excretion of absorbed 2-phenoxyethanol and its metabolite 2-phenoxyacetic acid was quantitated by high-pressure liquid chromatography. In the most immature newborn (gestational age 23 6/7 weeks), a transient erythematous reaction was observed following application of the octenidine/phenoxyethanol solution prior to umbilical vessel catheterization. No other local reactions were observed. The urinary concentration of 2-phenoxyethanol was <2 ppm in all samples, while urinary 2-phenoxyacetic acid concentrations reached 5-95 ppm (median 24 ppm). One infant had a culture-proven septicaemia (Bacillus species) during the first seven days of life. We conclude that, in contrast to alcohol-based antiseptics, an aqueous solution of 0.1% octenidine and 2-phenoxyethanol does not cause major skin damage in premature newborn infants <27 weeks' gestation. 2-Phenoxyethanol is readily absorbed by the newborn's skin but apparently undergoes extensive oxidative metabolization to 2-phenoxyacetic acid.

Suppression of the contact hypersensitivity response following topical exposure to 2-butoxyethanol in female BALB/c mice.

The effects of route of exposure, time of exposure and metabolism of 2-butoxyethanol (BE) on the contact hypersensitivity response (CHR) were evaluated in female BALB/c mice. Mice were either orally exposed to 50, 150 or 400 mg BE/kg or topically exposed to 0.25, 1.0, 4.0 or 16.0 mg BE on the ear and the oxazolone (OXA)-induced CHR evaluated by measuring ear thickness before and after OXA challenge. While no modulation was observed following oral exposure to BE, topical exposure resulted in a significant decrease in the CHR. Application of 4.0 mg BE in 4:1 acetone and olive oil (AOO) vehicle at the time of sensitization, challenge or both, decreased the CHR by 18%, 18% and 22%, respectively. A time course study of the effects of topical exposure to 4.0 mg BE/ear during the challenge phase of the CHR revealed that BE must be applied at the time of OXA challenge to significantly reduce the ear swelling response. In order to determine if metabolism of topically applied BE was required for suppression of the CHR, butoxyacetic acid (BAA), the primary metabolite of BE, was applied to the ear immediately following OXA challenge. No topical dose of BAA (2.0,4.0 and 8.0 mg BAA/ear) administered in this study altered the CHR. Blocking the metabolism of BE by oral administration of 4-methylpyrazole (MP), further reduced OXA-induced ear swelling when compared to mice exposed to BE without MP treatment. Taken together, these studies indicated that suppression of the CHR in mice following topical exposure to this glycol ether was due to the activity of BE itself and was not dependent on metabolic activation of the compound. Further studies were undertaken to identify a potential mechanism of BE-induced reduction of the CHR. Epidermal cells from untreated BALB/c mice were isolated and exposed to BE in vitro (10(-12), 10(-10), 10(-8), 10(-6) and l0(-4) M BE). In vitro exposure to BE at these concentrations did not significantly affect expression of MHC class II surface protein or protein synthesis in epidermal Langerhans cells, failing to provide in vitro evidence that BE-associated suppression of the CHR is associated with a reduction in MHC class II expression.