Nanostructured transdermal hormone replacement therapy for relieving menopausal symptoms: a confocal Raman spectroscopy study

Directory of Open Access Journals (Sweden)

Marco Antonio Botelho

2014-02-01

Full Text Available OBJECTIVE: To determine the safety and efficacy of a transdermal nanostructured formulation of progesterone (10% combined with estriol (0.1% + estradiol (0.25% for relieving postmenopausal symptoms. METHODS: A total of 66 postmenopausal Brazilian women with climacteric symptoms of natural menopause received transdermal nanostructured formulations of progesterone and estrogens in the forearm daily for 60 months to mimic the normal ovarian secretory pattern. Confocal Raman spectroscopy of hormones in skin layers was performed. Clinical parameters, serum concentrations of estradiol and follicle-stimulating hormone, blood pressure, BI-RADS classification from bilateral mammography, and symptomatic relief were compared between baseline and 60 months post-treatment. Clinicaltrials.gov: NCT02033512. RESULTS: An improvement in climacteric symptoms was reported in 92.5% of women evaluated before and after 60 months of treatment. The serum concentrations of estradiol and follicle-stimulating hormone changed significantly (p<0.05 after treatment; the values of serum follicle-stimulating hormone decreased after 60 months from 82.04±4.9 to 57.12±4.1 IU/mL. A bilateral mammography assessment of the breasts revealed normal results in all women. No adverse health-related events were attributed to this hormone replacement therapy protocol. CONCLUSION: The nanostructured formulation is safe and effective in re-establishing optimal serum levels of estradiol and follicle-stimulating hormone and relieving the symptoms of menopause. This transdermal hormone replacement therapy may alleviate climacteric symptoms in postmenopausal women.

Nanostructured transdermal hormone replacement therapy for relieving menopausal symptoms: a confocal Raman spectroscopy study

International Nuclear Information System (INIS)

Botelho, Marco Antonio; Queiroz, Dinalva Brito; Barros, Gisele; Guerreiro, Stela; Umbelino, Sonia; Lyra, Arao; Borges, Boniek; Freitas, Allan; Almeida, Jackson Guedes; Quintans Junior, Lucindo

2014-01-01

Objective:to determine the safety and efficacy of a transdermal nanostructured formulation of progesterone (10%) combined with estriol (0.1%) + estradiol (0.25%) for relieving postmenopausal symptoms. Methods: a total of 66 postmenopausal Brazilian women with climacteric symptoms of natural menopause received transdermal nanostructured formulations of progesterone and estrogens in the forearm daily for 60 months to mimic the normal ovarian secretory pattern. Confocal Raman spectroscopy of hormones in skin layers was performed. Clinical parameters, serum concentrations of estradiol and follicle-stimulating hormone, blood pressure, BI-RADS classification from bilateral mammography, and symptomatic relief were compared between baseline and 60 months post-treatment. Clinicaltrials.gov: NCT02033512. Results: an improvement in climacteric symptoms was reported in 92.5% of women evaluated before and after 60 months of treatment. The serum concentrations of estradiol and follicle-stimulating hormone changed significantly (p<0.05) after treatment; the values of serum follicle-stimulating hormone decreased after 60 months from 82.04 ± 4.9 to 57.12 ± 4.1 IU/mL. A bilateral mammography assessment of the breasts revealed normal results in all women. No adverse health-related events were attributed to this hormone replacement therapy protocol. Conclusion: the nanostructured formulation is safe and effective in re-establishing optimal serum levels of estradiol and follicle-stimulating hormone and relieving the symptoms of menopause. This transdermal hormone replacement therapy may alleviate climacteric symptoms in postmenopausal women. (author)

Nanostructured transdermal hormone replacement therapy for relieving menopausal symptoms: a confocal Raman spectroscopy study

Energy Technology Data Exchange (ETDEWEB)

Botelho, Marco Antonio; Queiroz, Dinalva Brito; Barros, Gisele; Guerreiro, Stela; Umbelino, Sonia; Lyra, Arao; Borges, Boniek; Freitas, Allan, E-mail: marcobotelho@pq.cnpq.br [Universidade Potiguar, Natal, RN (Brazil). Lab. de Nanotecnologia; Fechine, Pierre [Universidade Federal do Ceara (GQMAT/UFCE), Fortaleza, CE (Brazil). Dept. de Quimica Analitica. Grupo Avancado de Biomateriais em Quimica; Queiroz, Danilo Caldas de [Instituto Federal de Ciencia e Tecnologia (IFCT), Fortaleza, CE (Brazil). Lab. de Biotecnologia; Ruela, Ronaldo [Instituto de Biotecnologia Aplicada (INBIOS), Fortaleza, CE (Brazil); Almeida, Jackson Guedes [Universidade Federal do Vale de Sao Francisco (UNIVALE), Petrolina, PE (Brazil). Fac. de Ciencias Farmaceuticas; Quintans Junior, Lucindo [Universidade Federal de Sergipe (UFSE), Sao Cristovao, SE (Brazil). Dept. de Fisiologia

2014-06-01

Objective:to determine the safety and efficacy of a transdermal nanostructured formulation of progesterone (10%) combined with estriol (0.1%) + estradiol (0.25%) for relieving postmenopausal symptoms. Methods: a total of 66 postmenopausal Brazilian women with climacteric symptoms of natural menopause received transdermal nanostructured formulations of progesterone and estrogens in the forearm daily for 60 months to mimic the normal ovarian secretory pattern. Confocal Raman spectroscopy of hormones in skin layers was performed. Clinical parameters, serum concentrations of estradiol and follicle-stimulating hormone, blood pressure, BI-RADS classification from bilateral mammography, and symptomatic relief were compared between baseline and 60 months post-treatment. Clinicaltrials.gov: NCT02033512. Results: an improvement in climacteric symptoms was reported in 92.5% of women evaluated before and after 60 months of treatment. The serum concentrations of estradiol and follicle-stimulating hormone changed significantly (p<0.05) after treatment; the values of serum follicle-stimulating hormone decreased after 60 months from 82.04 ± 4.9 to 57.12 ± 4.1 IU/mL. A bilateral mammography assessment of the breasts revealed normal results in all women. No adverse health-related events were attributed to this hormone replacement therapy protocol. Conclusion: the nanostructured formulation is safe and effective in re-establishing optimal serum levels of estradiol and follicle-stimulating hormone and relieving the symptoms of menopause. This transdermal hormone replacement therapy may alleviate climacteric symptoms in postmenopausal women. (author)

Nanoparticle-Enabled Transdermal Drug Delivery Systems for Enhanced Dose Control and Tissue Targeting

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Brian C. Palmer

2016-12-01

Full Text Available Transdermal drug delivery systems have been around for decades, and current technologies (e.g., patches, ointments, and creams enhance the skin permeation of low molecular weight, lipophilic drugs that are efficacious at low doses. The objective of current transdermal drug delivery research is to discover ways to enhance skin penetration of larger, hydrophilic drugs and macromolecules for disease treatment and vaccination. Nanocarriers made of lipids, metals, or polymers have been successfully used to increase penetration of drugs or vaccines, control drug release, and target drugs to specific areas of skin in vivo. While more research is needed to identify the safety of nanocarriers, this technology has the potential to expand the use of transdermal routes of administration to a wide array of therapeutics. Here, we review the current state of nanoparticle skin delivery systems with special emphasis on targeting skin diseases.

Randomized Controlled Trial of Low-Dose Estradiol and the SNRI Venlafaxine for Vasomotor Symptoms

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Joffe, Hadine; Guthrie, Katherine A.; LaCroix, Andrea Z.; Reed, Susan D.; Ensrud, Kristine E.; Manson, JoAnn E.; Newton, Katherine M.; Freeman, Ellen W.; Anderson, Garnet L.; Larson, Joseph C.; Hunt, Julie; Shifren, Jan; Rexrode, Kathryn M.; Caan, Bette; Sternfeld, Barbara; Carpenter, Janet S.; Cohen, Lee

2014-01-01

Importance Estrogen therapy is the gold standard treatment for hot flashes and night sweats, but some women are unable or unwilling to use it because of associated risks. The serotonin-norepinephrine reuptake inhibitor venlafaxine is used widely as a non-hormonal treatment. While clinical impression is that serotonin-norepinephrine reuptake inhibitors are less effective than estrogen, these medications have not been simultaneously evaluated in one clinical trial. Objective To determine the efficacy and tolerability of low-dose oral 17-beta-estradiol and low-dose venlafaxine XR in alleviating vasomotor symptoms. Design and Participants 339 peri- and postmenopausal women with ≥2 bothersome vasomotor symptoms per day (mean 8.1, SD 5.3/day) were recruited from the community to MsFLASH (Menopause Strategies: Finding Lasting Answers for Symptoms and Health) clinical network sites November 2011—October 2012. Interventions Participants were randomized to double-blinded treatment with low-dose oral 17-beta-estradiol 0.5-mg/day (n=97), low-dose venlafaxine XR 75-mg/day (n=96), or placebo (n=146) for 8 weeks. Main Outcomes Primary outcome was the mean daily frequency of vasomotor symptoms after 8 weeks of treatment. Secondary outcomes were vasomotor symptom severity, bother and interference. Intent-to-treat analyses compared change in vasomotor symptom frequency between each active intervention and placebo and between the two active treatments. Results Compared to baseline, mean vasomotor symptom frequency at week 8 decreased by 53% with estradiol, 48% with venlafaxine, and 29% with placebo. Estradiol reduced the frequency of symptoms by 2.3 (95% CI 1.3–3.4) more per day than placebo (p<0.001), and venlafaxine by 1.8 (95% CI 0.8–2.7) more per day than placebo (p=0.005). Results were consistent for VMS severity, bother and interference. Low-dose estradiol reduced symptom frequency by 0.6 more per day than venlafaxine (95% CI, 1.8 more per day to 0.6 fewer per day than

The lowest-dose, extended-cycle combined oral contraceptive pill with continuous ethinyl estradiol in the United States: a review of the literature on ethinyl estradiol 20 µg/levonorgestrel 100 µg + ethinyl estradiol 10 µg

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Sheila Krishnan

2010-08-01

Full Text Available Sheila Krishnan, Jessica KileyDepartment of Obstetrics and Gynecology, Northwestern University, Chicago, Illinois, USAAbstract: Extended-cycle oral contraceptives (OCs are increasing in popularity in the United States. A new extended-cycle OC that contains the lowest doses of ethinyl estradiol (EE and levonorgestrel (LNG + continuous EE throughout the cycle is now available. It provides 84 days of a low-dose, combined active pill containing levonorgestrel 100 µg and ethinyl estradiol 20 µg. Instead of 7 days of placebo following the active pills, the regimen delivers 7 days of ethinyl estradiol 10 µg. Existing studies reveal a similar efficacy and adverse effect profile compared with other extended-regimen OCs. Specifically, the unscheduled bleeding profile is similar to other extended-cycle OCs and improves with the increase in the duration of use. Although lower daily doses of hormonal exposure have potential benefit, to our knowledge, there are no published studies indicating that this specific regimen offers a lower incidence of hormone-related side effects or adverse events. In summary, this new extended-cycle OC provides patients a low-dose, extended-regimen OC option without sacrificing efficacy or tolerability.Keywords: continuous regimen, ethinyl estradiol, extended cycle, oral contraceptive

Prostate enlargement in mice due to fetal exposure to low doses of estradiol or diethylstilbestrol and opposite effects at high doses

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Saal, Frederick S. vom; Timms, Barry G.; Montano, Monica M.; Palanza, Paola; Thayer, Kristina A.; Nagel, Susan C.; Dhar, Minati D.; Ganjam, V. K.; Parmigiani, Stefano; Welshons, Wade V.

1997-01-01

On the basis of results of studies using high doses of estrogens, exposure to estrogen during fetal life is known to inhibit prostate development. However, it is recognized in endocrinology that low concentrations of a hormone can stimulate a tissue, while high concentrations can have the opposite effect. We report here that a 50% increase in free-serum estradiol in male mouse fetuses (released by a maternal Silastic estradiol implant) induced a 40% increase in the number of developing prostatic glands during fetal life; subsequently, in adulthood, the number of prostatic androgen receptors per cell was permanently increased by 2-fold, and the prostate was enlarged by 30% (due to hyperplasia) relative to untreated males. However, as the free serum estradiol concentration in male fetuses was increased from 2- to 8-fold, adult prostate weight decreased relative to males exposed to the 50% increase in estradiol. As a model for fetal exposure to man-made estrogens, pregnant mice were fed diethylstilbestrol (DES) from gestation days 11 to 17. Relative to controls, DES doses of 0.02, 0.2, and 2.0 ng per g of body weight per day increased adult prostate weight, whereas a 200-ng-per-g dose decreased adult prostate weight in male offspring. Our findings suggest that a small increase in estrogen may modulate the action of androgen in regulating prostate differentiation, resulting in a permanent increase in prostatic androgen receptors and prostate size. For both estradiol and DES, prostate weight first increased then decreased with dose, resulting in an inverted-U dose-response relationship. PMID:9050904

Administration route-dependent effects of estrogens on IGF-I levels during fixed GH replacement in women with hypopituitarism

NARCIS (Netherlands)

van der Klaauw, Agatha A.; Biermasz, Nienke R.; Zelissen, Pierre M. J.; Pereira, Alberto M.; Lentjes, Eef G. W. M.; Smit, Johannes W. A.; van Thiel, Sjoerd W.; Romijn, Johannes A.; Roelfsema, Ferdinand

2007-01-01

GH-deficient women using oral estradiol treatment require higher doses of recombinant human GH (rhGH) to achieve similar IGF-I levels when compared with men and women on transdermal estradiol replacement. The aim of this study was to evaluate the effects of oral versus transdermal estrogen

Microdose transdermal estrogen therapy for relief of vulvovaginal symptoms in postmenopausal women.

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Bachmann, Gloria A; Schaefers, Matthias; Uddin, Alkaz; Utian, Wulf H

2009-01-01

The aim of this study was to investigate the effectiveness of microdose transdermal 17beta-estradiol (E2) therapy in postmenopausal women with moderate to severe vulvovaginal symptoms. This report is based on a subset of 121 women who reported most bothersome moderate or severe vulvovaginal symptoms at baseline, from a previous randomized, double-blind, placebo-controlled, multicenter study of 425 healthy, symptomatic, postmenopausal women. Recruits had experienced at least 7 moderate or severe hot flushes daily for at least 1 week or at least 50 moderate or severe hot flushes per week for at least 1 week. Effects on coprimary efficacy variables have been reported previously. Participants received low-dose transdermal E2 plus levonorgestrel (n = 43; nominal delivery 0.023 mg/d E2/0.0075 mg/d levonorgestrel), microdose E2 (n = 42; nominal delivery 0.014 mg/d), or placebo (n = 36) for 12 weeks. Secondary efficacy variables reported herein include mean change from baseline in vaginal pH and vaginal maturation index, the proportion of women with symptoms of vulvar and vaginal atrophy at baseline and week 12, and the proportion of women with moderate-to-severe symptoms of vulvar and vaginal atrophy. Microdose transdermal E2 treatment was associated with a consistent benefit versus placebo in women with vulvovaginal atrophy. There was a statistically significant difference between both E2 versus placebo for changes in vaginal pH and vaginal maturation index. Microdose transdermal E2 offers a useful addition to the therapeutic armamentarium for postmenopausal women in whom vulvovaginal symptoms are particularly troublesome.

Transdermal drug delivery

OpenAIRE

Prausnitz, Mark R.; Langer, Robert

2008-01-01

Transdermal drug delivery has made an important contribution to medical practice, but has yet to fully achieve its potential as an alternative to oral delivery and hypodermic injections. First-generation transdermal delivery systems have continued their steady increase in clinical use for delivery of small, lipophilic, low-dose drugs. Second-generation delivery systems using chemical enhancers, non-cavitational ultrasound and iontophoresis have also resulted in clinical products; the ability ...

Evidence that 17alpha-estradiol is biologically active in the uterine tissue: Antiuterotonic and antiuterotrophic action

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Navarrete Erika

2005-07-01

Full Text Available Abstract Background 17alpha-Estradiol has been considered as the hormonally inactive isomer of 17beta-estradiol. Recently, nongenomic (smooth muscle relaxation and genomic (light estrogenic activity effects of 17alpha-estradiol have been reported, but no reports have yet determined its possible antiestrogenic activity. Therefore, this study investigated: the nongenomic action of 17alpha-estradiol on uterine contractile activity and its potential agonist-antagonist activity on uterine growth. Methods Uterine rings from rats were isometrically recorded. Different concentrations (0.2–200 microM of 17alpha-estradiol were tested on spontaneous contraction and equimolarly compared with 17beta-estradiol. To examine the mechanism of 17alpha-estradiol action, its effect was studied in presence of beta2-antagonist (propranolol, antiestrogens (tamoxifen and ICI 182,780 or inhibitors of protein synthesis (cycloheximide and transcription (actinomycin D. Moreover, contractions induced by high potassium (KCl solution or calcium in depolarized tissues by KCl-calcium free solution were exposed to 17alpha-estradiol. Collaterally, we performed an uterotrophic assay in adult ovariectomized rats measuring the uterine wet weight. The administration for three days of 0.3 microM/day/Kg 17beta-estradiol was equimolarly compared with the response produced by 17alpha-estradiol. Antiuterotrophic activity was assayed by administration of 0.3 microM/day/Kg 17beta-estradiol and various doses ratios (1:1, 1:3, 1:5, and 1:100 of 17alpha-estradiol. Results The estradiol isomers elicited an immediate relaxation, concentration-dependent and reversible on spontaneous contraction. 17alpha-Estradiol presented lower potency than 17beta-estradiol although it did not antagonize 17beta-estradiol-induced relaxation. Relaxation to 17alpha-estradiol was not inhibited by propranolol, tamoxifen, ICI 182,780, cycloheximide or actinomycin D. The KCl contractions were also sensitive to 17alpha-estradiol

Efficacy and safety of a transdermal contraceptive system.

Science.gov (United States)

Smallwood, G H; Meador, M L; Lenihan, J P; Shangold, G A; Fisher, A C; Creasy, G W

2001-11-01

To evaluate the efficacy, cycle control, compliance, and safety of a transdermal contraceptive system that delivers norelgestromin 150 microg and ethinyl estradiol 20 microg daily. In this open-label, 73-center study, 1672 healthy, ovulatory, sexually active women received ORTHO EVRA/EVRA for six (n = 1171) or 13 cycles (n = 501). The treatment regimen for each cycle was three consecutive 7-day patches (21 days) followed by 1 patch-free week. The overall and method-failure probabilities of pregnancy through 13 cycles were 0.7% and 0.4%, respectively. The incidence of breakthrough bleeding was low throughout the study. Perfect compliance (21 consecutive days of dosing, followed by a 7-day drug-free interval; no patch could be worn for more than 7 days) was achieved in 90% of subject cycles; only 1.9% of patches detached completely. Adverse events were typical of hormonal contraception, and most were mild-to-moderate in severity and not treatment limiting. The most common adverse events resulting in discontinuation were application site reactions (1.9%), nausea (1.8%), emotional lability (1.5%), headache (1.1%), and breast discomfort (1.0%). The transdermal contraceptive patch provides effective contraception and cycle control, and is well tolerated. The weekly change schedule for the contraceptive patch is associated with excellent compliance and wearability characteristics.

Inefficacy of high-dose transdermal fentanyl in a patient with neuropathic pain, a case report.

NARCIS (Netherlands)

Bleeker, C.P.; Bremer, R.; Dongelmans, D.A.; Dongen, R.T.M. van; Crul, B.J.P.

2001-01-01

Pain partially responsive to opioids can lead to rapid escalating dosages due to tolerance development. In this report the case of a 58-year-old female with neuropathic pain using increasing transdermal (TTS) fentanyl dosages to a maximum dose of 3400 microg/h resulting in fentanyl plasma levels of

Transdermal testosterone replacement therapy in men

Directory of Open Access Journals (Sweden)

Ullah MI

2014-01-01

Full Text Available M Iftekhar Ullah,1 Daniel M Riche,1,2 Christian A Koch1,31Department of Medicine, University of Mississippi Medical Center, 2Department of Pharmacy Practice, The University of Mississippi, 3GV (Sonny Montgomery VA Medical Center, Jackson, MS, USAAbstract: Androgen deficiency syndrome in men is a frequently diagnosed condition associated with clinical symptoms including fatigue, decreased libido, erectile dysfunction, and metabolic syndrome. Serum testosterone concentrations decline steadily with age. The prevalence of androgen deficiency syndrome in men varies depending on the age group, known and unknown comorbidities, and the respective study group. Reported prevalence rates may be underestimated, as not every man with symptoms of androgen deficiency seeks treatment. Additionally, men reporting symptoms of androgen deficiency may not be correctly diagnosed due to the vagueness of the symptom quality. The treatment of androgen deficiency syndrome or male hypogonadism may sometimes be difficult due to various reasons. There is no consensus as to when to start treating a respective man or with regards to the best treatment option for an individual patient. There is also lack of familiarity with treatment options among general practitioners. The formulations currently available on the market are generally expensive and dose adjustment protocols for each differ. All these factors add to the complexity of testosterone replacement therapy. In this article we will discuss the general indications of transdermal testosterone replacement therapy, available formulations, dosage, application sites, and recommended titration schedule.Keywords: hypogonadism, transdermal, testosterone, sexual function, testosterone replacement therapy, estradiol

Effects of oral and transdermal estrogen on IGF1, IGFBP3, IGFBP1, serum lipids, and glucose in patients with hypopituitarism during GH treatment: a randomized study.

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Isotton, Ana Lúcia; Wender, Maria Celeste Osorio; Casagrande, Alessandra; Rollin, Guilherme; Czepielewski, Mauro Antônio

2012-02-01

To evaluate the effects of oral estradiol and transdermal 17β-estradiol on serum concentrations of IGF1 and its binding proteins in women with hypopituitarism. Prospective, comparative study. Eleven patients with hypopituitarism were randomly allocated to receive 2 mg oral estradiol (n=6) or 50 μg/day of transdermal 17β-estradiol (n=5) for 3 months. The oral estrogen group showed a significant reduction in IGF1 levels (mean: 42.7%±41.4, P=0.046); no difference was observed in the transdermal estrogen group. There was a significant increase in IGFBP1 levels (mean: 170.2%±230.9, P=0.028) in the oral group, but not in the transdermal group. There was no significant difference within either group in terms of median IGFBP3 levels. In relation to lipid profiles, there was a significant increase in mean high-density lipoprotein cholesterol levels in the oral group after 3 months of treatment, (27.8±9.3, P=0.003). We found no differences in the anthropometric measurements, blood pressure, heart rate, glucose, insulin, C-peptide, or the homeostasis model assessment index after treatment. Our preliminary data indicate that different estrogen administration routes can influence IGF1 and IGFBP1 levels. These findings in patients with hypopituitarism have an impact on their response to treatment with GH, since patients receiving oral estrogen require increased GH dosage. These results suggest that oral estrogens may reduce the beneficial effects of GH replacement on fat and protein metabolism, body composition, and quality of life.

Transdermal patches: history, development and pharmacology

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Pastore, Michael N; Kalia, Yogeshvar N; Horstmann, Michael; Roberts, Michael S

2015-01-01

Transdermal patches are now widely used as cosmetic, topical and transdermal delivery systems. These patches represent a key outcome from the growth in skin science, technology and expertise developed through trial and error, clinical observation and evidence-based studies that date back to the first existing human records. This review begins with the earliest topical therapies and traces topical delivery to the present-day transdermal patches, describing along the way the initial trials, devices and drug delivery systems that underpin current transdermal patches and their actives. This is followed by consideration of the evolution in the various patch designs and their limitations as well as requirements for actives to be used for transdermal delivery. The properties of and issues associated with the use of currently marketed products, such as variability, safety and regulatory aspects, are then described. The review concludes by examining future prospects for transdermal patches and drug delivery systems, such as the combination of active delivery systems with patches, minimally invasive microneedle patches and cutaneous solutions, including metered-dose systems. PMID:25560046

Transdermal drug delivery

Science.gov (United States)

Prausnitz, Mark R.; Langer, Robert

2009-01-01

Transdermal drug delivery has made an important contribution to medical practice, but has yet to fully achieve its potential as an alternative to oral delivery and hypodermic injections. First-generation transdermal delivery systems have continued their steady increase in clinical use for delivery of small, lipophilic, low-dose drugs. Second-generation delivery systems using chemical enhancers, non-cavitational ultrasound and iontophoresis have also resulted in clinical products; the ability of iontophoresis to control delivery rates in real time provides added functionality. Third-generation delivery systems target their effects to skin’s barrier layer of stratum corneum using microneedles, thermal ablation, microdermabrasion, electroporation and cavitational ultrasound. Microneedles and thermal ablation are currently progressing through clinical trials for delivery of macromolecules and vaccines, such as insulin, parathyroid hormone and influenza vaccine. Using these novel second- and third-generation enhancement strategies, transdermal delivery is poised to significantly increase impact on medicine. PMID:18997767

Transdermal granisetron.

Science.gov (United States)

Duggan, Sean T; Curran, Monique P

2009-01-01

Granisetron is a highly selective serotonin 5-HT(3) receptor antagonist for the prevention of chemotherapy-induced nausea and vomiting. The transdermal granisetron system delivers continuous granisetron (3.1 mg/day) into the systemic circulation (via passive diffusion) for up to 7 days. In a large phase III trial in cancer patients receiving multi-day (3-5 days) moderately or highly emetogenic chemotherapy, transdermal granisetron applied 24-48 hours prior to chemotherapy and remaining in place for 7 days was noninferior to oral granisetron 2 mg once daily administered for 3-5 days 1 hour prior to chemotherapy. Efficacy was assessed according to the proportion of patients achieving complete response (no vomiting and/or retching, no more than mild nausea, no rescue medication) from the first day, until 24 hours after the start of the last day, of administration of the chemotherapy regimen. In a phase II trial in patients with cancer receiving single-day, moderately-emetogenic chemotherapy, transdermal granisetron applied at least 24 hours prior to chemotherapy and removed after 5 days was as effective as a single oral dose of granisetron 2 mg in achieving total control (no nausea, no vomiting/retching, no use of rescue medication and no study withdrawal) during the delayed (24-120 hours; primary endpoint) period after chemotherapy. Transdermal granisetron was generally well tolerated in clinical trials, with few adverse events being treatment related.

Effect of microdose transdermal 17beta-estradiol compared with raloxifene in the prevention of bone loss in healthy postmenopausal women: a 2-year, randomized, double-blind trial.

Science.gov (United States)

Schaefers, Matthias; Muysers, Christoph; Alexandersen, Peter; Christiansen, Claus

2009-01-01

Declining estrogen levels after menopause result in bone loss and increased fracture risk. This study investigated whether transdermal microdose 17beta-estradiol (E2) has efficacy and safety comparable to those of raloxifene, a selective estrogen-receptor modulator approved for the prevention and treatment of postmenopausal osteoporosis. This study involved a multicenter, randomized, double-blind, active-controlled, noninferiority trial in 500 osteopenic postmenopausal women comparing transdermal microdose E2 (0.014 mg/d) versus oral raloxifene (60 mg/d), administered for 2 years. Percent change from baseline in bone mineral density at the lumbar spine was measured after 2 years of treatment. Secondary endpoints included proportion of women with no loss of bone mineral density in lumbar spine, change in bone mineral density at hip, biochemical markers of bone turnover, and safety parameters. In the per protocol set, lumbar spine bone mineral density increased by 2.4% (95% CI, 1.9-2.9) with microdose E2 versus 3.0% (95% CI, 2.5-3.5) with raloxifene after 2 years; 77.3% of E2 recipients and 80.5% of those taking raloxifene had no bone loss in the lumbar spine. Both treatments were well tolerated. Most women (99% in the E2 group and 100% in the raloxifene group) showed no histological evidence of endometrial stimulation after 2 years. Mean dense area in breast mammograms was 19.8% in the E2 group versus 19.0% in the raloxifene group after 2 years. Transdermal microdose E2 was similarly effective as raloxifene in preventing bone loss at the lumbar spine. Both treatments were well tolerated, with no clinically significant effect on endometrium or breast density.

Pharmacokinetic characteristics of formulated alendronate transdermal delivery systems in rats and humans.

Science.gov (United States)

Choi, Ahyoung; Gang, Hyesil; Whang, Jiae; Gwak, Hyesun

2010-05-01

The objective of this study was to examine the absorption of alendronate from formulated transdermal delivery systems in rats and humans. When alendronate was applied to rats by transdermal delivery systems (7.2 mg) and oral administration (30 mg/kg), a statistically significant difference was found in the amount remaining to be excreted at time t (Ae(t)) and the amount remaining to be excreted at time 0 (Ae(infinity)) (p transdermal delivery systems. There was a linear relationship (r(2) = 0.9854) between the drug loading dose and Ae(infinity). The Ae(infinity) values from the transdermal delivery system containing 6% caprylic acid (53.8 mg as alendronate) and an oral product (Fosamax), 70 mg as alendronate) in humans were 127.0 +/- 34.2 microg and 237.2 +/- 56.3 microg, respectively. The dose-adjusted relative Ae(infinity) ratio of the transdermal delivery system to oral product was calculated to be 69.7%. The long half-life of alendronate in the transdermal delivery system (50.6 +/- 6.4 h), compared to that of the oral product (3.5 +/- 1.1 h) could allow less-frequent dosing. In conclusion, this study showed that a transdermal delivery system containing 6% caprylic acid in PG could be a favorable alternative for alendronate administration.

Spray-on transdermal drug delivery systems.

Science.gov (United States)

Ibrahim, Sarah A

2015-02-01

Transdermal drug delivery possesses superior advantages over other routes of administration, particularly minimizing first-pass metabolism. Transdermal drug delivery is challenged by the barrier nature of skin. Numerous technologies have been developed to overcome the relatively low skin permeability, including spray-on transdermal systems. A transdermal spray-on system (TSS) usually consists of a solution containing the drug, a volatile solvent and in many cases a chemical penetration enhancer. TSS promotes drug delivery via the complex interplay between solvent evaporation and drug-solvent drag into skin. The volatile solvent carries the drug into the upper layers of the stratum corneum, and as the volatile solvent evaporates, an increase in the thermodynamic activity of the drug occurs resulting in an increased drug loading in skin. TSS is easily applied, delivering flexible drug dosage and associated with lower incidence of skin irritation. TSS provides a fast-drying product where the volatile solvent enables uniform drug distribution with minimal vehicle deposition on skin. TSS ensures precise dose administration that is aesthetically appealing and eliminates concerns of residual drug associated with transdermal patches. Furthermore, it provides a better alternative to traditional transdermal products due to ease of product development and manufacturing.

Effect of oral and transdermal hormone therapy on hyaluronic acid in women with and without a history of intrahepatic cholestasis of pregnancy.

Science.gov (United States)

Tuomikoski, Pauliina; Aittomäki, Kristiina; Mikkola, Tomi S; Ropponen, Anne; Ylikorkala, Olavi

2008-04-01

Intrahepatic cholestasis of pregnancy predisposes women to liver disorders years after affected pregnancy. We compared the basal levels and responses of hyaluronic acid, a marker of liver fibrosis, and liver transaminases to postmenopausal hormone therapy in women with (n = 20) and without (n = 20) a history of intrahepatic cholestasis of pregnancy. This was a randomized, double-blind, placebo-controlled, crossover trial. Basal levels of hyaluronic acid were similar in both groups. Two weeks of oral estradiol 2.0 mg/day led to significant but similar (10.9% to 15.4%) rises in hyaluronic acid in both groups. Increasing the dose of oral estradiol to 4.0 mg/day resulted in normalization of the levels, whereas the addition of medroxyprogesterone acetate led to falls (11.0% to 10.7 %) in hyaluronic acid. Transdermal estradiol 50 microg led to a rise (3.2 %) in hyaluronic acid only in the control group. Other liver markers were normal at baseline and during hormone therapy. Normal basal levels and/or normal responses of hyaluronic acid and other liver markers to hormone therapy in women with previous intrahepatic cholestasis suggest that this therapy does not predispose these women to liver diseases.

A new once-a-day fentanyl citrate patch (Fentos Tape) could be a new treatment option in patients with end-of-dose failure using a 72-h transdermal fentanyl matrix patch.

Science.gov (United States)

Koike, Kazuhiko; Terui, Takeshi; Nagasako, Tomokazu; Horiuchi, Iori; Machino, Takayuki; Kusakabe, Toshiro; Hirayama, Yasuo; Mihara, Hiroyoshi; Yamakage, Michiaki; Kato, Junji; Nishisato, Takuji; Ishitani, Kunihiko

2016-03-01

The recommended dosing interval for transdermal fentanyl is every 72 h. However, some patients will have "end-of-dose failure," which may be seen as an increase of episodes of severe pain flares at the third day after application of the patch. A new once-a-day fentanyl patch was developed in Japan since 2010. This study aimed to assess the efficacy of the once-a-day fentanyl citrate patch for patients with cancer-related pain receiving the 72-h transdermal fentanyl not lasting 72 h. We performed a cross-sectional retrospective analysis of 445 inpatients with the 72-h transdermal fentanyl at Higashi Sapporo Hospital. We could switch to the once-a-day fentanyl citrate patch if patients reported inadequate pain relief beyond 48 h after application of the 72-h transdermal fentanyl. Patients recorded baseline scores for background pain intensity (PI) and the frequency of use of daily rescue medication for breakthrough cancer pain (BTcP). Of all patients, 10.1% showed the increase in PI of 30% or more baseline PI on the third day after application of the 72-h transdermal fentanyl. Of patients, 84.4% were converted from equivalent dose of the 72-h transdermal fentanyl to the once-a-day fentanyl citrate patch. On the third day after switching, 60.5% of patients showed a reduction of more than 30% from baseline PI. Switching to the once-a-day fentanyl citrate patch significantly reduced the mean frequency of daily rescue dose for BTcP. A once-a-day fentanyl citrate patch provided stable pain control. Its use may be considered as the dominant strategy for patients receiving a 72-h transdermal fentanyl not lasting 72 h.

High-dose estradiol improves cognition for women with AD: results of a randomized study.

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Asthana, S; Baker, L D; Craft, S; Stanczyk, F Z; Veith, R C; Raskind, M A; Plymate, S R

2001-08-28

To characterize the cognitive and neuroendocrine response to treatment with a high dose of estrogen for postmenopausal women with AD. Twenty postmenopausal women with AD were randomized to receive either 0.10 mg/day of 17 beta-estradiol by skin patch or a placebo patch for 8 weeks. Subjects were evaluated at baseline, at weeks 3, 5, and 8 during treatment, and again 8 weeks after treatment termination. During each visit, cognition was assessed with a battery of neuropsychological tests, and blood samples were collected to measure plasma estradiol as well as several other neuroendocrine markers of interest. Significant effects of estrogen treatment were observed on attention (Stroop Color Word Interference Test), verbal memory (Buschke Selective Reminding Test), and visual memory (Figure Copy/Memory). In addition, women treated with estrogen demonstrated improved performance on a test of semantic memory (Boston Naming Test) compared with subjects who received a placebo. Estrogen appeared to have a suppressive effect on the insulin-like growth factor (IGF) system such that plasma concentration of IGF binding protein-3 was significantly reduced and plasma levels of estradiol and IGF-I were negatively correlated during estrogen treatment. Administration of a higher dose of estrogen may enhance attention and memory for postmenopausal women with AD. Although these findings provide further clinical evidence to support a cognitive benefit of estrogen for women with AD, studies evaluating the effect of estradiol administration, in particular, using larger sample sizes and for longer treatment durations are warranted before the therapeutic potential of estrogen replacement for women with AD can be firmly established.

Efficacy of a single dose of a transdermal diclofenac patch as pre ...

African Journals Online (AJOL)

Background: We compared the analgesic efficacy of a transdermal diclofenac patch 100 mg (NuPatch® 100, Zydus Cadila, Ahmedabad, India) and intramuscular diclofenac sodium 75 mg (Voveran®, Novartis, India) for postoperative analgesia, and the associated side-effects of the transdermal diclofenac patch. Method: ...

Peptide-chaperone-directed transdermal protein delivery requires energy.

Science.gov (United States)

Ruan, Renquan; Jin, Peipei; Zhang, Li; Wang, Changli; Chen, Chuanjun; Ding, Weiping; Wen, Longping

2014-11-03

The biologically inspired transdermal enhanced peptide TD1 has been discovered to specifically facilitate transdermal delivery of biological macromolecules. However, the biological behavior of TD1 has not been fully defined. In this study, we find that energy is required for the TD1-mediated transdermal protein delivery through rat and human skins. Our results show that the permeation activity of TD1-hEGF, a fusion protein composed of human epidermal growth factor (hEGF) and the TD1 sequence connected with a glycine-serine linker (GGGGS), can be inhibited by the energy inhibitor, rotenone or oligomycin. In addition, adenosine triphosphate (ATP), the essential energetic molecule in organic systems, can effectively facilitate the TD1 directed permeation of the protein-based drug into the skin in a dose-dependent fashion. Our results here demonstrate a novel energy-dependent permeation process during the TD1-mediated transdermal protein delivery that could be valuable for the future development of promising new transdermal drugs.

Evaluation of the Percutaneous Absorption of Ketamine HCl, Gabapentin, Clonidine HCl, and Baclofen, in Compounded Transdermal Pain Formulations, Using the Franz Finite Dose Model.

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Bassani, August S; Banov, Daniel

2016-02-01

This study evaluates the ability of four commonly used analgesics (ketamine HCl, gabapentin, clonidine HCl, and baclofen), when incorporated into two transdermal compounding bases, Lipoderm and Lipoderm ActiveMax, to penetrate human cadaver trunk skin in vitro, using the Franz finite dose model. In vitro experimental study. Methods. Ketamine HCl 5% w/w, gabapentin 10% w/w, clonidine HCl 0.2% w/w, and baclofen 2% w/w were compounded into two transdermal bases, Lipoderm and Lipoderm ActiveMax. Each compounded drug formulation was tested on skin from three different donors and three replicate skin sections per donor. The Franz finite dose model was used in this study to evaluate the percutaneous absorption and distribution of drugs within each formulation. Rapid penetration to peak flux was detected for gabapentin and baclofen at approximately 1 hour after application. Clonidine HCl also had a rapid penetration to peak flux occurring approximately 1 hour after application and had a secondary peak at approximately 40 hours. Ketamine HCl exhibited higher overall absorption rates than the other drugs, and peaked at 6–10 hours. Similar patterns of drug distribution within the skin were also observed using both transdermal bases. This study suggests that the combination of these 4 analgesic drugs can be successfully delivered transdermally, using either Lipoderm or Lipoderm ActiveMax. Compounded transdermal drug preparations may then provide physicians with an alternative to traditional oral pain management regimens that can be personalized to the specific patient with the potential for enhanced pain control.

High-Dose Estradiol-Replacement Therapy Enhances the Renal Vascular Response to Angiotensin II via an AT2-Receptor Dependent Mechanism

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Tahereh Safari

2015-01-01

Full Text Available Physiological levels of estrogen appear to enhance angiotensin type 2 receptor- (AT2R- mediated vasodilatation. However, the effects of supraphysiological levels of estrogen, analogous to those achieved with high-dose estrogen replacement therapy in postmenopausal women, remain unknown. Therefore, we pretreated ovariectomized rats with a relatively high dose of estrogen (0.5 mg/kg/week for two weeks. Subsequently, renal hemodynamic responses to intravenous angiotensin II (Ang II, 30–300 ng/kg/min were tested under anesthesia, while renal perfusion pressure was held constant. The role of AT2R was examined by pretreating groups of rats with PD123319 or its vehicle. Renal blood flow (RBF decreased in a dose-related manner in response to Ang II. Responses to Ang II were enhanced by pretreatment with estradiol. For example, at 300 ng kg−1 min−1, Ang II reduced RBF by 45.7±1.9% in estradiol-treated rats but only by 27.3±5.1% in vehicle-treated rats. Pretreatment with PD123319 blunted the response of RBF to Ang II in estradiol-treated rats, so that reductions in RBF were similar to those in rats not treated with estradiol. We conclude that supraphysiological levels of estrogen promote AT2R-mediated renal vasoconstriction. This mechanism could potentially contribute to the increased risk of cardiovascular disease associated with hormone replacement therapy using high-dose estrogen.

Micro-dosing for early biokinetic studies in humans

International Nuclear Information System (INIS)

Stenstroem, K.; Sydoff, M.; Mattsson, S.

2010-01-01

Micro-dosing is a new concept in drug development that-if implemented in the pharmaceutical industry-would mean that new drugs can be tested earlier in humans than done today. The human micro-dosing concept-or 'Phase 0'-may offer improved candidate selection, reduced failure rates in the drug development line and a reduction in the use of laboratory animals in early drug development, factors which will help to speed up drug development and also reduce the costs. Micro-dosing utilises sub-pharmacological amounts of the substance to open opportunities for early studies in man. Three technologies are used for micro-dosing: accelerator mass spectrometry (AMS), positron emission tomography and liquid chromatography-tandem mass spectrometry. This paper focuses on the principle of AMS and discusses the current status of micro-dosing with AMS. (authors)

In vitro human skin permeation of endoxifen: potential for local transdermal therapy for primary prevention and carcinoma in situ of the breast

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Lee O

2011-07-01

Full Text Available Oukseub Lee1, David Ivancic1, Robert T Chatterton Jr2, Alfred W Rademaker3, Seema A Khan11Department of Surgery, 2Department of Obstetrics/Gynecology, 3Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USAPurpose: Oral tamoxifen, a triphenylethylene (TPE, is useful for breast cancer prevention, but its adverse effects limit acceptance by women. Tamoxifen efficacy is related to its major metabolites 4-hydroxytamoxifen (4-OHT and N-desmethyl-4-hydroxytamoxifen (endoxifen [ENX]. Transdermal delivery of these to the breast may avert the toxicity of oral tamoxifen while maintaining efficacy. We evaluated the relative efficiency of skin permeation of 4-OHT and ENX in vitro, and tested oleic acid (OA as a permeation-enhancer.Methods: 4-OHT, ENX, and estradiol (E2 (0.2 mg/mL of 0.5 µCi 3H/mg were dissolved in 60% ethanol-phosphate buffer, ±OA (0.1%–5%. Permeation through EpiDermTM (Matek Corp, Ashland, MA and split-thickness human skin was calculated based on the amount of the agents recovered from the receiver fluid and skin using liquid scintillation counting over 24 hours.Results: In the EpiDerm model, the absorption of 4-OHT and ENX was 10%–11%; total penetration (TP was 26%–29% at 24 hours and was decreased by OA. In normal human skin, the absorption of 4-OHT and ENX was 0.3%; TP was 2%–4% at 24 hours. The addition of 1% OA improved the permeation of ENX significantly more than that of 4-OHT (P < 0.004; further titration of OA at 0.25%–0.5% further improved the permeation of ENX to a level similar to that of estradiol.Conclusion: The addition of OA to ENX results in a favorable rapid delivery equivalent to that of estradiol, a widely used transdermal hormone. The transdermal delivery of ENX to the breast should be further developed in preclinical and clinical studies.Keywords: endoxifen, breast cancer prevention, human skin, transdermal, oleic acid

Minimization of CYP2D6 Polymorphic Differences and Improved Bioavailability via Transdermal Administration: Latrepirdine Example.

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Chew, Marci L; Mordenti, Joyce; Yeoh, Thean; Ranade, Gautam; Qiu, Ruolun; Fang, Juanzhi; Liang, Yali; Corrigan, Brian

2016-08-01

Transdermal delivery has the potential to offer improved bioavailability by circumventing first-pass gut and hepatic metabolism. This study evaluated the pharmacokinetics of oral immediate release and transdermal latrepirdine in extensive and poor CYP2D6 metabolizers (EM/PM). Latrepirdine transdermal solution was prepared extemporaneously. The solution was applied with occlusive dressing to upper or middle back for 24 h. Each subject received a single dose of 8.14 mg oral, 5 mg transdermal, and 10 mg transdermal (EMs only) latrepirdine free base in a fixed sequence. Twelve EMs and 7 PMs (50-79 years) enrolled and completed the study. Latrepirdine was well tolerated following both routes of administration. Dose-normalized latrepirdine total exposures were approximately 11-fold and 1.5-fold higher in EMs and PMs, respectively following administration of transdermal relative to oral. Differences between EM and PM latrepirdine exposures were decreased, with PMs having 1.9- and 2.7-fold higher peak and total exposures, respectively, following transdermal administration compared to 11- and 20-fold higher exposures, respectively, following oral administration. Transdermal delivery can potentially mitigate the large intersubject differences observed with compounds metabolized primarily by CYP2D6. Transdermal delivery was readily accomplished in the clinic using an extemporaneously prepared solution [NCT00990613].

Involvement of CART in estradiol-induced anorexia.

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Dandekar, Manoj P; Nakhate, Kartik T; Kokare, Dadasaheb M; Subhedar, Nishikant K

2012-01-18

Since estradiol exercises inhibitory effect on food intake, we wanted to find out if this influence of estradiol is mediated by cocaine- and amphetamine-regulated transcript peptide (CART), a well established anorectic agent in the brain. Ovariectomized (OVX) rats, replaced with estradiol to produce estrous-phase like conditions, showed a significant decrease in food intake as compared with that in OVX controls. Intracerebroventricular (icv) administration of CART (0.5-1 μg/rat) to OVX rats, resulted in a dose-dependent reduction in the food intake. The lower dose (0.25 μg) had no effect, and was considered subeffective. In estradiol replaced OVX rats, CART at subeffective dose, further reduced food intake. However, CART failed to reduce food intake in estradiol replaced OVX rats pretreated with anti-estrogenic agent tamoxifen (3 mg/kg, subcutaneous). Administration of CART antibody (1:500 dilution/rat, i.c.v.) significantly attenuated estradiol-induced anorexia in the OVX rats. While estradiol replacement significantly increased CART-immunoreactivity in the cells/fibers of paraventricular nucleus (PVN) of OVX rats, fibers in the anteroventral periventricular nucleus (AVPV), and cells/fibers in the arcuate nucleus (ARC) showed considerable reduction. These changes were attenuated following concurrent injection of tamoxifen to the estradiol replaced OVX rats. However, CART-immunoreactive cells/fibers in the periventricular area did not respond to any of the treatments. We suggest that estradiol treatment might influence the hypothalamic CART system in a site specific manner. While increased CART activity in the PVN might produce anorexia, reduction of CART in ARC and AVPV might represent a compensatory homeostatic response. Copyright © 2011 Elsevier Inc. All rights reserved.

Assessment of simvastatin niosomes for pediatric transdermal drug delivery.

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Zidan, Ahmed S; Hosny, Khaled M; Ahmed, Osama A A; Fahmy, Usama A

2016-06-01

The prevalence of childhood dyslipidemia increases and is considered as an important risk factor for the incidence of cardiovascular disease in the adulthood. To improve dosing accuracy and facilitate the determination of dosing regimens in function of the body weight, the proposed study aims at preparing transdermal niosomal gels of simvastatin as possible transdermal drug delivery system for pediatric applications. Twelve formulations were prepared to screen the influence of formulation and processing variables on critical niosomal characteristics. Nano-sized niosomes with 0.31 μm number-weighted size displayed highest simvastatin release rate with 8.5% entrapment capacity. The niosomal surface coverage by negative charges was calculated according to Langmuir isotherm with n = 0.42 to suggest that the surface association was site-independent, probably producing surface rearrangements. Hypolipidemic activities after transdermal administration of niosomal gels to rats showed significant reduction in cholesterol and triglyceride levels while increasing plasma high-density lipoproteins concentration. Bioavailability estimation in rats revealed an augmentation in simvastatin bioavailability by 3.35 and 2.9 folds from formulation F3 and F10, respectively, compared with oral drug suspension. Hence, this transdermal simvastatin niosomes not only exhibited remarkable potential to enhance its bioavailability and hypolipidemic activity but also considered a promising pediatric antihyperlipidemic formulation.

Fertilizer micro-dosing

International Development Research Centre (IDRC) Digital Library (Canada)

Localized application of small quantities of fertilizer (micro-dosing), combined with improved planting pits for rainwater harvesting, has generated greater profits and food security for women farmers in the Sahel. • Women are 25% more likely to use combined applications, and have expanded areas of food crops (cowpea,.

Microneedle-based drug delivery systems for transdermal route.

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Pierre, Maria Bernadete Riemma; Rossetti, Fabia Cristina

2014-03-01

Transdermal delivery offers an attractive, noninvasive administration route but it is limited by the skin's barrier to penetration. Minimally invasive techniques, such as the use of microneedles (MNs), bypass the stratum corneum (SC) barrier to permit the drug's direct access to the viable epidermis. These novel micro devices have been developed to puncture the skin for the transdermal delivery of hydrophilic drugs and macromolecules, including peptides, DNA and other molecules, that would otherwise have difficulty passing the outermost layer of the skin, the SC. Using the tools of the microelectronics industry, MNs have been fabricated with a range of sizes, shapes and materials. MNs have been shown to be robust enough to penetrate the skin and dramatically increase the skin permeability of several drugs. Moreover, MNs have reduced needle insertion pain and tissue trauma and provided controlled delivery across the skin. This review focuses on the current state of the art in the transdermal delivery of drugs using various types of MNs and developments in the field of microscale devices, as well as examples of their uses and clinical safety.

Dose-dependent effects of 17-ß-estradiol on pituitary thyrotropin content and secretion in vitro

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Moreira R.M.

1997-01-01

Full Text Available We studied the basal and thyrotropin-releasing hormone (TRH (50 nM induced thyrotropin (TSH release in isolated hemipituitaries of ovariectomized rats treated with near-physiological or high doses of 17-ß-estradiol benzoate (EB; sc, daily for 10 days or with vehicle (untreated control rats, OVX. One group was sham-operated (normal control. The anterior pituitary glands were incubated in Krebs-Ringer bicarbonate medium, pH 7.4, at 37oC in an atmosphere of 95% O2/5% CO2. Medium and pituitary TSH was measured by specific RIA (NIDDK-RP-3. Ovariectomy induced a decrease (P<0.05 in basal TSH release (normal control = 44.1 ± 7.2; OVX = 14.7 ± 3.0 ng/ml and tended to reduce TRH-stimulated TSH release (normal control = 33.0 ± 8.1; OVX = 16.6 ± 2.4 ng/ml. The lowest dose of EB (0.7 µg/100 g body weight did not reverse this alteration, but markedly increased the pituitary TSH content (0.6 ± 0.06 µg/hemipituitary; P<0.05 above that of OVX (0.4 ± 0.03 µg/hemipituitary and normal rats (0.46 ± 0.03 µg/hemipituitary. The intermediate EB dose (1.4 µg/100 g body weight induced a nonsignificant tendency to a higher TSH response to TRH compared to OVX and a lower response compared to normal rats. Conversely, in the rats treated with the highest dose (14 µg/100 g body weight, serum 17-ß-estradiol was 17 times higher than normal, and the basal and TRH-stimulated TSH release, as well as the pituitary TSH content, was significantly (P<0.05 reduced compared to normal rats and tended to be even lower than the values observed for the vehicle-treated OVX group, suggesting an inhibitory effect of hyperestrogenism. In conclusion, while reinforcing the concept of a positive physiological regulatory role of estradiol on the TSH response to TRH and on the pituitary stores of the hormone, the present results suggest an inhibitory effect of high levels of estrogen on these responses

Human Growth Hormone Delivery with a Microneedle Transdermal System: Preclinical Formulation, Stability, Delivery and PK of Therapeutically Relevant Doses

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Mahmoud Ameri

2014-05-01

Full Text Available This study evaluated the feasibility of coating formulated recombinant human growth hormone (rhGH on a titanium microneedle transdermal delivery system, Zosano Pharma (ZP-hGH, and assessed preclinical patch delivery performance. Formulation rheology and surface activity were assessed by viscometry and contact angle measurement. rhGH liquid formulation was coated onto titanium microneedles by dip-coating and drying. The stability of coated rhGH was determined by size exclusion chromatography-high performance liquid chromatography (SEC-HPLC. Preclinical delivery and pharmacokinetic studies were conducted in female hairless guinea pigs (HGP using rhGH coated microneedle patches at 0.5 and 1 mg doses and compared to Norditropin® a commercially approved rhGH subcutaneous injection. Studies demonstrated successful rhGH formulation development and coating on microneedle arrays. The ZP-hGH patches remained stable at 40 °C for six months with no significant change in % aggregates. Pharmacokinetic studies showed that the rhGH-coated microneedle patches, delivered with high efficiency and the doses delivered indicated linearity with average Tmax of 30 min. The absolute bioavailability of the microneedle rhGH patches was similar to subcutaneous Norditropin® injections. These results suggest that ZP-transdermal microneedle patch delivery of rhGH is feasible and may offer an effective and patient-friendly alternative to currently marketed rhGH injectables.

Human Growth Hormone Delivery with a Microneedle Transdermal System: Preclinical Formulation, Stability, Delivery and PK of Therapeutically Relevant Doses.

Science.gov (United States)

Ameri, Mahmoud; Kadkhodayan, Miryam; Nguyen, Joe; Bravo, Joseph A; Su, Rebeca; Chan, Kenneth; Samiee, Ahmad; Daddona, Peter E

2014-05-15

This study evaluated the feasibility of coating formulated recombinant human growth hormone (rhGH) on a titanium microneedle transdermal delivery system, Zosano Pharma (ZP)-hGH, and assessed preclinical patch delivery performance. Formulation rheology and surface activity were assessed by viscometry and contact angle measurement. rhGH liquid formulation was coated onto titanium microneedles by dip-coating and drying. The stability of coated rhGH was determined by size exclusion chromatography-high performance liquid chromatography (SEC-HPLC). Preclinical delivery and pharmacokinetic studies were conducted in female hairless guinea pigs (HGP) using rhGH coated microneedle patches at 0.5 and 1 mg doses and compared to Norditropin® a commercially approved rhGH subcutaneous injection. Studies demonstrated successful rhGH formulation development and coating on microneedle arrays. The ZP-hGH patches remained stable at 40 °C for six months with no significant change in % aggregates. Pharmacokinetic studies showed that the rhGH-coated microneedle patches, delivered with high efficiency and the doses delivered indicated linearity with average Tmax of 30 min. The absolute bioavailability of the microneedle rhGH patches was similar to subcutaneous Norditropin® injections. These results suggest that ZP-transdermal microneedle patch delivery of rhGH is feasible and may offer an effective and patient-friendly alternative to currently marketed rhGH injectables.

Electron beam processed transdermal delivery system for administration of an anti-anginal agent

Science.gov (United States)

Kotiyan, P. N.; Vavia, P. R.; Bharadwaj, Y. K.; Sabarwal, S.; Majali, A. B.

2002-12-01

Electron beam irradiation was used to synthesize a matrix type transdermal system of isosorbide dinitrate, an effective anti-anginal agent. The drug was dissolved in two monomeric systems, 2-ethylhexyl acrylate (EHA) and 2-ethylhexyl acrylate : methyl methacrylate (9 : 1). The solutions were then directly irradiated on a backing membrane (Scotchpak ®1006) at different doses to get transdermal patches. The developed systems were evaluated for residual monomer content, equilibrium weight swelling ratio, weight uniformity, thickness uniformity, drug content, peel strength, in vitro release and skin permeation kinetics. They possessed excellent tack and adhesive properties. In the case of isosorbide dinitrate-EHA systems, an increase in the peel strength values with respect to the skin was observed with increasing radiation doses. The systems exhibited promising skin permeation kinetics favorable for transdermal drug delivery. The radiation stability of the drug in the pure solid state form was also assessed.

Electron beam processed transdermal delivery system for administration of an anti-anginal agent

Energy Technology Data Exchange (ETDEWEB)

Kotiyan, P.N. E-mail: pramila-kotiyan@uiowa.edu; Vavia, P.R.; Bharadwaj, Y.K.; Sabarwal, S.; Majali, A.B

2002-12-01

Electron beam irradiation was used to synthesize a matrix type transdermal system of isosorbide dinitrate, an effective anti-anginal agent. The drug was dissolved in two monomeric systems, 2-ethylhexyl acrylate (EHA) and 2-ethylhexyl acrylate : methyl methacrylate (9 : 1). The solutions were then directly irradiated on a backing membrane (Scotchpak[reg]1006) at different doses to get transdermal patches. The developed systems were evaluated for residual monomer content, equilibrium weight swelling ratio, weight uniformity, thickness uniformity, drug content, peel strength, in vitro release and skin permeation kinetics. They possessed excellent tack and adhesive properties. In the case of isosorbide dinitrate-EHA systems, an increase in the peel strength values with respect to the skin was observed with increasing radiation doses. The systems exhibited promising skin permeation kinetics favorable for transdermal drug delivery. The radiation stability of the drug in the pure solid state form was also assessed.

Electron beam processed transdermal delivery system for administration of an anti-anginal agent

International Nuclear Information System (INIS)

Kotiyan, P.N.; Vavia, P.R.; Bharadwaj, Y.K.; Sabarwal, S.; Majali, A.B.

2002-01-01

Electron beam irradiation was used to synthesize a matrix type transdermal system of isosorbide dinitrate, an effective anti-anginal agent. The drug was dissolved in two monomeric systems, 2-ethylhexyl acrylate (EHA) and 2-ethylhexyl acrylate : methyl methacrylate (9 : 1). The solutions were then directly irradiated on a backing membrane (Scotchpak[reg]1006) at different doses to get transdermal patches. The developed systems were evaluated for residual monomer content, equilibrium weight swelling ratio, weight uniformity, thickness uniformity, drug content, peel strength, in vitro release and skin permeation kinetics. They possessed excellent tack and adhesive properties. In the case of isosorbide dinitrate-EHA systems, an increase in the peel strength values with respect to the skin was observed with increasing radiation doses. The systems exhibited promising skin permeation kinetics favorable for transdermal drug delivery. The radiation stability of the drug in the pure solid state form was also assessed

Exposure to Fentanyl After Transdermal Patch Administration for Cancer Pain Management.

Science.gov (United States)

Bista, Sudeep R; Haywood, Alison; Hardy, Janet; Norris, Ross; Hennig, Stefanie

2016-06-01

This study aimed to describe exposure after fentanyl transdermal patch administration in patients with advanced cancer to quantify variability around the exposure. Patients (n  =  56) with advanced cancer who received transdermal fentanyl (Durogesic®; median dose, 50 μg/h; range, 12-200 μg/h) provided venous blood samples (n  =  163) at various times (0.5-72 hours) during several patch application intervals. Plasma fentanyl concentration was determined (median, 0.9 μg/L; range, 0.04-9.7 μg/L) by high-performance liquid chromatography coupled to tandem mass spectrometry. Pharmacokinetic analysis was performed using nonlinear mixed-effects modeling with NONMEM. A 1-compartment distribution model with first-order absorption and elimination described fentanyl exposure after transdermal patch administration. Fentanyl apparent clearance (between-subject variability [BSV], %) was estimated at 122 L/h/70 kg and 38.5%, respectively. The absorption rate constant was 0.013 h(-1) . Between-occasion variability on apparent clearance was 22.0%, which was lower than BSV, suggesting predictable exposure within the same patient and justifying therapeutic drug monitoring. Except for weight-based dosing, no other patient characteristic could be identified to guide initial fentanyl dose selection in patients with advanced cancer. © 2015, The American College of Clinical Pharmacology.

Multiscale modeling of transdermal drug delivery

Science.gov (United States)

Rim, Jee Eun

2006-04-01

This study addresses the modeling of transdermal diffusion of drugs, to better understand the permeation of molecules through the skin, and especially the stratum corneum, which forms the main permeation barrier of the skin. In transdermal delivery of systemic drugs, the drugs diffuse from a patch placed on the skin through the epidermis to the underlying blood vessels. The epidermis is the outermost layer of the skin and can be further divided into the stratum corneum (SC) and the viable epidermis layers. The SC consists of keratinous cells (corneocytes) embedded in the lipid multi-bilayers of the intercellular space. It is widely accepted that the barrier properties of the skin mostly arises from the ordered structure of the lipid bilayers. The diffusion path, at least for lipophilic molecules, seems to be mainly through the lipid bilayers. Despite the advantages of transdermal drug delivery compared to other drug delivery routes such as oral dosing and injections, the low percutaneous permeability of most compounds is a major difficulty in the wide application of transdermal drug delivery. In fact, many transdermal drug formulations include one or more permeation enhancers that increase the permeation of the drug significantly. During the last two decades, many researchers have studied percutaneous absorption of drugs both experimentally and theoretically. However, many are based on pharmacokinetic compartmental models, in which steady or pseudo-steady state conditions are assumed, with constant diffusivity and partitioning for single component systems. This study presents a framework for studying the multi-component diffusion of drugs coupled with enhancers through the skin by considering the microstructure of the stratum corneum (SC). A multiscale framework of modeling the transdermal diffusion of molecules is presented, by first calculating the microscopic diffusion coefficient in the lipid bilayers of the SC using molecular dynamics (MD). Then a

Nonaqueous gel for the transdermal delivery of a DTPA penta-ethyl ester prodrug.

Science.gov (United States)

Zhang, Yong; Sadgrove, Matthew P; Sueda, Katsuhiko; Yang, Yu-Tsai; Pacyniak, Erik K; Kagel, John R; Braun, Brenda A; Zamboni, William C; Mumper, Russell J; Jay, Michael

2013-04-01

Diethylenetriamine pentaacetic acid penta-ethyl ester, designated as C2E5, was successfully incorporated into a nonaqueous gel for transdermal delivery. The thermal and rheological properties of a formulation containing 40% C2E5, 20% ethyl cellulose, and 40% Miglyol 840® prepared using the solvent evaporation method demonstrated that the gel had acceptable content uniformity and flow properties. In vitro studies showed that C2E5 was steadily released from the gel at a rate suitable for transdermal delivery. Topical application of the gel at a 200 mg C2E5/kg dose level in rats achieved significantly higher plasma exposures of several active metabolites compared with neat C2E5 oil at the same dose level. The results suggest that transdermal delivery of a chelator prodrug is an effective radionuclide decorporation strategy by delivering chelators to the circulation with a pharmacokinetic profile that is more consistent with the biokinetic profile of transuranic elements in contaminated individuals.

Transdermal drug delivery: approaches and significance

OpenAIRE

Murthy, SATHYANARAYANA

2012-01-01

S Narasimha MurthyDepartment of Pharmaceutics, The University of Mississippi, USATransdermal drug delivery systems deliver drugs through the skin as an alternative to oral, intravascular, subcutaneous, and transmucosal routes. Potential advantages of transdermal delivery include, but are not limited to, elimination of first-pass metabolism, steady delivery/blood levels, better patient compliance, reduced systemic drug interactions, possible dose intervention, avoidance of medically assisted d...

Therapeutic dosage assessment based on population pharmacokinetics of a novel single-dose transdermal donepezil patch in healthy volunteers.

Science.gov (United States)

Choi, Hee Youn; Kim, Yo Han; Hong, Donghyun; Kim, Seong Su; Bae, Kyun-Seop; Lim, Hyeong-Seok

2015-08-01

We performed population pharmacokinetic (PK) analysis of a novel transdermal donepezil patch in healthy subjects who participated in a phase I trial. We also studied the optimal dosage regimen with repeated patch application for achieving a therapeutic range using a PK simulation model. This study used data from a randomized, single-dose escalation phase I clinical trial conducted in Korea. The population PK analysis was performed using NONMEM software, version 7.3. From the final PK model, we simulated repeat patch application results assuming various transdermal absorption rates. Based on the clinical trial data, novel donepezil patches with doses of 43.75 mg/12.5 cm(2), 87.5 mg/25 cm(2), and 175 mg/50 cm(2) were placed on each subject. A linear one-compartment, first-order elimination with sequential zero- and first-order absorption model best described the donepezil plasma concentrations after patch application. Simulated results on the basis of the PK model showed that repeat application of the patches of 87.5 mg/25 cm(2) and 175 mg/50 cm(2) every 72 h would cover the therapeutic range of donepezil and reach steady-state faster with fewer fluctuations in concentration compared to typical oral administrations. A linear one-compartment with sequential zero- and first-order absorption model was effective for describing the PKs of donepezil after application of patch. Based on this analysis, 87.5 mg/25 cm(2) or 175 mg/50 cm(2) patch application every 72 h is expected to achieve the desired plasma concentration of donepezil.

From high doses of oral rivastigmine to transdermal rivastigmine patches: user experience and satisfaction among caregivers of patients with mild to moderate Alzheimer disease.

Science.gov (United States)

Reñé, R; Ricart, J; Hernández, B

2014-03-01

Rivastigmine, a treatment for mild to moderate Alzheimer disease (AD), is the first cholinesterase inhibitor to be available in the transdermal format. We aim to describe user experience and satisfaction with the rivastigmine patch, as well as any clinical changes perceived in patients. Observational, cross-sectional, multicentre study with 239 investigators and 1851 informal caregivers of patients with mild to moderate AD. Patients were treated with transdermal rivastigmine patches for ≥ 6 months and had previously received high doses of oral rivastigmine. Mean caregiver age was 59.8±14.4 years and 70.9% were women. They spent 10.0±7.1hours per day providing care and 79.8% lived with the patient. Patch instructions were described as easy to follow by 97.1% of the caregivers and 92.1% of them rated patch application as easy or very easy. The most commonly cited disadvantage was adhesion problems (26.8%). Discontinuation of treatment was due to cutaneous reactions in most cases. Overall, 76.5% of the caregivers were satisfied or very satisfied with transdermal treatment and 77.4% considered that its interference with daily activities was minimal or null. The patch was preferred to oral treatment by 94.3% of caregivers. Clinical Global Impression of Change ratings improved according to 61.3% of the caregivers and 53% of the investigators. Few caregivers reported medication forgetfulness. Most caregivers of patients with mild to moderate AD preferred the transdermal format of rivastigmine to the oral format. Caregivers also reported overall satisfaction, ease of use, and reduced impact on daily activities for transdermal rivastigmine format, in addition to patient improvement compared to their condition under the previous treatment. Copyright © 2012 Sociedad Española de Neurología. Published by Elsevier Espana. All rights reserved.

Alfuzosin hydrochloride transdermal films: evaluation of physicochemical, in vitro human cadaver skin permeation and thermodynamic parameters

Directory of Open Access Journals (Sweden)

Satyanarayan Pattnaik

2009-12-01

Full Text Available Purpose: The main objective of the investigation was to develop a transdermal therapeutic system for alfuzosin hydrochloride and to study the effects of polymeric system and loading dose on the in vitro skin permeation pattern. Materials and methods: Principles of experimental design have been exploited to develop the dosage form. Ratio of ethyl cellulose (EC and polyvinyl pyrrolidone (PVP and loading dose were selected as independent variables and their influence on the cumulative amount of alfuzosin hydrochloride permeated per cm2 of human cadaver skin at 24 h (Q24, permeation flux (J and steady state permeability coefficient (P SS were studied using experimental design. Various physicochemical parameters of the transdermal films were also evaluated. Activation energy for in vitro transdermal permeation has been estimated. Results: Ratio of EC and PVP was found to be the main influential factor for all the dependent variables studied. Drug loading dose was also found to influence the dependent variables but to a lesser extent. Physicochemical parameters of the prepared films were evaluated and found satisfactory. Activation energy for alfuzosin permeation has also been estimated and reported. Conclusion: The therapeutic system was found to be dermatologically non-irritant and hence, a therapeutically effective amount of alfuzosin hydrochloride can be delivered via a transdermal route.

Transdermal and Topical Drug Administration in the Treatment of Pain

Directory of Open Access Journals (Sweden)

Wojciech Leppert

2018-03-01

Full Text Available The comprehensive treatment of pain is multidimodal, with pharmacotherapy playing a key role. An effective therapy for pain depends on the intensity and type of pain, the patients’ age, comorbidities, and appropriate choice of analgesic, its dose and route of administration. This review is aimed at presenting current knowledge on analgesics administered by transdermal and topical routes for physicians, nurses, pharmacists, and other health care professionals dealing with patients suffering from pain. Analgesics administered transdermally or topically act through different mechanisms. Opioids administered transdermally are absorbed into vessels located in subcutaneous tissue and, subsequently, are conveyed in the blood to opioid receptors localized in the central and peripheral nervous system. Non–steroidal anti–inflammatory drugs (NSAIDs applied topically render analgesia mainly through a high concentration in the structures of the joint and a provision of local anti–inflammatory effects. Topically administered drugs such as lidocaine and capsaicin in patches, capsaicin in cream, EMLA cream, and creams containing antidepressants (i.e., doxepin, amitriptyline act mainly locally in tissues through receptors and/or ion channels. Transdermal and topical routes offer some advantages over systemic analgesic administration. Analgesics administered topically have a much better profile for adverse effects as they relieve local pain with minimal systemic effects. The transdermal route apart from the above-mentioned advantages and provision of long period of analgesia may be more convenient, especially for patients who are unable to take drugs orally. Topically and transdermally administered opioids are characterised by a lower risk of addiction compared to oral and parenteral routes.

Granisetron Transdermal Patch

Science.gov (United States)

Granisetron transdermal patches are used to prevent nausea and vomiting caused by chemotherapy. Granisetron is in a class of medications called 5HT3 ... Granisetron transdermal comes as a patch to apply to the skin. It is usually applied 24 to ...

Systemic delivery of β-blockers via transdermal route for hypertension

Science.gov (United States)

Ahad, Abdul; Al-Jenoobi, Fahad I.; Al-Mohizea, Abdullah M.; Akhtar, Naseem; Raish, Mohammad; Aqil, Mohd.

2014-01-01

Hypertension is the most common cardiovascular disease worldwide. Moreover, management of hypertension requires long-term treatment that may result in poor patient compliance with conventional dosage forms due to greater frequency of drug administration. Although there is availability of a plethora of therapeutically effective antihypertensive molecules, inadequate patient welfare is observed; this arguably presents an opportunity to deliver antihypertensive agents through a different route. Ever since the transdermal drug delivery came into existence, it has offered great advantages including non-invasiveness, prolonged therapeutic effect, reduced side effects, improved bioavailability, better patient compliance and easy termination of drug therapy. Attempts were made to develop the transdermal therapeutic system for various antihypertensive agents, including β-blockers, an important antihypertensive class. β-blockers are potent, highly effective in the management of hypertension and other heart ailments by blocking the effects of normal amounts of adrenaline in the heart and blood vessels. The shortcomings associated with β-blockers such as more frequent dose administration, extensive first pass metabolism and variable bioavailability, make them an ideal candidate for transdermal therapeutic systems. The present article gives a brief view of different β-blockers formulated as transdermal therapeutic system in detail to enhance the bioavailability as well as to improve patient compliance. Constant improvement in this field holds promise for the long-term success in technologically advanced transdermal dosage forms being commercialized sooner rather than later. PMID:26702253

Use of rivastigmine transdermal patch in the treatment of Alzheimer's disease.

Science.gov (United States)

Winblad, Bengt; Machado, João Carlos

2008-12-01

Cholinesterase inhibitors such as rivastigmine and donepezil exhibit a dose-response relationship, with higher doses of the drugs demonstrating greater efficacy. Transdermal patches provide smooth continuous drug delivery, with the potential to offer efficacious levels of drug exposure while avoiding the peaks and troughs associated with side effects. As a small, lipophilic and hydrophilic molecule, rivastigmine (C14H22N2O2) is chemically well-suited to transdermal delivery. The technology underlying the rivastigmine patch allows it to be discreetly small and thin. The target dose 9.5 mg/24 h rivastigmine patch has a diameter of just 3.5 cm and a surface area of 10 cm2. A large randomized controlled trial has demonstrated that the target dose 9.5 mg/24 h rivastigmine patch provided similar efficacy to the highest rivastigmine capsule doses, yet with three times fewer reports of nausea and vomiting. Thus, the rivastigmine patch enables quick and easy access to high dose efficacy. The skin tolerability profile is good, and the patch has demonstrated excellent adhesion. The apparent success of rivastigmine patch, in terms of clinical utility and patient acceptability, suggests that it may mark the next generation of dementia treatment.

TRANSDERMAL DRUG DELIVERY SYSTEM: REVIEW

OpenAIRE

Vishvakarama Prabhakar; Agarwal Shivendra; Sharma Ritika; Saurabh Sharma

2012-01-01

Various new technologies have been developed for the transdermal delivery of some important drugs. Today about 74% of drugs are taken orally and are found not to be as effective as desired. To improve such characters transdermal drug delivery system was emerged. Drug delivery through the skin to achieve a systemic effect of a drug is commonly known as transdermal drug delivery and differs from traditional topical drug delivery. Transdermal drug delivery systems (TDDS) are dosage forms involve...

Pharmacokinetics of 2 Formulations of Transdermal Fentanyl in Cynomolgus Macaques (Macaca fascicularis)

Science.gov (United States)

Carlson, Amy M; Kelly, Richard; Fetterer, David P; Rico, Pedro J; Bailey, Emily J

2016-01-01

Fentanyl is a μ-opioid agonist that often is used as the analgesic component for balanced anesthesia in both human and veterinary patients. Minimal information has been published regarding appropriate dosing, and the pharmacokinetics of fentanyl are unknown in NHP. The pharmacokinetic properties of 2 transdermal fentanyl delivery methods, a solution (2.6 and 1.95 mg/kg) and a patch (25 µg/h), were determined when applied topically to the dorsal scapular area of cynomolgus macaques (Macaca fascicularis). Serum fentanyl concentrations were analyzed by using liquid chromatography–mass spectrometry. Compared with the patch, the transdermal fentanyl solution generated higher drug concentrations over longer time. Adverse reactions occurred in the macaques that received the transdermal fentanyl solution at 2.6 mg/kg. Both preparations showed significant interanimal variability in the maximal serum drug levels, time to achieve maximal fentanyl levels, elimination half-life, and AUC values. Both the maximal concentration and the time at which this concentration occurred were increased in macaques compared with most other species after application of the transdermal fentanyl patch and compared with dogs after application of the transdermal fentanyl solution. The pharmacokinetic properties of transdermal fentanyl in macaques are markedly different from those in other veterinary species and preclude its use as a long-acting analgesic drug in NHP. PMID:27423151

A rapid enhancement of locomotor sensitization to amphetamine by estradiol in female rats.

Science.gov (United States)

Zovkic, Iva B; McCormick, Cheryl M

2017-11-14

Estradiol moderates the effects of drugs of abuse in both humans and rodents. Estradiol's enhancement of behavioral effects resulting from high (>2.5mg/kg) doses of amphetamine is established in rats; there is less evidence for the role of estradiol in locomotor effects elicited by lower doses, which are less aversive, increase incentive motivation, involve different neural mechanisms than higher doses, and often more readily reveal group differences than do higher doses. Further, the extent to which estradiol is required for the induction versus the expression of sensitization is unknown. To establish a protocol, we replicated the effects of estradiol on locomotor sensitization to amphetamine reported in a previous study that involved a high locomotor-activating dose (1.5mg/kg) of amphetamine, but with a lower dose. Ovariectomized female rats received 5μg of estradiol benzoate (EB) or OIL 30min before each of 5 treatments of 1.0mg/kg amphetamine or saline; all received a 0.5mg/kg challenge dose three days later. Compared with results for OIL, EB enhanced the locomotor-activating effects of repeated 1.0mg/kg amphetamine across treatment days. In contrast, on challenge day, there was no difference between EB-saline and EB-amphetamine to the lower dose (i.e., no sensitization). Experiments 2 and 3 involved a shorter induction (2days) and a lengthier withdrawal (9days) before the challenge test for the expression of sensitization to better differentiate the induction phase from the expression phase. In Expt2, EB-, and not OIL-, treated rats showed sensitization to 0.5mg/kg amphetamine; neither group showed sensitization to 1.5mg/kg amphetamine (ceiling effect?). In Expt3, rats were treated with EB either in both the induction and expression phases, in one of the phases only, or in neither phase. There was an effect of hormone treatment on challenge day and not on induction day; rats given EB on Challenge day showed sensitization to 0.5mg/kg amphetamine; OIL rats did

Electroporation-delivered transdermal neostigmine in rats: equivalent action to intravenous administration.

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Berkó, Szilvia; Szűcs, Kálmán F; Balázs, Boglárka; Csányi, Erzsébet; Varju, Gábor; Sztojkov-Ivanov, Anita; Budai-Szűcs, Mária; Bóta, Judit; Gáspár, Róbert

2016-01-01

Transdermal electroporation has become one of the most promising noninvasive methods for drug administration, with greatly increased transport of macromolecules through the skin. The cecal-contracting effects of repeated transdermal electroporation delivery and intravenous administration of neostigmine were compared in anesthetized rats. The cecal contractions were detected with implantable strain gauge sensors, and the plasma levels of neostigmine were followed by high-performance liquid chromatography. Both intravenously and EP-administered neostigmine (0.2-66.7 μg/kg) increased the cecal contractions in a dose-dependent manner. For both the low doses and the highest dose, the neostigmine plasma concentrations were the same after the two modes of administration, while an insignificantly higher level was observed at a dose of 20 μg/kg after intravenous administration as compared with the electroporation route. The contractile responses did not differ significantly after the two administration routes. The results suggest that electroporation-delivered neostigmine elicits action equivalent to that observed after intravenous administration as concerning both time and intensity. Electroporation permits the delivery of even lower doses of water-soluble compounds through the skin, which is very promising for clinical practice.

Hepatic expression of heme oxygenase-1 and antioxidant response element-mediated genes following administration of ethinyl estradiol to rats

International Nuclear Information System (INIS)

Morio, Lisa A.; Leone, Angelique; Sawant, Sharmilee P.; Nie, Alex Y.; Brandon Parker, J.; Taggart, Peter; Barron, Alfred M.; McMillian, Michael K.; Lord, Peter

2006-01-01

Heme oxygenase-1 (HO-1) is one of several enzymes induced by hepatotoxicants, and is thought to have an important protective role against cellular stress during liver inflammation and injury. The objective of the present study was to evaluate the role of HO-1 in estradiol-induced liver injury. A single dose of ethinyl estradiol (500 mg/kg, po) resulted in mild liver injury. Repeated administration of ethinyl estradiol (500 mg/kg/day for 4 days, po) resulted in no detectable liver injury or dysfunction. Using RT-PCR analysis, we demonstrate that HO-1 gene expression in whole liver tissue is elevated (> 20-fold) after the single dose of ethinyl estradiol. The number and intensity of HO-1 immunoreactive macrophages were increased after the single dose of ethinyl estradiol. HO-1 expression was undetectable in hepatic parenchymal cells from rats receiving Methocel control or a single dose of ethinyl estradiol, however cytosolic HO-1 immunoreactivity in these cells after repeated dosing of ethinyl estradiol was pronounced. The increases in HO-1 mRNA and HO-1 immunoreactivity following administration of a single dose of ethinyl estradiol suggested that this enzyme might be responsible for the observed protection of the liver during repeated dosing. To investigate the effect of HO-1 expression on ethinyl estradiol-induced hepatotoxicity, rats were pretreated with hemin (50 μmol/kg, ip, a substrate and inducer of HO-1), with tin protoporphyrin IX (60 μmol/kg, ip, an HO-1 inhibitor), or with gadolinium chloride (10 mg/kg, iv, an inhibitor/toxin of Kupffer cells) 24 h before ethinyl estradiol treatment. Pretreatment with modulators of HO-1 expression and activity had generally minimal effects on ethinyl estradiol-induced liver injury. These data suggest that HO-1 plays a limited role in antioxidant defense against ethinyl estradiol-induced oxidative stress and hepatotoxicity, and suggests that other coordinately induced enzymes are responsible for protection observed with

Impact of various progestins with or without transdermal testosterone on gonadotropin levels for non-invasive hormonal male contraception: a randomized clinical trial.

Science.gov (United States)

Zitzmann, M; Rohayem, J; Raidt, J; Kliesch, S; Kumar, N; Sitruk-Ware, R; Nieschlag, E

2017-05-01

Although several progestins have been tested for hormonal male contraception, the effects of dosage and nature of various progestins on gonadotropin suppression combined with and without additional testosterone has not been performed in a comparative trial. The aim of this study was to evaluate the differential impact of four oral or transdermal progestins on the suppression of gonadotropins in healthy men: oral: cyproterone acetate (CPA), levonorgestrel (LNG), norethisterone acetate (NETA), and transdermal: Nestorone ® (NES), all in combination with transdermal testosterone (T). Randomized clinical trial testing was performed with four progestins at two doses each. After a 2-week progestin-only treatment, transdermal T was added for further 4 weeks and was followed by a 3-week recovery period. Progestin-dose per day: CPA 10 mg/20 mg, NES 2 mg/3 mg/dose e.g. 200/300 μg/day absorbed, NETA 5 mg/10 mg, LNG 120 μg/240 μg. From an andrology outpatient clinic, 56 healthy men aged 18-50 years, with body mass index ≤33 kg × m -2 were included in the study. Serum concentrations of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) were studied. Secondary outcome measure included were serum testosterone concentrations, sperm concentrations, and safety parameters. Intergroup comparisons demonstrated that CPA and LNG had the strongest effect on LH/FSH suppression. Nevertheless, every substance showed significant inhibitory effects on gonadotropin secretion, especially in combination with transdermal T. A decrease in hematocrit and insulin sensitivity as well as cholesterol subfractions and triglycerides was uniformly seen for every group. The combination of oral or transdermal progestins with a transdermal testosterone preparation is able to suppress gonadotropins. Further dose titration studies with sperm suppression as an end-point should be conducted to determine the lowest effective dose for hormonal male contraception. © 2017 American

Treatment with subcutaneous and transdermal fentanyl: results from a population pharmacokinetic study in cancer patients.

Science.gov (United States)

Oosten, Astrid W; Abrantes, João A; Jönsson, Siv; de Bruijn, Peter; Kuip, Evelien J M; Falcão, Amílcar; van der Rijt, Carin C D; Mathijssen, Ron H J

2016-04-01

Transdermal fentanyl is effective for the treatment of moderate to severe cancer-related pain but is unsuitable for fast titration. In this setting, continuous subcutaneous fentanyl may be used. As data on the pharmacokinetics of continuous subcutaneous fentanyl are lacking, we studied the pharmacokinetics of subcutaneous and transdermal fentanyl. Furthermore, we evaluated rotations from the subcutaneous to the transdermal route. Fifty-two patients treated with subcutaneous and/or transdermal fentanyl for moderate to severe cancer-related pain participated. A population pharmacokinetic model was developed and evaluated using non-linear mixed-effects modelling. For rotations from subcutaneous to transdermal fentanyl, a 1:1 dose conversion ratio was used while the subcutaneous infusion was continued for 12 h (with a 50 % tapering after 6 h). A 6-h scheme with 50 % tapering after 3 h was simulated using the final model. A one-compartment model with first-order elimination and separate first-order absorption processes for each route adequately described the data. The estimated apparent clearance of fentanyl was 49.6 L/h; the absorption rate constant for subcutaneous and transdermal fentanyl was 0.0358 and 0.0135 h(-1), respectively. Moderate to large inter-individual and inter-occasion variability was found. Around rotation from subcutaneous to transdermal fentanyl, measured and simulated plasma fentanyl concentrations rose and increasing side effects were observed. We describe the pharmacokinetics of subcutaneous and transdermal fentanyl in one patient cohort and report several findings that are relevant for clinical practice. Further research is warranted to study the optimal scheme for rotations from the subcutaneous to the transdermal route.

Drug profile: transdermal rivastigmine patch in the treatment of Alzheimer disease.

Science.gov (United States)

Emre, Murat; Bernabei, Roberto; Blesa, Rafael; Bullock, Roger; Cunha, Luis; Daniëls, Hugo; Dziadulewicz, Edward; Förstl, Hans; Frölich, Lutz; Gabryelewicz, Tomasz; Levin, Oleg; Lindesay, James; Martínez-Lage, Pablo; Monsch, Andreas; Tsolaki, Magda; van Laar, Teus

2010-08-01

Cholinesterase inhibitors constitute one of the mainstays of treatment of Alzheimer disease (AD). Gastrointestinal side effects, difficulty accessing therapeutic doses and poor patient compliance have been identified as barriers to effective treatment with these substances. The rivastigmine transdermal patch provides continuous delivery of drug through the skin into the bloodstream, avoiding the fluctuations in plasma concentration associated with oral administration. This pharmacokinetic profile is associated with reduced side effects, resulting in easier access to expected target doses. These benefits, along with other practical advantages of the transdermal patch, may contribute to enhanced patient compliance. Here, we present a review of the current literature on rivastigmine patch, and offer advice based on our own collective clinical experience. Rivastigmine patch provides an efficient option for managing patients with AD, to be considered among the first line therapies for the disease.

Heat: A Highly Efficient Skin Enhancer for Transdermal Drug Delivery.

Science.gov (United States)

Szunerits, Sabine; Boukherroub, Rabah

2018-01-01

Advances in materials science and bionanotechnology have allowed the refinements of current drug delivery systems, expected to facilitate the development of personalized medicine. While dermatological topical pharmaceutical formulations such as foams, creams, lotions, gels, etc., have been proposed for decades, these systems target mainly skin-based diseases. To treat systemic medical conditions as well as localized problems such as joint or muscle concerns, transdermal delivery systems (TDDSs), which use the skin as the main route of drug delivery, are very appealing. Over the years, these systems have shown to offer important advantages over oral as well as intravenous drug delivery routes. Besides being non-invasive and painless, TDDSs are able to deliver drugs with a short-half-life time more easily and are well adapted to eliminate frequent administrations to maintain constant drug delivery. The possibility of self-administration of a predetermined drug dose at defined time intervals makes it also the most convenient personalized point-of-care approach. The transdermal market still remains limited to a narrow range of drugs. While small and lipophilic drugs have been successfully delivered using TDDSs, this approach fails to deliver therapeutic macromolecules due to size-limited transport across the stratum corneum , the outermost layer of the epidermis. The low permeability of the stratum corneum to water-soluble drugs as well as macromolecules poses important challenges to transdermal administration. To widen the scope of drugs for transdermal delivery, new procedures to enhance skin permeation to hydrophilic drugs and macromolecules are under development. Next to iontophoresis and microneedle-based concepts, thermal-based approaches have shown great promise to enhance transdermal drug delivery of different therapeutics. In this inaugural article for the section "Frontiers in Bioengineering and Biotechnology," the advances in this field and the handful of

Challenges and opportunities in dermal/transdermal delivery

Science.gov (United States)

Paudel, Kalpana S; Milewski, Mikolaj; Swadley, Courtney L; Brogden, Nicole K; Ghosh, Priyanka; Stinchcomb, Audra L

2010-01-01

Transdermal drug delivery is an exciting and challenging area. There are numerous transdermal delivery systems currently available on the market. However, the transdermal market still remains limited to a narrow range of drugs. Further advances in transdermal delivery depend on the ability to overcome the challenges faced regarding the permeation and skin irritation of the drug molecules. Emergence of novel techniques for skin permeation enhancement and development of methods to lessen skin irritation would widen the transdermal market for hydrophilic compounds, macromolecules and conventional drugs for new therapeutic indications. As evident from the ongoing clinical trials of a wide variety of drugs for various clinical conditions, there is a great future for transdermal delivery of drugs. PMID:21132122

Myth or Reality-Transdermal Magnesium?

Science.gov (United States)

Gröber, Uwe; Werner, Tanja; Vormann, Jürgen; Kisters, Klaus

2017-07-28

In the following review, we evaluated the current literature and evidence-based data on transdermal magnesium application and show that the propagation of transdermal magnesium is scientifically unsupported. The importance of magnesium and the positive effects of magnesium supplementation are extensively documented in magnesium deficiency, e.g., cardiovascular disease and diabetes mellitus. The effectiveness of oral magnesium supplementation for the treatment of magnesium deficiency has been studied in detail. However, the proven and well-documented oral magnesium supplementation has become questioned in the recent years through intensive marketing for its transdermal application (e.g., magnesium-containing sprays, magnesium flakes, and magnesium salt baths). In both, specialist and lay press as well as on the internet, there are increasing numbers of articles claiming the effectiveness and superiority of transdermal magnesium over an oral application. It is claimed that the transdermal absorption of magnesium in comparison to oral application is more effective due to better absorption and fewer side effects as it bypasses the gastrointestinal tract.

Efficacy of a single dose of a transdermal diclofenac patch as pre ...

African Journals Online (AJOL)

2012-01-25

Jan 25, 2012 ... When the side-effects were compared between the groups using a test of proportions, it was not significant. Discussion. The results of our study suggest that when applied at the beginning of surgery, a transdermal patch of diclofenac is as effective as intramuscular diclofenac in prolonging the requirement ...

STUDY & ANALYSIS OF MICRO NEEDLE MATERIAL BY ANSYS

OpenAIRE

Santosh Kumar Singh*, Prabhat Sinha, N.N. Singh, Nagendra Kumar

2017-01-01

In this research the concept of design and analysis, silicon and stainless steel based on hollow micro-needles for transdermal drug delivery(TDD) have been evaluated by Using ANSYS & computational fluid dynamic (CFD), structural. Micro fluidic analysis has performed to ensure the micro-needles design suitability for Drug delivery. The effect of axial and transverse load on single and micro-needle array has investigated with the mechanical properties of micro-needle. The analysis predicte...

Alghedon Fentanyl Transdermal System.

Science.gov (United States)

Romualdi, Patrizia; Santi, Patrizia; Candeletti, Sanzio

2017-04-01

The efficacy of transdermal fentanyl for cancer pain and chronic non-cancer pain (chronic lower back pain, rheumatoid arthritis, osteoarthritis, neuropathic pain) is well established. Several formulations of fentanyl transdermal systems have been developed to improve the drug delivery and prevent misuse of the active principle. The addition of a rate controlling membrane to the matrix system represented an important advance. The design and functional features of Alghedon patch are compared with other approved generic fentanyl transdermal systems, emphasizing the distinctiveness of Alghedon patch. Alghedon patch has no liquid component in the finished product, therefore no leakage of active ingredient from the system can occur. A rate-controlling membrane provides controlled release of the active substance from the matrix reservoir, ensuring that fentanyl delivery and entry into the microcirculation is not solely controlled by the skin's permeability to this active substance. Alghedon patch contains part of the drug (approximately 15%) in the skin-contact adhesive: this innovative solution allows to overcome a typical drawback of transdermal patches, i.e. the long lag-time before the drug appears in plasma after the first administration, and provides rapid analgesia during the first hours of administration. Alghedon Fentanyl Transdermal System employs materials commonly used in other transdermal applications and having established safety profiles. For each strength level, the fentanyl content - and, thus, the resulting residual fentanyl remaining in the patch after use - is at the lowest end of the range used in commercially available fentanyl patches, minimizing the potential for abuse and misuse.

A Transdermal Drug Delivery System Based on LIGA Technology and Soft Lithography

Science.gov (United States)

Matteucci, Marco; Perennes, Frederic; Marmiroli, Benedetta; Di Fabrizio, Enzo

2007-01-01

This report presents a transdermal drug delivery system based on LIGA fabricated microparts. It is a portable device combining a magnetically actuated micro gear pump with a microneedle array. The fluidic behaviour of the system is analyzed in order to predict its performance according to the dimension of the microparts and then compared to experimental data. The manufacturing process of both micropump and microneedle array are described.

Electrospun polymeric nanofibers for transdermal drug delivery

Directory of Open Access Journals (Sweden)

Mahya Rahmani

2017-04-01

Full Text Available Conventional transdermal drug delivery systems (TDDS have been designed for drug delivery through the skin. These systems use the permeability property of stratum corneum, the outermost surface layer of the skin. Applying polymeric micro and nanofibers in drug delivery has recently attracted great attention and the electrospinning technique is the preferred method for polymeric micro-nanofibers fabrication with a great potential for drug delivery. More studies in the field of nanofibers containing drug are divided two categories: first, preparation and characterization of nanofibers containing drug and second, investigation of their therapeutic applications. Drugs used in electrospun nanofibers can be categorized into three main groups, including antibiotics and antimicrobial agents, anti-inflammatory agents and vitamins with therapeutic applications. In this paper, we review the application of electrospun polymeric scaffolds in TDDS and also introduce several pharmaceutical and therapeutic agents which have been used in polymer nanofibrous patches.

Challenges and opportunities in dermal/transdermal delivery

OpenAIRE

Paudel, Kalpana S; Milewski, Mikolaj; Swadley, Courtney L; Brogden, Nicole K; Ghosh, Priyanka; Stinchcomb, Audra L

2010-01-01

Transdermal drug delivery is an exciting and challenging area. There are numerous transdermal delivery systems currently available on the market. However, the transdermal market still remains limited to a narrow range of drugs. Further advances in transdermal delivery depend on the ability to overcome the challenges faced regarding the permeation and skin irritation of the drug molecules. Emergence of novel techniques for skin permeation enhancement and development of methods to lessen skin i...

Decreased nitric oxide levels in the hippocampus may play a role in learning and memory deficits in ovariectomized rats treated by a high dose of estradiol

Directory of Open Access Journals (Sweden)

Reihaneh Sadeghian

2012-11-01

Full Text Available The effects of a high estradiol dose on memory and on nitric oxide metabolites in hippocampal tissues were investigated. Sham-Est and OVX-Est Groups were treated with 4 mg/kg of estradiol valerate for 12 weeks. Time latency and path length were significantly higher in the Sham-Est and OVX-Est Groups than in the Sham and OVX Groups, respectively (p<0.001. The animals in the Sham-Est and OVX-Est Groups spent lower time in the target quadrant (Q1 than those of the Sham and OVX Groups during the probe trial test (p<0.05 and <0.001, respectively. Significantly lower nitric oxide metabolite levels in the hippocampi of the Sham-Est and OVX-Est Groups were observed than in the Sham and OVX ones (p<0.001. These results suggest that decreased nitric oxide levels in the hippocampus may play a role in the learning and memory deficits observed after treatment with a high dose of estradiol, although the precise underlying mechanisms remain to be elucidated.

Assessment of two-dimensional (2D) and three-dimensional (3D) lower limb measurements in adults: Comparison of micro-dose and low-dose biplanar radiographs

International Nuclear Information System (INIS)

Rosskopf, Andrea B.; Pfirrmann, Christian W.A.; Buck, Florian M.

2016-01-01

To evaluate reliability of 2D and 3D lower limb measurements in adults using micro-dose compared to low-dose biplanar radiographs(BPR). One hundred patients (mean 54.9 years) were examined twice using micro-dose and low-dose BPR. Length and mechanical axis of lower limbs were measured on the antero-posterior(ap) micro-dose and low-dose images by two independent readers. Femoral and tibial torsions of 50 patients were measured by two independent readers using reconstructed 3D-models based on the micro-dose and low-dose BPR. Intermethod and interreader agreements were calculated using descriptive statistics, intraclass-correlation-coefficient(ICC), and Bland-Altman analysis. Mean interreader-differences on micro-dose were 0.3 cm(range 0-1.0)/ 0.7 (0-2.9) for limb length/axis and 0.4 cm (0-1.0)/0.8 (0-3.3) on low-dose BPR. Mean intermethod-difference was 0.04 cm ± 0.2/0.04 ± 0.6 for limb length/axis. Interreader-ICC for limb length/axis was 0.999/0.991 on micro-dose and 0.999/0.987 on low-dose BPR. Interreader-ICC for micro-dose was 0.879/0.826 for femoral/tibial torsion, for low-dose BPR was 0.924/0.909. Mean interreader-differences on micro-dose/low-dose BPR were 3 (0-13 )/2 (0 -12 ) for femoral and 4 (0-18 )/3 (0 -10 ) for tibial torsion. Mean intermethod-difference was -0.1 ± 5.0/-0.4 ± 2.9 for femoral/tibial torsion. Mean dose-area-product was significantly lower (9.9 times;p < 0.001) for micro-dose BPR. 2D-and 3D-measurements of lower limbs based on micro-dose BPR are reliable and provide a 10-times lower radiation dose. (orig.)

Electroporation-delivered transdermal neostigmine in rats: equivalent action to intravenous administration

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Berkó S

2016-05-01

Full Text Available Szilvia Berkó,1,* Kálmán F Szűcs,2,* Boglárka Balázs,1,3 Erzsébet Csányi,1 Gábor Varju,4 Anita Sztojkov-Ivanov,2 Mária Budai-Szűcs,1 Judit Bóta,2 Róbert Gáspár2 1Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Szeged, Szeged, Hungary; 2Department of Pharmacodynamics and Biopharmacy, Faculty of Pharmacy, University of Szeged, Szeged, Hungary; 3Gedeon Richter Plc., Budapest, 4Dr Derm Clinic of Anti-Aging Dermatology, Aesthetic Laser and Plastic Surgery, Budapest, Hungary *These authors contributed equally to this work Purpose: Transdermal electroporation has become one of the most promising noninvasive methods for drug administration, with greatly increased transport of macromolecules through the skin. The cecal-contracting effects of repeated transdermal electroporation delivery and intravenous administration of neostigmine were compared in anesthetized rats. Methods: The cecal contractions were detected with implantable strain gauge sensors, and the plasma levels of neostigmine were followed by high-performance liquid chromatography. Results: Both intravenously and EP-administered neostigmine (0.2–66.7 µg/kg increased the cecal contractions in a dose-dependent manner. For both the low doses and the highest dose, the neostigmine plasma concentrations were the same after the two modes of administration, while an insignificantly higher level was observed at a dose of 20 µg/kg after intravenous administration as compared with the electroporation route. The contractile responses did not differ significantly after the two administration routes. Conclusion: The results suggest that electroporation-delivered neostigmine elicits action equivalent to that observed after intravenous administration as concerning both time and intensity. Electroporation permits the delivery of even lower doses of water-soluble compounds through the skin, which is very promising for clinical practice. Keywords: transdermal

Therapeutic serum phenobarbital concentrations obtained using chronic transdermal administration of phenobarbital in healthy cats.

Science.gov (United States)

Delamaide Gasper, Joy A; Barnes Heller, Heidi L; Robertson, Michelle; Trepanier, Lauren A

2015-04-01

Seizures are a common cause of neurologic disease, and phenobarbital (PB) is the most commonly used antiepileptic drug. Chronic oral dosing can be challenging for cat owners, leading to poor compliance. The purpose of this study was to determine if the transdermal administration of PB could achieve serum PB concentrations of between 15 and 45 μg/ml in healthy cats. Nineteen healthy cats were enrolled in three groups. Transdermal PB in pluronic lecithin organogel (PLO) was applied to the pinnae for 14 days at a dosage of 3 mg/kg q12h in group 1 (n = 6 cats) and 9 mg/kg q12h in group 2 (n = 7 cats). Transdermal PB in Lipoderm Activemax was similarly applied at 9 mg/kg q12h for 14 days in group 3 (n = 6 cats). Steady-state serum PB concentrations were measured at trough, and at 2, 4 and 6 h after the morning dose on day 15. In group 1, median concentrations ranged from 6.0-7.5 μg/ml throughout the day (observed range 0-11 μg/ml). Group 2 median concentrations were 26.0 μg/ml (observed range 18.0-37.0 μg/ml). For group 3, median concentrations ranged from 15.0-17.0 μg/ml throughout the day (range 5-29 μg/ml). Side effects were mild. One cat was withdrawn from group 2 owing to ataxia and sedation. These results show therapeutic serum PB concentrations can be achieved in cats following chronic transdermal administration of PB in PLO at a dosage of 9 mg/kg q12h. More individual variation was noted using Lipoderm Activemax. Transdermal administration may be an alternative for cats that are difficult to medicate orally. © ISFM and AAFP 2014.

Heat: A Highly Efficient Skin Enhancer for Transdermal Drug Delivery

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Sabine Szunerits

2018-02-01

Full Text Available Advances in materials science and bionanotechnology have allowed the refinements of current drug delivery systems, expected to facilitate the development of personalized medicine. While dermatological topical pharmaceutical formulations such as foams, creams, lotions, gels, etc., have been proposed for decades, these systems target mainly skin-based diseases. To treat systemic medical conditions as well as localized problems such as joint or muscle concerns, transdermal delivery systems (TDDSs, which use the skin as the main route of drug delivery, are very appealing. Over the years, these systems have shown to offer important advantages over oral as well as intravenous drug delivery routes. Besides being non-invasive and painless, TDDSs are able to deliver drugs with a short-half-life time more easily and are well adapted to eliminate frequent administrations to maintain constant drug delivery. The possibility of self-administration of a predetermined drug dose at defined time intervals makes it also the most convenient personalized point-of-care approach. The transdermal market still remains limited to a narrow range of drugs. While small and lipophilic drugs have been successfully delivered using TDDSs, this approach fails to deliver therapeutic macromolecules due to size-limited transport across the stratum corneum, the outermost layer of the epidermis. The low permeability of the stratum corneum to water-soluble drugs as well as macromolecules poses important challenges to transdermal administration. To widen the scope of drugs for transdermal delivery, new procedures to enhance skin permeation to hydrophilic drugs and macromolecules are under development. Next to iontophoresis and microneedle-based concepts, thermal-based approaches have shown great promise to enhance transdermal drug delivery of different therapeutics. In this inaugural article for the section “Frontiers in Bioengineering and Biotechnology,” the advances in this field

Heat: A Highly Efficient Skin Enhancer for Transdermal Drug Delivery

Science.gov (United States)

Szunerits, Sabine; Boukherroub, Rabah

2018-01-01

Advances in materials science and bionanotechnology have allowed the refinements of current drug delivery systems, expected to facilitate the development of personalized medicine. While dermatological topical pharmaceutical formulations such as foams, creams, lotions, gels, etc., have been proposed for decades, these systems target mainly skin-based diseases. To treat systemic medical conditions as well as localized problems such as joint or muscle concerns, transdermal delivery systems (TDDSs), which use the skin as the main route of drug delivery, are very appealing. Over the years, these systems have shown to offer important advantages over oral as well as intravenous drug delivery routes. Besides being non-invasive and painless, TDDSs are able to deliver drugs with a short-half-life time more easily and are well adapted to eliminate frequent administrations to maintain constant drug delivery. The possibility of self-administration of a predetermined drug dose at defined time intervals makes it also the most convenient personalized point-of-care approach. The transdermal market still remains limited to a narrow range of drugs. While small and lipophilic drugs have been successfully delivered using TDDSs, this approach fails to deliver therapeutic macromolecules due to size-limited transport across the stratum corneum, the outermost layer of the epidermis. The low permeability of the stratum corneum to water-soluble drugs as well as macromolecules poses important challenges to transdermal administration. To widen the scope of drugs for transdermal delivery, new procedures to enhance skin permeation to hydrophilic drugs and macromolecules are under development. Next to iontophoresis and microneedle-based concepts, thermal-based approaches have shown great promise to enhance transdermal drug delivery of different therapeutics. In this inaugural article for the section “Frontiers in Bioengineering and Biotechnology,” the advances in this field and the handful of

Carbon Nanotube Membranes for use in the Transdermal Treatment of Nicotine Addiction and Opioid Withdrawal Symptoms

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Caroline L. Strasinger

2009-01-01

Full Text Available Transdermal systems are attractive methods of drug administration specifically when treating patients for drug addiction. Current systems however are deficient in therapies that allow variable flux values of drug, such as nicotine for smoking cessation or complex dosing regimens using clonidine when treating opioid withdrawal symptoms. Through the use of functionalized carbon nanotube (CNT membranes, drug delivery to the skin can be controlled by applying a small electrical bias to create a programmable drug delivery system. Clearly, a transdermal patch system that can be tailored to an individual's needs will increase patient compliance as well as provide much more efficient therapy. The purpose of this paper is to discuss the applicability of using carbon nanotube membranes in transdermal systems for treatment of drug abuse.

Brain tissue oxidative damage as a possible mechanism for the deleterious effect of a chronic high dose of estradiol on learning and memory in ovariectomized rats Dano oxidativo ao tecido cerebral como possível mecanismo de efeito deletério da alta dose crônica de estradiol no aprendizado e memória de ratas ooforectomizadas

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Fatimeh Khodabandehloo

2013-05-01

Full Text Available In addition to antioxidative effects, estrogens also exert pro-oxidative actions. The effect of chronic administration of a high dose of estradiol valerate on Morris water maze tasks and brain tissues oxidative damage was investigated. The Sham-Est and OVX-Est groups were treated with estradiol valerate (4 mg/kg for 12 weeks. Escape latency and traveled path in the Sham-Est and OVX-Est groups were significantly higher than in the Sham and OVX groups (p≪0.01 and p≪0.001. In the probe trial, the animals of the Sham-Est and OVX-Est groups spent lower time in Q1 compared to Sham and OVX groups (p≪0.05 and p≪0.001. In Sham-Est and OVX-Est groups, the brain tissue total thiol concentration was significantly lower, and malondialdehyde (MDA concentrations were higher than in the Sham and OVX groups (p≪0.05 and p≪0.001. It is concluded that administration of high exogenous levels of estradiol impairs performance and enhances oxidative stress.Além dos efeitos antioxidantes, os estrógenos também têm ação pró-oxidativa. Foi investigado o efeito da administração crônica de alta dose de valereato de estradiol no desempenho do labirinto aquático de Morris e o dano oxidativo ao tecido cerebral. Os grupos Sham-Est e OVX-Est foram tratados com valereato de estradiol (4 mg/kg por 12 semanas. O tempo de latência para escapada e o caminho percorrido foram significativamente maiores nos grupos Sham-Est e OVX-Est em relação aos grupos Sham e OVX (p≪0,01 e p≪0,001. No estudo probe, os animais dos grupos Sham-Est e OVX-Est levaram menos tempo no Q1 em comparação aos grupos Sham e OVX (p≪0,05 e p≪0,001. Nos grupos Sham-Est e OVX-Est, a concentração total de tiol foi significativamente menor, enquanto a concentração de malondialdehydo (MDA for maior do que aquela dos grupos Sham e OVX (p≪0,05 e p≪0,001. Concluiu-se que a administração de altas doses de estradiol exógeno compromete o desempenho e aumenta o estresse oxidativo

A clinical study of transdermal contraceptive patch in Thai adolescence women.

Science.gov (United States)

Piyasirisilp, Rachatapon; Taneepanichskul, Surasak

2008-02-01

To study cycle control, compliance and safety of a transdermal contraceptive patch in adolescent Thai women. Fifty-eight healthy women were assigned to receive 3 cycles of contraceptive patch (ethinyl estradiol 20 microg and norelgestromin 150 microg/day). All participants aged 16-20 years were invited to participate from the family planning clinic at King Chulalongkorn Memorial Hospital. Data were collected on adverse effects, perceived advantages and disadvantages, body weight, blood pressure, patch detachments and compliance. Data were analyzed using mean, percentage and student's t-test. The participants' average age was 19.4 years, height 158.8 cm, weight 51.8 kg, BMI 20.8 Kg/m2. The most location of patch application was the abdomen and the most adverse event was breast tenderness (31.0%) followed by application site reaction, nausea vomiting and headache respectively. The breast symptom was mild in severity. The participants reported decrease in dysmenorrhea and shorter duration of bleeding. There were no significant changes in body weight and blood pressure. The improvement of their facial acne was reported. There were no pregnancies during use and the adhesion of the contraceptive patch is excellent. Partial patch detachment was reported in only 6.9%. No completed patch detachment was found. The present study found an overall positive impression of a new transdermal contraceptive patch. The good compliance and few side effects were demonstrated. The adhesive patch contraceptive was excellent.

Perspectives on Transdermal Electroporation

Science.gov (United States)

Ita, Kevin

2016-01-01

Transdermal drug delivery offers several advantages, including avoidance of erratic absorption, absence of gastric irritation, painlessness, noninvasiveness, as well as improvement in patient compliance. With this mode of drug administration, there is no pre-systemic metabolism and it is possible to increase drug bioavailability and half-life. However, only a few molecules can be delivered across the skin in therapeutic quantities. This is because of the hindrance provided by the stratum corneum. Several techniques have been developed and used over the last few decades for transdermal drug delivery enhancement. These include sonophoresis, iontophoresis, microneedles, and electroporation. Electroporation, which refers to the temporary perturbation of the skin following the application of high voltage electric pulses, has been used to increase transcutaneous flux values by several research groups. In this review, transdermal electroporation is discussed and the use of the technique for percutaneous transport of low and high molecular weight compounds described. This review also examines our current knowledge regarding the mechanisms of electroporation and safety concerns arising from the use of this transdermal drug delivery technique. Safety considerations are especially important because electroporation utilizes high voltage pulses which may have deleterious effects in some cases. PMID:26999191

Ultra-low-dose continuous combined estradiol and norethisterone acetate: improved bleeding profile in postmenopausal women

DEFF Research Database (Denmark)

Sturdee, D.W.; Archer, D.F.; Rakov, V.

2008-01-01

OBJECTIVE: To evaluate the effect of two ultra-low-dose hormone treatments containing estradiol (E2) 0.5 mg and norethisterone acetate (NETA) 0.1 or 0.25 mg on the endometrium and bleeding. METHODS: A prospective, randomized, placebo-controlled trial of 6 months. Local Ethics Committee approval...... and informed consent were obtained prior to initiation and enrollment. Out of 577 postmenopausal women randomized, 575 took E2/NETA 0.1 (n = 194), or E2/NETA 0.25 (n = 181) or placebo (n = 200). Endometrial bleeding was monitored by daily diary cards and endometrial thickness by transvaginal ultrasound......: The ultra-low-dose combination of E2/NETA 0.1 or E2/NETA 0.25 resulted in a high incidence of amenorrhea and no bleeding in postmenopausal women, and a corresponding high level of compliance. Overall, there was no significant change in mean endometrial thickness during 6 months of active treatment...

Methylphenidate Transdermal System in Adult ADHD and Impact on Emotional and Oppositional Symptoms

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Marchant, Barrie K.; Reimherr, Frederick W.; Robison, Reid J.; Olsen, John L.; Kondo, Douglas G.

2011-01-01

Objective: This trial evaluated the effect of methylphenidate transdermal system (MTS) on the full spectrum of adult symptoms (attention-disorganization, hyperactivity-impulsivity, emotional dysregulation [ED], and oppositional-defiant disorder [ODD]) found in this disorder. Method: This placebo-controlled, double-blind, flexible-dose, crossover…

Encapsulated Curcumin for Transdermal Administration

African Journals Online (AJOL)

Purpose: To develop a proniosomal carrier system of curcumin for transdermal delivery. Methods: Proniosomes of curcumin were prepared by encapsulation of the drug in a mixture of Span 80, cholesterol and diethyl ether by ether injection method, and then investigated as a transdermal drug delivery system (TDDS).

Oral and transdermal DL-methylphenidate-ethanol interactions in C57BL/6J mice: potentiation of locomotor activity with oral delivery.

Science.gov (United States)

Bell, Guinevere H; Griffin, William C; Patrick, Kennerly S

2011-12-01

Many abusers of dl-methylphenidate co-abuse ethanol. The present animal study examined behavioral effects of oral or transdermal DL-methylphenidate in combination with a high, depressive dose of ethanol to model co-abuse. Locomotor activity of C57BL/6J mice was recorded for 3 h following dosing with either oral DL-methylphenidate (7.5 mg/kg) or transdermal DL-methylphenidate (Daytrana®;1/4 of a 12.5 cm(2) patch; mean dose 7.5 mg/kg), with or without oral ethanol (3 g/kg). Brains were enantiospecifically analyzed for the isomers of methylphenidate and the transesterification metabolite ethylphenidate. An otherwise depressive dose of ethanol significantly potentiated oral DL-methylphenidate induced increases in total distance traveled for the first 100 min (pbrain D-methylphenidate concentrations were significantly elevated by ethanol in both the oral (65% increase) and transdermal (88% increase) groups. The corresponding L-ethylphenidate concentrations were 10 ng/g and 130 ng/g. Stimulant induced motor activity in rodents may correlate with abuse liability. Potentiation of DL-methylphenidate motor effects by concomitant ethanol carries implications regarding increased abuse potential of DL-methylphenidate when combined with ethanol. Copyright © 2011 Elsevier Inc. All rights reserved.

Carbon Nanotube Membranes for use in the Transdermal Treatment of Nicotine Addiction and Opioid Withdrawal Symptoms

Directory of Open Access Journals (Sweden)

Audra L. Stinchcomb

2009-01-01

Full Text Available Transdermal systems are attractive methods of drug administration specifically when treating patients for drug addiction. Current systems however are deficient in therapies that allow variable flux values of drug, such as nicotine for smoking cessation or complex dosing regimens using clonidine when treating opioid withdrawal symptoms. Through the use of functionalized carbon nanotube (CNT membranes, drug delivery to the skin can be controlled by applying a small electrical bias to create a programmable drug delivery system. Clearly, a transdermal patch system that can be tailored to an individual’s needs will increase patient compliance as well as provide much more efficient therapy. The purpose of this paper is to discuss the applicability of using carbon nanotube membranes in transdermal systems for treatment of drug abuse.

Transdermal hyoscine induced unilateral mydriasis.

LENUS (Irish Health Repository)

Hannon, Breffni

2012-03-20

The authors present a case of unilateral mydriasis in a teenager prescribed transdermal hyoscine hydrobromide (scopolamine) for chemotherapy induced nausea and vomiting. The authors discuss the ocular side-effects associated with this particular drug and delivery system and the potential use of transdermal hyoscine as an antiemetic agent in this group.

Dose, image quality and spine modeling assessment of biplanar EOS micro-dose radiographs for the follow-up of in-brace adolescent idiopathic scoliosis patients.

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Morel, Baptiste; Moueddeb, Sonia; Blondiaux, Eleonore; Richard, Stephen; Bachy, Manon; Vialle, Raphael; Ducou Le Pointe, Hubert

2018-05-01

The aim of this study was to compare the radiation dose, image quality and 3D spine parameter measurements of EOS low-dose and micro-dose protocols for in-brace adolescent idiopathic scoliosis (AIS) patients. We prospectively included 25 consecutive patients (20 females, 5 males) followed for AIS and undergoing brace treatment. The mean age was 12 years (SD 2 years, range 8-15 years). For each patient, in-brace biplanar EOS radiographs were acquired in a standing position using both the conventional low-dose and micro-dose protocols. Dose area product (DAP) was systematically recorded. Diagnostic image quality was qualitatively assessed by two radiologists for visibility of anatomical structures. The reliability of 3D spine modeling between two operators was quantitatively evaluated for the most clinically relevant 3D radiological parameters using intraclass correlation coefficient (ICC). The mean DAP for the posteroanterior and lateral acquisitions was 300 ± 134 and 433 ± 181 mGy cm 2 for the low-dose radiographs, and 41 ± 19 and 81 ± 39 mGy cm 2 for micro-dose radiographs. Image quality was lower with the micro-dose protocol. The agreement was "good" to "very good" for all measured clinical parameters when comparing the low-dose and micro-dose protocols (ICC > 0.73). The micro-dose protocol substantially reduced the delivered dose (by a factor of 5-7 compared to the low-dose protocol) in braced children with AIS. Although image quality was reduced, the micro-dose protocol proved to be adapted to radiological follow-up, with adequate image quality and reliable clinical measurements. These slides can be retrieved under Electronic Supplementary Material.

Some Recent Advances in Transdermal Drug Delivery Systems ...

African Journals Online (AJOL)

Some Recent Advances in Transdermal Drug Delivery Systems. ... Advances in Transdermal Drug Delivery Systems. EC Ibezim, B Kabele-Toge, CO Anie, C Njoku. Abstract. Transdermal delivery systems are forms of drug delivery involving the dermis, as distinct from topical, oral or other forms of parenteral dosage forms.

Transdermal delivery of isoniazid and rifampin in guinea pigs by electro-phonophoresis.

Science.gov (United States)

Chen, Suting; Han, Yi; Yu, Daping; Huo, Fengmin; Wang, Fen; Li, Yunxu; Dong, Lingling; Liu, Zhidong; Huang, Hairong

2017-11-01

Electro-phonophoresis (EP) has been used as a drug delivery approach in clinical fields. The objective of the present study is to evaluate the skin permeability of isoniazid and rifampin in guinea pigs by EP to provide reference basis for clinical applications of such transdermal delivery system in the treatment of patients with superficial tuberculosis. Isoniazid and rifampin solutions were delivered transdermally with or without EP in health guinea pigs for 0.5 h. Local skin and blood samples were collected serially at 0, 1/2, 1, 2, 4, 6 and 24 h after dosing. Drug concentrations in local skin and blood were evaluated by high-performance liquid chromatography. Isoniazid concentrations in local skin of guinea pigs receiving isoniazid through EP transdermal delivery were significantly higher than in animals receiving only isoniazid with transdermal patch. However, for rifampin, patches alone group presented almost uniform concentration versus time curve with that of EP group, and both groups had concentrations much higher than the therapeutic concentration of the drug over sustainable time. After EP transdermal delivery, the mean peak concentrations of isoniazid and rifampin in skin were 771.0 ± 163.4 μg/mL and 81.2 ± 17.3 μg/mL respectively. Neither isoniazid nor rifampin concentration in blood could be detected (below the lower detection limit of 1 μg/mL) at any time point. The present study showed that application of EP significantly enhanced INH penetration through skin in guinea pigs, while RIF patch alone obtained therapeutic concentration in local skin. Our work suggests several possible medication approaches for efficient treatment of superficial tuberculosis.

Permeation enhancer strategies in transdermal drug delivery.

Science.gov (United States)

Marwah, Harneet; Garg, Tarun; Goyal, Amit K; Rath, Goutam

2016-01-01

Today, ∼74% of drugs are taken orally and are not found to be as effective as desired. To improve such characteristics, transdermal drug delivery was brought to existence. This delivery system is capable of transporting the drug or macromolecules painlessly through skin into the blood circulation at fixed rate. Topical administration of therapeutic agents offers many advantages over conventional oral and invasive techniques of drug delivery. Several important advantages of transdermal drug delivery are prevention from hepatic first pass metabolism, enhancement of therapeutic efficiency and maintenance of steady plasma level of the drug. Human skin surface, as a site of drug application for both local and systemic effects, is the most eligible candidate available. New controlled transdermal drug delivery systems (TDDS) technologies (electrically-based, structure-based and velocity-based) have been developed and commercialized for the transdermal delivery of troublesome drugs. This review article covers most of the new active transport technologies involved in enhancing the transdermal permeation via effective drug delivery system.

The effects of compounded bioidentical transdermal hormone therapy on hemostatic, inflammatory, immune factors; cardiovascular biomarkers; quality-of-life measures; and health outcomes in perimenopausal and postmenopausal women.

Science.gov (United States)

Stephenson, Kenna; Neuenschwander, Pierre F; Kurdowska, Anna K

2013-01-01

Menopause impacts 25 million women world wide each year, and the World Health Organization estimates 1.2 billion women will be postmenopausal by 2030. Menopause has been associated with symptoms of hot flashes, night sweats, dysphoric mood, sleep disturbance, and conditions of cardiovascular disease, depression, osteoporosis, osteoarthritis, depression, dementia, and frailty. Conventional hormone replacement therapy results in increased thrombotic events, and an increased risk of breast cancer and dementia as evidenced in large prospective clinical trials including Heart and Estrogen/Progestin Replacement Study I and the Women's Health Initiative. A possible mechanism for these adverse events is the unfavorable net effects of conjugated equine estrogens and medroxyprogesterone acetate on the hemostatic balance and inflammatory and immune factors. Physiologic sex steroid therapy with transdermal delivery for peri/postmenopausal women may offer a different risk/benefit profile, yet long-term studies of this treatment model are lacking. The objective of this study was to examine the long-term effects of compounded bioidentical transdermal sex steroid therapy including estriol, estradiol, progesterone, DHEA, and testosterone on cardiovascular biomarkers, hemostatic, inflammatory, immune signaling factors; quality-of-life measures; and health outcomes in peri/postmenopausal women within the context of a hormone restoration model of care. A prospective, cohort, closed-label study received approval from the Human Subjects Committee. Recruitment from outpatient clinics at an academic medical center and the community at large resulted in three hundred women giving signed consent. Seventy-five women who met strict inclusion/exclusion criteria were enrolled. Baseline hormone evaluation was performed along with baseline experimental measures. Following this, women received compounded transdermal bioidentical hormone therapy of BiEst (80%Estriol/20%Estradiol), and

Effects of estradiol and venlafaxine on insomnia symptoms and sleep quality in women with hot flashes.

Science.gov (United States)

Ensrud, Kristine E; Guthrie, Katherine A; Hohensee, Chancellor; Caan, Bette; Carpenter, Janet S; Freeman, Ellen W; LaCroix, Andrea Z; Landis, Carol A; Manson, JoAnn; Newton, Katherine M; Otte, Julie; Reed, Susan D; Shifren, Jan L; Sternfeld, Barbara; Woods, Nancy F; Joffe, Hadine

2015-01-01

Determine effects of low-dose estradiol and low-dose venlafaxine on self-reported sleep measures in menopausal women with hot flashes. 3-arm double-blind randomized trial. Participants assigned in a 2:2:3 ratio to 17β estradiol 0.5 mg/day (n = 97), venlafaxine XR 75 mg/day (n = 96), or placebo (n = 146) for 8 weeks. Academic research centers. 339 community-dwelling perimenopausal and postmenopausal women with ≥2 bothersome hot flashes per day. Insomnia symptoms (Insomnia Severity Index [ISI]) and sleep quality (Pittsburgh Sleep Quality Index [PSQI]) at baseline, week 4 and 8; 325 women (96%) provided ISI data and 312 women (92%) provided PSQI data at baseline and follow-up. At baseline, mean (SD) hot flash frequency was 8.1/day (5.3), mean ISI was 11.1 (6.0), and mean PSQI was 7.5 (3.4). Mean (95% CI) change from baseline in ISI at week 8 was -4.1 points (-5.3 to -3.0) with estradiol, -5.0 points (-6.1 to -3.9) with venlafaxine, and -3.0 points (-3.8 to -2.3) with placebo (P overall treatment effect vs. placebo 0.09 for estradiol and 0.007 for venlafaxine). Mean (95% CI) change from baseline in PSQI at week 8 was -2.2 points (-2.8 to -1.6) with estradiol, -2.3 points (-2.9 to -1.6) with venlafaxine, and -1.2 points (-1.7 to -0.8) with placebo (P overall treatment effect vs. placebo 0.04 for estradiol and 0.06 for venlafaxine). Among perimenopausal and postmenopausal women with hot flashes, both low dose oral estradiol and low-dose venlafaxine compared with placebo modestly reduced insomnia symptoms and improved subjective sleep quality. NCT01418209 at www.clinicaltrials.gov. © 2014 Associated Professional Sleep Societies, LLC.

Safety, efficacy and patient acceptability of the combined estrogen and progestin transdermal contraceptive patch: a review

Directory of Open Access Journals (Sweden)

Alessandra Graziottin

2008-11-01

Full Text Available Alessandra GraziottinCenter of Gynecology and Medical Sexology, H San Raffaele Resnati, Via Santa Croce 10/a, 20123 Milano, ItalyAbstract: The worldwide introduction of the first, unique patch for hormonal contraception (ethinyl estradiol/norelgestromin, EE/NGMN patch was widely recognized as a significant event in the development of drug delivery systems. This innovation offers a number of advantages over the oral route, and extensive clinical trials have proved its safety, efficacy, effectiveness, and tolerability. The weekly administration and ease of use/simplicity of the EE/NGMN patch contribute to its acceptability, and help to resolve the two main problems of non-adherence, namely early discontinuation and inconsistent use. The patch offers additional benefits to adolescents (improvement of dysmenorrhea and acne, adults (improvement in emotional and physical well-being, premenstrual syndrome, and menstrual irregularities, and perimenopausal women (correction of hormonal imbalance, modulation of premenopausal symptoms, thus providing high satisfaction rates (in nearly 90% of users. Since its introduction, the transdermal contraceptive patch has proved to be a useful choice for women who seek a convenient formulation which is easy to use, with additional, non-contraceptive tailored benefits for all the ages.Keywords: transdermal, hormonal contraceptive, patient satisfaction, patient adherence

Dose-response relationships in gene expression profiles in a harbor seal B lymphoma cell line exposed to 17α-ethinyl estradiol

Directory of Open Access Journals (Sweden)

Christine Kleinert

2017-05-01

Full Text Available The determination of changes in gene expression profiles with xenobiotic dose will allow identifying biomarkers and modes of toxicant action. The harbor seal (Phoca vitulina 11B7501 B lymphoma cell line was exposed to 1, 10, 100, 1000, 10,000, or 25,000 μg/L 17α-ethinyl estradiol (EE2, the active compound of the contraceptive pill for 24 h. Following exposure, RNA was extracted and transformed into cDNA. Transcript expression in exposed vs. control lymphocytes was analyzed via RT-qPCR to identify genes with altered expression. Our analysis indicates that gene expression for all but the reference gene varied with dose, suggesting that different doses induce distinct physiological responses. These findings demonstrate that RT-qPCR could be used to identify immunotoxicity and relative dose in harbor seal leukocytes.

Viral vector-mediated overexpression of estrogen receptor-alpha in striatum enhances the estradiol-induced motor activity in female rats and estradiol-modulated GABA release.

Science.gov (United States)

Schultz, Kristin N; von Esenwein, Silke A; Hu, Ming; Bennett, Amy L; Kennedy, Robert T; Musatov, Sergei; Toran-Allerand, C Dominique; Kaplitt, Michael G; Young, Larry J; Becker, Jill B

2009-02-11

Classical estrogen receptor-signaling mechanisms involve estradiol binding to intracellular nuclear receptors [estrogen receptor-alpha (ERalpha) and estrogen receptor-beta (ERbeta)] to promote changes in protein expression. Estradiol can also exert effects within seconds to minutes, however, a timescale incongruent with genomic signaling. In the brain, estradiol rapidly potentiates stimulated dopamine release in the striatum of female rats and enhances spontaneous rotational behavior. Furthermore, estradiol rapidly attenuates the K(+)-evoked increase of GABA in dialysate. We hypothesize that these rapid effects of estradiol in the striatum are mediated by ERalpha located on the membrane of medium spiny GABAergic neurons. This experiment examined whether overexpression of ERalpha in the striatum would enhance the effect of estradiol on rotational behavior and the K(+)-evoked increase in GABA in dialysate. Ovariectomized female rats were tested for rotational behavior or underwent microdialysis experiments after unilateral intrastriatal injections of a recombinant adeno-associated virus (AAV) containing the human ERalpha cDNA (AAV.ERalpha) into the striatum; controls received either the same vector into areas outside the striatum or an AAV containing the human alkaline phosphatase gene into the striatum (AAV.ALP). Animals that received AAV.ERalpha in the striatum exhibited significantly greater estradiol-induced contralateral rotations compared with controls and exhibited behavioral sensitization of contralateral rotations induced by a low-dose of amphetamine. ERalpha overexpression also enhanced the inhibitory effect of estradiol on K(+)-evoked GABA release suggesting that disinhibition of dopamine release from terminals in the striatum resulted in the enhanced rotational behavior.

Treatment of Severe Cancer Pain by Transdermal Fentanyl

Directory of Open Access Journals (Sweden)

Dženita Ljuca

2010-05-01

Full Text Available The goal of research was to determine the frequency, intensity, time of occurrence, duration and causes of breakthrough pain (BTP in patients whose carcinoma pain was treated by transdermal fentanyl. (TDF. A prospective study was conducted in a hospice for recumbent patients of the Centre for Palliative Care (hospice University Clinical Centre Tuzla from October 2009 to December 2010. 33 patients in terminal stage of carcinoma, who had been treated by transdermal fentanyl due to their excruciating pain (7-10 mark on numerica! scale with initial dosage of 25 μg as a strong opiate analgesic, were monitored within the time period of 10 days. In the statistics we used the even T - test, the Wilcox test and Mann -Whitney test. The difference was seen to be significant at p < 0,05. Treatment by transdermal fentanyl significantly reduces the intensity of strong carcinoma pain (p < 0.0001, with a frequent requirement for dose increase with bone metastasis. The intensity of BTP is higher compared to the pain experienced upon reception. The frequency and intensity of BTP are significantly reduced already in the second day of treatment by transdermal fentanyl (p = 0,0024. The BTP is most intense in patients with neck and head tumours (9,26 ± 0,66, and most frequent with abdomen and pelvic tumour. The biggest number of BTP (68.3 % occurs within first three days of treatment. BTP most frequently occurs in the evening or at night (between 18:00 and 06:00 h in 62,2 % of the cases, with the duration of usually less than 15 minutes (65,2% of the cases. In 61,6 % cases the occurrence of BTP is related to physical activities or psychosocial incidents, while the cause is undetermined in 38,4 % of examinees.BTP is most frequent within first three days of treatment by TDF. Using the optimal dosage a good control of carcinoma pain is enabled, regardless of the occurrence of bone metastasis, while it also helps reduce the frequency and intensity of BTP.

Beta particle dose rates to micro-organisms in soil

International Nuclear Information System (INIS)

Kabir, M.; Spiers, F.W.; Iinuma, Takeshi.

1977-01-01

Studies were made to estimate the beta-particle dose rates to micro-organisms of various sizes in soil. The small insects and organisms living in soil are constantly exposed to beta-radiation arising from naturally occuring radionuclides in soil as in this case no overlying tissue shields them. The technique of measuring beta-particle dose rate consisted of using of a thin plastic scintillator to measure the pulse height distribution as the beta particle traverses the scintillator. The integrated response was determined by the number and size of the photomultiplier pulses. From the data of soil analyses it was estimated that typically about 29% of the beta particles emitted per gm. of soil were contributed by the U/Ra series, 21% by the Th series and about 50% by potassium. By combining the individual spectra of these three radionuclides in the proportion found in a typical soil, a resultant spectrum was computed representing the energy distribution of the beta particles. The dose rate received by micro-organisms of different shape and size in soil was derived from the equilibrium dose rates combined with a 'Geometrical Factor' of the organisms. For small organisms, the dose rates did not vary between the spherical and cylindrical types, but in the case of larger organisms, the dose rates were found to be greater for the spherical types of the same diameter. (auth.)

Fentanyl sublingual spray for breakthrough cancer pain in patients receiving transdermal fentanyl.

Science.gov (United States)

Alberts, David S; Smith, Christina Cognata; Parikh, Neha; Rauck, Richard L

2016-10-01

To investigate the relationship between effective fentanyl sublingual spray (FSS) doses for breakthrough cancer pain (BTCP) and around-the-clock (ATC) transdermal fentanyl patch (TFP). Adults tolerating ATC opioids received open-label FSS for 26 days, followed by a 26-day double-blind phase for patients achieving an effective dose (100-1600 µg). Out of 50 patients on ATC TFP at baseline, 32 (64%) achieved an effective dose. FSS effective dose moderately correlated with mean TFP dose (r = 0.4; p = 0.03). Patient satisfaction increased during the study. Common adverse event included nausea (9%) and peripheral edema (9%). FSS can be safely titrated to an effective dose for BTCP in patients receiving ATC TFP as chronic cancer pain medication. ClinicalTrials.gov identifier: NCT00538850.

Dissolving and biodegradable microneedle technologies for transdermal sustained delivery of drug and vaccine

Directory of Open Access Journals (Sweden)

Hong X

2013-09-01

Full Text Available Xiaoyun Hong,1,2,* Liangming Wei,3,* Fei Wu,2,* Zaozhan Wu,2 Lizhu Chen,2 Zhenguo Liu,1 Weien Yuan2 1Department of Neurology, Xinhua Hospital, Shanghai, People's Republic of China; 2School of Pharmacy, Shanghai JiaoTong University, Shanghai, People's Republic of China; 3Research Institute of Micro/Nano Science and Technology, Shanghai JiaoTong University, Shanghai, People's Republic of China *These authors contributed equally to this work Abstract: Microneedles were first conceptualized for drug delivery many decades ago, overcoming the shortages and preserving the advantages of hypodermic needle and conventional transdermal drug-delivery systems to some extent. Dissolving and biodegradable microneedle technologies have been used for transdermal sustained deliveries of different drugs and vaccines. This review describes microneedle geometry and the representative dissolving and biodegradable microneedle delivery methods via the skin, followed by the fabricating methods. Finally, this review puts forward some perspectives that require further investigation. Keywords: microneedle, dissolving, biodegradable, sustained release

Advanced progress of microencapsulation technologies: in vivo and in vitro models for studying oral and transdermal drug deliveries.

Science.gov (United States)

Lam, P L; Gambari, R

2014-03-28

This review provides an overall discussion of microencapsulation systems for both oral and transdermal drug deliveries. Clinically, many drugs, especially proteins and peptides, are susceptible to the gastrointestinal tract and the first-pass metabolism after oral administration while some drugs exhibit low skin permeability through transdermal delivery route. Medicated microcapsules as oral and transdermal drug delivery vehicles are believed to offer an extended drug effect at a relatively low dose and provide a better patient compliance. The polymeric microcapsules can be produced by different microencapsulation methods and the drug microencapsulation technology provides the quality preservation for drug stabilization. The release of the entrapped drug is controlled and prolonged for specific usages. Some recent studies have focused on the evaluation of drug containing microcapsules on potential biological and therapeutic applications. For the oral delivery, in vivo animal models were used for evaluating possible treatment effects of drug containing microcapsules. For the transdermal drug delivery, skin delivery models were introduced to investigate the potential skin delivery of medicated microcapsules. Finally, the challenges and limitations of drug microencapsulation in real life are discussed and the commercially available drug formulations using microencapsulation technology for oral and transdermal applications are shown. Copyright © 2014 Elsevier B.V. All rights reserved.

Viral Vector Mediated Over-Expression of Estrogen Receptor–α in Striatum Enhances the Estradiol-induced Motor Activity in Female Rats and Estradiol Modulated GABA Release

Science.gov (United States)

Schultz, Kristin N.; von Esenwein, Silke A.; Hu, Ming; Bennett, Amy L.; Kennedy, Robert T.; Musatov, Sergei; Toran-Allerand, C. Dominique; Kaplitt, Michael G.; Young, Larry J.; Becker, Jill B.

2009-01-01

Classical estrogen receptor signaling mechanisms involve estradiol binding to intracellular nuclear receptors (estrogen receptor-α (ERα) and estrogen receptor-β (ERβ)) to promote changes in protein expression. Estradiol can also exert effects within seconds to minutes, however, a timescale incongruent with genomic signaling. In the brain, estradiol rapidly potentiates stimulated dopamine release in the striatum of female rats and enhances spontaneous rotational behavior. Furthermore, estradiol rapidly attenuates the K+- evoked increase of GABA in dialysate. We hypothesize that these rapid effects of estradiol in the striatum are mediated by ERα located on the membrane of medium spiny GABAergic neurons. This experiment examined whether over-expression of ERα in the striatum would enhance the effect of estradiol on rotational behavior and the K+- evoked increase in GABA in dialysate. Ovariectomized female rats were tested for rotational behavior or underwent microdialysis experiments after unilateral intrastriatal injections of a recombinant adeno-associated virus (AAV) containing the human ERα cDNA (AAV.ERα) into the striatum; controls received either the same vector into areas outside the striatum or an AAV containing the human alkaline phosphatase gene into the striatum (AAV.ALP). Animals that received AAV.ERα in the striatum exhibited significantly greater estradiol-induced contralateral rotations compared to controls and exhibited behavioral sensitization of contralateral rotations induced by a low dose of amphetamine. ERα over-expression also enhanced the inhibitory effect of estradiol on K+- evoked GABA release suggesting that disinhibition of dopamine release from terminals in the striatum resulted in the enhanced rotational behavior. PMID:19211896

A Transdermal Measurement Platform Based on Microfluidics

Directory of Open Access Journals (Sweden)

Wen-Ying Huang

2017-01-01

Full Text Available The Franz diffusion cell is one of the most widely used devices to evaluate transdermal drug delivery. However, this static and nonflowing system has some limitations, such as a relatively large solution volume and skin area and the development of gas bubbles during sampling. To overcome these disadvantages, this study provides a proof of concept for miniaturizing models of transdermal delivery by using a microfluidic chip combined with a diffusion cell. The proposed diffusion microchip system requires only 80 μL of sample solution and provides flow circulation. Two model compounds, Coomassie Brilliant Blue G-250 and potassium ferricyanide, were successfully tested for transdermal delivery experiments. The diffusion rate is high for a high sample concentration or a large membrane pore size. The developed diffusion microchip system, which is feasible, can be applied for transdermal measurement in the future.

A Comprehensive Review on: Transdermal drug delivery systems.

OpenAIRE

Kharat, Rekha; Bathe, Ritesh Suresh

2016-01-01

Transdermal drug delivery system was introduced to overcome the difficulties of drug delivery through oral route. Despite their relatively higher costs, transdermal delivery systems have proved advantageous for delivery of selected drugs, such as estrogens, testosterone, clonidine and nitro-glycerine. Transdermal delivery provides a leading edge over injectable and oral routes by increasing patient compliance and avoiding first pass metabolism respectively. Topical  administration  of  therap...

New low-dose, extended-cycle pills with levonorgestrel and ethinyl estradiol: an evolutionary step in birth control.

Science.gov (United States)

Nelson, Anita

2010-08-09

To review milestones in development of oral contraceptive pills since their introduction in the US 50 years ago in order to better understand how a new formulation with low-dose estrogen in an extended-cycle pattern fits into the evolution of birth control pills. This is a review of trends in the development of various birth controls pills and includes data from phase III clinical trials for this new formulation. The first birth control pill was a very high-dose monophasic formulation with the prodrug estrogen mestranol and a first-generation progestin. Over the decades, the doses of hormones have been markedly reduced, and a new estrogen and several different progestins were developed and used in different dosing patterns. The final element to undergo change was the 7-day pill-free interval. Many of these same changes have been made in the development of extended-cycle pill formulation. The newest extended-cycle oral contraceptive formulation with 84 active pills, each containing 20 μg ethinyl estradiol and 100 μg levonorgestrel, represents an important evolution in birth control that incorporates lower doses of estrogen (to reduce side effects and possibly reduce risk of thrombosis), fewer scheduled bleeding episodes (to meet women's desires for fewer and shorter menses) and the use of low-dose estrogen in place of placebo pills (to reduce the number of days of unscheduled spotting and bleeding). Hopefully, this unique formation will motivate women to be more successful contraceptors.

Effect of two oral doses of 17beta-estradiol associated with dydrogesterone on thrombin generation in healthy menopausal women: a randomized double-blind placebo-controlled study.

Science.gov (United States)

Rousseau, Alexandra; Robert, Annie; Gerotziafas, Grigoris; Torchin, Dahlia; Zannad, Faiez; Lacut, Karine; Libersa, Christian; Dasque, Eric; Démolis, Jean-Louis; Elalamy, Ismail; Simon, Tabassome

2010-04-01

Oral hormone therapy is associated with an increased risk of venous thrombosis. Drug agencies recommend the use of the lowest efficient dose to treat menopausal symptoms for a better risk/ratio profile, although this profile has not been totally investigated yet. The aim of the study was to compare the effect of the standard dose of 17beta-estradiol to a lower one on thrombin generation (TG). In a 2-month study, healthy menopausal women were randomized to receive daily 1mg or 2 mg of 17beta-estradiol (E1, n = 24 and E2, n = 26; respectively) with 10 mg dydrogesterone or placebo (PL, n = 22). Plasma levels factors VII, X, VIII and II were assessed before and after treatment as well as Tissue factor triggered TG, which allows the investigation of the different phases of coagulation process. The peak of thrombin was higher in hormone therapy groups (E1: 42.39 +/- 50.23 nm, E2: 31.08 +/- 85.86 nm vs. 10.52 +/- 40.63 nm in PL, P = 0.002 and P = 0.01). Time to reach the peak was also shortened (PL: 0.26 +/- 0.69 min vs. E1: -0.26 +/- 0.80 min, E2: -0.55 +/- 0.79 min, P <10(-3) for both comparisons) and mean rate index of the propagation phase of TG was significantly increased. Among the studied clotting factors, only the levels of FVII were significantly increased after treatment administration. The two doses of 17beta-estradiol induced in a similar degree an acceleration of the initiation and propagation phase of tissue factor triggered thrombin generation and a significant increase of FVII coagulant activity.

Chemical Penetration Enhancers for Transdermal Drug Delivery ...

African Journals Online (AJOL)

for transdermal administration. The permeation of drug through skin can be enhanced by both chemical penetration enhancement and physical methods. In this review, we have discussed the chemical penetration enhancement technology for transdermal drug delivery as well as the probable mechanisms of action.

Transdermal delivery of naltrexol and skin permeability lifetime after microneedle treatment in hairless guinea pigs

OpenAIRE

Banks, Stan L.; Pinninti, Raghotham R.; Gill, Harvinder S.; Paudel, Kalpana S.; Crooks, Peter A.; Brogden, Nicole K.; Prausnitz, Mark R.; Stinchcomb, Audra L.

2010-01-01

Controlled-release delivery of 6-β-naltrexol (NTXOL), the major active metabolite of naltrexone, via a transdermal patch is desirable for treatment of alcoholism. Unfortunately, NTXOL does not diffuse across skin at a therapeutic rate. Therefore, the focus of this study was to evaluate microneedle (MN) skin permeation enhancement of NTXOL's hydrochloride salt in hairless guinea pigs. Specifically, these studies were designed to determine the lifetime of MN-created aqueous pore pathways. Micro...

Dose-responsiveness and persistence of microRNA expression alterations induced by cigarette smoke in mouse lung

International Nuclear Information System (INIS)

Izzotti, Alberto; Larghero, Patrizia; Longobardi, Mariagrazia; Cartiglia, Cristina; Camoirano, Anna; Steele, Vernon E.; De Flora, Silvio

2011-01-01

Our previous studies demonstrated that exposure to cigarette smoke (CS), either mainstream or environmental, results in a remarkable downregulation of microRNA expression in the lung of both mice and rats. The goals of the present study were to evaluate the dose responsiveness to CS and the persistence of microRNA alterations after smoking cessation. ICR (CD-1) neonatal mice were exposed whole-body to mainstream CS, at the doses of 119, 292, 438, and 631 mg/m 3 of total particulate matter. Exposure started within 12 h after birth and continued daily for 4 weeks. The levels of bulky DNA adducts and 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodGuo) were measured by 32 P postlabeling procedures, and the expression of 697 mouse microRNAs was analyzed by microarray. The highest CS dose was lethal. Exposure to CS caused a dose-dependent increase of DNA alterations. DNA adducts and, even more sharply, 8-oxodGuo were reverted 1 and 4 weeks after smoking cessation. Exposure to CS resulted in an evident dysregulation of microRNA expression profiles, mainly in the sense of downregulation. The two lowest doses were not particularly effective, while the highest nonlethal dose produced extensive microRNA alterations. The expression of most downregulated microRNAs, including among others 7 members of the let-7 family, was restored one week after smoking cessation. However, the recovery was incomplete for a limited array of microRNAs, including mir-34b, mir-345, mir-421, mir-450b, mir-466, and mir-469. Thus, it appears that microRNAs mainly behave as biomarkers of effect and that exposure to high-dose, lasting for an adequate period of time, is needed to trigger the CS-related carcinogenesis process in the experimental animal model used.

Dose-dependent effect of 17 beta-estradiol determined by growth curves and flow cytometric DNA analysis of a human breast carcinoma (T61) grown in nude mice

DEFF Research Database (Denmark)

Brünner, N; Spang-Thomsen, M; Vindeløv, L

1985-01-01

fraction of polyploid cells. The results suggest that estradiol induces a dose-dependent cell killing effect in the T61 human breast carcinoma. The correlation between the treatment-induced growth delay and the effect on the cell cycle distribution indicates that the changes in the cell cycle...

Interactions between estradiol and haloperidol on perseveration and reversal learning in amphetamine-sensitized female rats.

Science.gov (United States)

Almey, Anne; Arena, Lauren; Oliel, Joshua; Shams, Waqqas M; Hafez, Nada; Mancinelli, Cynthia; Henning, Lukas; Tsanev, Aleks; Brake, Wayne G

2017-03-01

There are sex differences associated with schizophrenia, as women exhibit later onset of the disorder, less severe symptomatology, and better response to antipsychotic medications. Estrogens are thought to play a role in these sex differences; estrogens facilitate the effects of antipsychotic medications to reduce the positive symptoms of schizophrenia, but it remains unclear whether estrogens protect against the cognitive symptoms of this disorder. Amphetamine sensitization is used to model some symptoms of schizophrenia in rats, including cognitive deficits like excessive perseveration and slower reversal learning. In this experiment female rats were administered a sensitizing regimen of amphetamine to mimic these cognitive symptoms. They were ovariectomized and administered either low or high estradiol replacement as well as chronic administration of the antipsychotic haloperidol, and were assessed in tests of perseveration and reversal learning. Results of these experiments demonstrated that, in amphetamine-sensitized rats, estradiol alone does not affect perseveration or reversal learning. However, low estradiol facilitates a 0.25mg/day dose of haloperidol to reduce perseveration and improve reversal learning. Combined high estradiol and 0.25mg/day haloperidol has no effect on perseveration or reversal learning, but high estradiol facilitates the effects of 0.13mg/day haloperidol to reduce perseveration and improve reversal learning. Thus, in amphetamine-sensitized female rats, 0.25mg/day haloperidol only improved perseveration and reversal learning when estradiol was low, while 0.13mg/day haloperidol only improved these cognitive processes when estradiol was high. These findings suggest that estradiol facilitates the effects of haloperidol to improve perseveration and reversal learning in a dose-dependent manner. Copyright © 2017 Elsevier Inc. All rights reserved.

Liposomal Encapsulation for Systemic Delivery of Propranolol via Transdermal Iontophoresis Improves Bone Microarchitecture in Ovariectomized Rats.

Science.gov (United States)

Teong, Benjamin; Kuo, Shyh Ming; Tsai, Wei-Hsin; Ho, Mei-Ling; Chen, Chung-Hwan; Huang, Han Hsiang

2017-04-13

The stimulatory effects of liposomal propranolol (PRP) on proliferation and differentiation of human osteoblastic cells suggested that the prepared liposomes-encapsulated PRP exerts anabolic effects on bone in vivo. Iontophoresis provides merits such as sustained release of drugs and circumvention of first pass metabolism. This study further investigated and evaluated the anti-osteoporotic effects of liposomal PRP in ovariectomized (OVX) rats via iontophoresis. Rats subjected to OVX were administered with pure or liposomal PRP via iontophoresis or subcutaneous injection twice a week for 12 weeks. Changes in the microarchitecture at the proximal tibia and the fourth lumbar spine were assessed between pure or liposomal PRP treated and non-treated groups using micro-computed tomography. Administration of liposomal PRP at low dose (0.05 mg/kg) via iontophoresis over 2-fold elevated ratio between bone volume and total tissue volume (BV/TV) in proximal tibia to 9.0% whereas treatment with liposomal PRP at low and high (0.5 mg/kg) doses via subcutaneous injection resulted in smaller increases in BV/TV. Significant improvement of BV/TV and bone mineral density (BMD) was also found in the fourth lumbar spine when low-dose liposomal PRP was iontophoretically administered. Iontophoretic low-dose liposomal PRP also elevated trabecular numbers in tibia and trabecular thickness in spine. Enhancement of bone microarchitecture volumes has highlighted that liposomal formulation with transdermal iontophoresis is promising for PRP treatment at the lower dose and with longer duration than its clinical therapeutic range and duration to exhibit optimal effects against bone loss in vivo.

A commentary on transdermal drug delivery systems in clinical trials.

Science.gov (United States)

Watkinson, Adam C

2013-09-01

The number of drugs available as marketed transdermal products is limited to those that exhibit the correct physicochemical and pharmacokinetic properties that enable their effective delivery across the skin. In this respect, there are less than 20 drugs that are currently marketed in the US and EU as products that deliver systemic levels of their active ingredients. An analysis of clinical trials conducted in the transdermal sector shows a similar picture with only nine drugs accounting for approximately 80% of all transdermal clinical trials listed on ClinicalTrials.gov. Those drugs for which there are very few transdermal trials listed consist mostly of molecules that are inherently unsuitable for transdermal delivery and serve as a clear warning to drug developers that the science that governs transdermal drug delivery is well reflected by the successes and failures of drugs in development as well as those that make it to the market. Copyright © 2013 Wiley Periodicals, Inc.

Maternal low-dose estradiol-17β exposure during pregnancy impairs postnatal progeny weight development and body composition

International Nuclear Information System (INIS)

Werner Fürst, Rainer; Pistek, Veronika Leopoldine; Kliem, Heike; Skurk, Thomas; Hauner, Hans; Meyer, Heinrich Herman Dietrich; Ulbrich, Susanne Ernestine

2012-01-01

Endocrine disrupting chemicals with estrogenic activity play an important role as obesogens. However, studies investigating the most potent natural estrogen, estradiol-17β (E2), at low dose are lacking. We examined endocrine and physiological parameters in gilts receiving distinct concentrations of E2 during pregnancy. We then investigated whether adverse effects prevail in progeny due to a potential endocrine disruption. E2 was orally applied to gilts during the entire period of pregnancy. The concentrations represented a daily consumption at the recommended ADI level (0.05 μg/kg body weight/day), at the NOEL (10 μg/kg body weight/day) and at a high dosage (1000 μg/kg body weight/day). Plasma hormone concentrations were determined using enzyme immuno assays. Offspring body fat was assessed by dual-energy X-ray absorptiometry scanning. In treated gilts receiving 1000 μg E2/kg body weight/day we found significantly elevated plasma E2 levels during pregnancy, paralleled by an increased weight gain. While offspring showed similar weight at birth, piglets exhibited a significant reduction in weight at weaning even though their mothers had only received 0.05 μg E2/kg body weight/day. At 8 weeks of age, specifically males showed a significant increase in overall body fat percentage. In conclusion, prenatal exposure to low doses of E2 affected pig offspring development in terms of body weight and composition. In line with findings from other obesogens, our data suggest a programming effect during pregnancy for E2 causative for the depicted phenotypes. Therefore, E2 exposure may imply a possible contribution to childhood obesity. -- Highlights: ► We investigate the potential role of estradiol-17β (E2) as an obesogen. ► We orally apply E2 at the ADI, NOEL and a high dose to gilts during pregnancy. ► Offspring weight is similar at birth but reduced at weaning even after ADI treatment. ► Male offspring only exhibit an increase in overall body fat percentage

Maternal low-dose estradiol-17β exposure during pregnancy impairs postnatal progeny weight development and body composition

Energy Technology Data Exchange (ETDEWEB)

Werner Fürst, Rainer [Physiology Weihenstephan, Technische Universität München, 85354 Freising-Weihenstephan (Germany); ZIEL PhD Graduate school ‘Epigenetics, Imprinting and Nutrition’, Technische Universität München, 85354 Freising-Weihenstephan (Germany); Pistek, Veronika Leopoldine; Kliem, Heike [Physiology Weihenstephan, Technische Universität München, 85354 Freising-Weihenstephan (Germany); Skurk, Thomas; Hauner, Hans [ZIEL Dep. Nutritional Medicine, Technische Universität München, 85354 Freising-Weihenstephan (Germany); Klinikum rechts der Isar, Technische Universität München, 81675 München (Germany); Meyer, Heinrich Herman Dietrich [Physiology Weihenstephan, Technische Universität München, 85354 Freising-Weihenstephan (Germany); Ulbrich, Susanne Ernestine, E-mail: ulbrich@wzw.tum.de [Physiology Weihenstephan, Technische Universität München, 85354 Freising-Weihenstephan (Germany)

2012-09-15

Endocrine disrupting chemicals with estrogenic activity play an important role as obesogens. However, studies investigating the most potent natural estrogen, estradiol-17β (E2), at low dose are lacking. We examined endocrine and physiological parameters in gilts receiving distinct concentrations of E2 during pregnancy. We then investigated whether adverse effects prevail in progeny due to a potential endocrine disruption. E2 was orally applied to gilts during the entire period of pregnancy. The concentrations represented a daily consumption at the recommended ADI level (0.05 μg/kg body weight/day), at the NOEL (10 μg/kg body weight/day) and at a high dosage (1000 μg/kg body weight/day). Plasma hormone concentrations were determined using enzyme immuno assays. Offspring body fat was assessed by dual-energy X-ray absorptiometry scanning. In treated gilts receiving 1000 μg E2/kg body weight/day we found significantly elevated plasma E2 levels during pregnancy, paralleled by an increased weight gain. While offspring showed similar weight at birth, piglets exhibited a significant reduction in weight at weaning even though their mothers had only received 0.05 μg E2/kg body weight/day. At 8 weeks of age, specifically males showed a significant increase in overall body fat percentage. In conclusion, prenatal exposure to low doses of E2 affected pig offspring development in terms of body weight and composition. In line with findings from other obesogens, our data suggest a programming effect during pregnancy for E2 causative for the depicted phenotypes. Therefore, E2 exposure may imply a possible contribution to childhood obesity. -- Highlights: ► We investigate the potential role of estradiol-17β (E2) as an obesogen. ► We orally apply E2 at the ADI, NOEL and a high dose to gilts during pregnancy. ► Offspring weight is similar at birth but reduced at weaning even after ADI treatment. ► Male offspring only exhibit an increase in overall body fat percentage

Brain tissue oxidative damage as a possible mechanism for the deleterious effect of a chronic high dose of estradiol on learning and memory in ovariectomized rats

Directory of Open Access Journals (Sweden)

Fatimeh Khodabandehloo

2013-05-01

Full Text Available In addition to antioxidative effects, estrogens also exert pro-oxidative actions. The effect of chronic administration of a high dose of estradiol valerate on Morris water maze tasks and brain tissues oxidative damage was investigated. The Sham-Est and OVX-Est groups were treated with estradiol valerate (4 mg/kg for 12 weeks. Escape latency and traveled path in the Sham-Est and OVX-Est groups were significantly higher than in the Sham and OVX groups (p≪0.01 and p≪0.001. In the probe trial, the animals of the Sham-Est and OVX-Est groups spent lower time in Q1 compared to Sham and OVX groups (p≪0.05 and p≪0.001. In Sham-Est and OVX-Est groups, the brain tissue total thiol concentration was significantly lower, and malondialdehyde (MDA concentrations were higher than in the Sham and OVX groups (p≪0.05 and p≪0.001. It is concluded that administration of high exogenous levels of estradiol impairs performance and enhances oxidative stress.

Optimization of Microemulsion Based Transdermal Gel of Triamcinolone.

Science.gov (United States)

Jagdale, Swati; Chaudhari, Bhagyashree

2017-01-01

Triamcinolone is a long acting corticosteroid used in the treatment of arthritis, eczema, psoriasis and similar conditions which cause inflammation. Triamcinolone has half-life of 88min. Prolonged oral use is associated with gastrointestinal adverse effects as peptic ulcer, abdominal distention and ulcerative esophagitis as described in various patents. Microemulgel offers advantage of better stability, better loading capacity and controlled release especially for drug with short half life. Objective of the present study was to optimize microemulgel based transdermal delivery of triamcinolone. Saturated solubility of triamcinolone in various oils, surfactants and co-surfactants is estimated. Pseudo-ternary phase diagrams were constructed to determine the region of transparent microemulsion. Microemulsion was evaluated for globule size (FE-SEM, zetasizer), % transmittance, pH, viscosity, conductivity etc. Design of experiment was used to optimize microemulsion based gel. Carbopol 971P and HPMC K100M were used as independent variables. Microemulsion based gel was evaluated for in-vitro as well as ex-vivo parameters. Microemulsion was formulated with oleic acid, lauroglycol FCC and propylene glycol. PDI 0.197 indicated microemulsion is mono-disperse. 32 factorial design gave batch F8 as optimized. Design expert suggested drug release; gel viscosity and bio-adhesive strength were three significant dependant factors affecting the transdermal delivery. F8 showed drug release 92.62.16±1.22% through egg membrane, 95.23±1.44% through goat skin after 8hr and Korsmeyer-Peppas release model was followed. It can be concluded that a stable, effective controlled release transdermal microemulgel was optimised for triamcinolone. This would be a promising tool to deliver triamcinolone with enhanced bioavailability and reduced dosing frequency. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Study on the therapeutic effect of small dose of estradiol and progesterone on post-menopausal osteoporosis

International Nuclear Information System (INIS)

Li Wenqi; Li Xin; Zhou Jiwen; Zhou Zhengli

2004-01-01

Objective: To explore the therapeutic effect and possible adverse side-effects of small dose of estradiol and progesterone on postmenopausal osteoporosis. Methods: Applying a GBD-928 mono-photon BMD radiometer, 68 women (past-menopausal over 3 years, age 52-59, body weight index 2 0.5 mg with MPA (medroxyprogesterone acetate) 0.5 mg daily. The medication laster for a whole years and BMD value was measured again. All subjects underwent gynecological physical examination, vaginal sonography, vaginal smear study and breast examination with infra-red ray both before and after the test period. Results: After one year medication, mean value of BMD in Group A was 0.49 ± 0.05, three percentage points higher than before. In Group B, this was 0.52 ± 0.06, another three percentage points higher. Ten Women with mild lobular hyperplasia and nine women with small uterine myoma ( 3 ) were all allocated to the hormone treated group. The lesions showed either little change or slight regression after the test period. Conclusion: Osteoporotic women receiving additional small doses of female hormones responded much better than those receiving calcium only. The WHI report which advised against HRT should be more critically studied

Naturally-occurring estradiol-17β-fatty acid esters, but not estradiol-17β, preferentially induce mammary tumorigenesis in female rats: Implications for an important role in human breast cancer

International Nuclear Information System (INIS)

Mills, Laura H.; Yu Jina; Xu Xiaomeng; Lee, Anthony J.; Zhu Baoting

2008-01-01

Because mammary glands are surrounded by adipose tissues, we hypothesize that the ultra-lipophilic endogenous estrogen-17β-fatty acid esters may have preferential hormonal and carcinogenic effects in mammary tissues compared to other target organs (such as the uterus and pituitary). This hypothesis is tested in the present study. We found that all 46 rats implanted with an estradiol-17β pellet developed large pituitary tumors (average weight = 251 ±103 mg) and had to be terminated early, but only 48% of them developed mammary tumors. In addition, approximately one-fourth of them developed a huge uterus. In the 26 animals implanted with a mixture containing estradiol-17β-stearate and estradiol-17β-palmitate (two representative estradiol-17β-fatty acid esters) or in the 29 animals implanted with estradiol-17β-stearate alone (in the same molar dose as estradiol-17β), 73% and 79%, respectively, of them developed mammary tumors, whereas only 3 or 2 animals, respectively, had to be terminated early due to the presence of a large pituitary tumor. Both tumorous and normal mammary tissues contained much higher levels of estrogen esterase than other tissues, which catalyzes the releases of bioactive estrogens from their fatty acid esters. In conclusion, while estradiol-17β is much stronger in inducing pituitary tumor (100% incidence) than mammary tumor, estradiol-17β-fatty acid esters have a higher efficacy than estradiol-17β in inducing mammary tumor and yet it only has little ability to induce uterine out-growth and pituitary tumorigenesis. This study establishes the endogenous estrogen-17β-fatty acid esters as preferential inducers of mammary tumorigenesis

Fertilizer micro-dosing: a profitable innovation for Sahelian women ...

International Development Research Centre (IDRC) Digital Library (Canada)

2016-06-06

Jun 6, 2016 ... The localized application of small quantities of fertilizer (micro-dosing), combined with improved planting pits for rainwater harvesting, has generated greater profits and food security for women farmers in the Sahel. Women have taken to the new methods developed by West African and Canadian ...

TRANSDERMAL DRUG DELIVERY AND METHODS TO ENHANCE IT

Directory of Open Access Journals (Sweden)

E. G. Kuznetsova

2016-01-01

Full Text Available The paper presents the common methods employed in recent years for enhancing transdermal delivery of drug substances when applying transdermal therapeutic delivery systems. The chemical, physical and mechanical methods to enhance the transport of macromolecular compounds through the skin are considered in details. 

3D printing applications for transdermal drug delivery.

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Economidou, Sophia N; Lamprou, Dimitrios A; Douroumis, Dennis

2018-06-15

The role of two and three-dimensional printing as a fabrication technology for sophisticated transdermal drug delivery systems is explored in literature. 3D printing encompasses a family of distinct technologies that employ a virtual model to produce a physical object through numerically controlled apparatuses. The applicability of several printing technologies has been researched for the direct or indirect printing of microneedle arrays or for the modification of their surface through drug-containing coatings. The findings of the respective studies are presented. The range of printable materials that are currently used or potentially can be employed for 3D printing of transdermal drug delivery (TDD) systems is also reviewed. Moreover, the expected impact and challenges of the adoption of 3D printing as a manufacturing technique for transdermal drug delivery systems, are assessed. Finally, this paper outlines the current regulatory framework associated with 3D printed transdermal drug delivery systems. Copyright © 2018 Elsevier B.V. All rights reserved.

Long-term estradiol treatment improves VIP-mediated vasodilation in atherosclerotic proximal coronary arteries

DEFF Research Database (Denmark)

Dalsgaard, T.; Mortensen, Alicja; Larsen, C. R.

2003-01-01

arteries. Female ovariectomized homozygous Watanabe heritable hyperlipidemic rabbits were randomized to 16 weeks treatment with 17beta-estradiol or placebo. The diet was semisynthetic, thereby avoiding the influence of phytoestrogens. Artery ring segments were mounted for isometric tension recordings...... in myographs. Following precontraction, the dose-response relationships for VIP and PACAP were evaluated. Treatment with 17beta-estradiol significantly improved the maximum VIP-mediated vasodilation (E-max, percentage of precontraction) in proximal coronary arteries (45.8 +/- 9.6% vs. 24.1 +/- 3.7%, p ....05). In the same artery segment, 17β-estradiol induced a significant decrease in the relative ratio between the repeated contractile response to potassium 30 and 120 mM (100 +/- 7% vs. 132 +/- 11%, p

Blood Test: Estradiol

Science.gov (United States)

... the bloodstream. Estradiol plays an important role in sexual development: It's the most important form of the hormone ... while low levels may indicate a delay in sexual development. Estradiol levels also give important information on the ...

[Comparative study on transdermal osmosis in vitro of Aconitum brachypodium liniment, gel and patcher].

Science.gov (United States)

Lin, Ya-ping; Zhao, Ying; Zhang, Yong-ping; Liang, Guang-yi

2007-02-01

To study the transdermal osmosis process of Aconitum brachypodum's liniment, gel and patcher to provide basis for selecting dosage form and controlling the quality. Taking the cumulate rate of transdermal as index, a imitated Fick's diffusion device was used for the investigating the transdermal osmosis course of the three preparations. The best transdermal mathematics models are obtained and the relations between the transdermal course and the release course are analysed. The three preparations have different characteristics of transdermal osmosis course. The liniment meets dynamics 0 order process, the gel and the patcher meet dynamic 0 order process of non-corroded drug system. And the relation is good cubic equation between their transdermal course and release course. The transdermal osmosis experiment in vitro for three preparations can provide basis for selecting dosage form and the quality control in future studies.

Sexual Function in Women on Estradiol or Venlafaxine for Hot Flushes: A Randomized Controlled Trial

Science.gov (United States)

Reed, Susan D.; Mitchell, Caroline M.; Joffe, Hadine; Cohen, Lee; Shifren, Jan L.; Newton, Katherine M.; Freeman, Ellen W.; Larson, Joseph C.; Manson, JoAnn E.; LaCroix, Andrea Z.; Guthrie, Katherine A.

2014-01-01

Objective To evaluate sexual function in midlife women taking low-dose oral estradiol or venlafaxine for hot flushes. Methods In an 8-week randomized controlled trial among women aged 40-62 years, sexual function was compared between oral estradiol 0.5 mg/day or venlafaxine 75 mg/day (both compared with placebo). Measures included composite and 6 domain scores from the Female Sexual Function Index (FSFI) and sexually related personal distress. Results Participants were aged 54.6 (standard deviation [SD] 3.8) years, 59% Caucasian, with 8.1 (SD 5.3) daily hot flushes. Median composite baseline FSFI score was 16.3 (SD 11.9, n=256) for all women and 21.7 (SD 9.3, n=198) among sexually active women. Composite mean FSFI change from baseline to week-8 was 1.4 (95% Confidence Interval [CI] -0.4, 3.2) for estradiol, 1.1 (95% CI -0.5, 2.7) for venlafaxine and -0.3 (95% CI -1.6, 1.0) for placebo. Composite FSFI and sexually-related distress change from baseline did not differ between estradiol and placebo (p= 0.38, p=0.30) or venlafaxine and placebo (p=0.79, p=0.48). Among sexually active women, FSFI domain score change from baseline differences (active compared with placebo) in desire was 0.3 (95% CI 0.0, 0.6) for estradiol; -0.6 (95% CI -1.2, 0.0) in orgasm for venlafaxine, and 0.9 (95% CI 0.2, 1.6) in penetration pain for venlafaxine. No women reported adverse events related to sexual dysfunction. Conclusions Overall sexual function among nondepressed midlife women experiencing hot flushes did not change over 8-weeks with low-dose oral estradiol or venlafaxine (compared with placebo), although subtle increase in desire (estradiol), and decreases in orgasm and pain (venlafaxine) may exist. PMID:25004335

Reproducibility study of TLD-100 micro-cubes at radiotherapy dose level

International Nuclear Information System (INIS)

Rosa, Luiz Antonio R. da; Regulla, Dieter F.; Fill, Ute A.

1999-01-01

The precision of the thermoluminescent response of Harshaw micro-cube dosimeters (TLD-100), evaluated in both Harshaw thermoluminescent readers 5500 and 3500, for 1 Gy dose value, was investigated. The mean reproducibility for micro-cubes, pre-readout annealed at 100 deg. C for 15 min, evaluated with the manual planchet reader 3500, is 0.61% (1 standard deviation). When micro-cubes are evaluated with the automated hot-gas reader 5500, reproducibility values are undoubtedly worse, mean reproducibility for numerically stabilised dosimeters being equal to 3.27% (1 standard deviation). These results indicate that the reader model 5500, or, at least, the instrument used for the present measurements, is not adequate for micro-cube evaluation, if precise and accurate dosimetry is required. The difference in precision is apparently due to geometry inconsistencies in the orientation of the imperfect micro-cube faces during readout, requiring careful and manual reproducible arrangement of the selected micro-cube faces in contact with the manual reader planchet

Rotigotine transdermal patch for the treatment of Parkinson's Disease.

Science.gov (United States)

Perez-Lloret, Santiago; Rey, María Verónica; Ratti, Pietro Lucca; Rascol, Olivier

2013-02-01

Rotigotine, a non-ergot dopamine agonist, has been developed as a novel transdermal formulation. The rotigotine transdermal patch has received EMEA marketing authorization for the treatment of adult patients with early or advanced Parkinson's disease (PD) or with moderate to severe restless legs syndrome (RLS). FDA originally granted a marketing authorization for early PD, which was later suspended, and is now studying the authorization for RLS. The aim of this review is to review the pharmacokinetics, pharmacodynamics as well as the clinical efficacy and tolerability of the rotigotine transdermal patch in PD. Source material was identified using a PubMed search for the term 'rotigotine' and PD. Articles published up to January 2011 or abstract submitted to most relevant international neurology congresses were reviewed. The rotigotine transdermal patch is efficacious for the treatment of PD. Tolerability profile appears to be well within the range of that observed with other non-ergot dopamine agonists in PD. Application-site reactions were the most frequent adverse event, and they were considered mild to moderate in the majority of cases. The rotigotine transdermal patch offers a safe and efficacious alternative for the treatment of PD. Further studies should focus on the possibility that continuous dopamine stimulation by means of the transdermal patch has any influence on levodopa-related motor complications. © 2012 The Authors Fundamental and Clinical Pharmacology © 2012 Société Française de Pharmacologie et de Thérapeutique.

The effect of transdermal nicotine patches on sleep and dreams.

Science.gov (United States)

Page, F; Coleman, G; Conduit, R

2006-07-30

This study was undertaken to determine the effect of 24-h transdermal nicotine patches on sleep and dream mentation in 15 smokers aged 20 to 33. Utilising a repeated measures design, it was found that more time awake and more ASDA micro-arousals occurred while wearing the nicotine patch compared to placebo. Also, the percentage of REM sleep decreased, but REM latency and the proportion of time spent in NREM sleep stages did not change significantly. Dream reports containing visual imagery, visual imagery ratings and the number of visualizable nouns were significantly greater from REM compared to Stage 2 awakenings, regardless of patch condition. However, a general interaction effect was observed. Stage 2 dream variables remained equivalent across nicotine and placebo conditions. Within REM sleep, more dream reports containing visual imagery occurred while wearing the nicotine patch, and these were rated as more vivid. The greater frequency of visual imagery reports and higher imagery ratings specifically from REM sleep suggests that previously reported dreaming side effects from 24-h nicotine patches may be specific to REM sleep. Combined with previous animal studies showing that transdermally delivered nicotine blocks PGO activity in REM sleep, the current results do no appear consistent with PGO-based hypotheses of dreaming, such as the Activation-Synthesis (AS) or Activation, Input and Modulation (AIM) models.

Response to intravenous fentanyl infusion predicts subsequent response to transdermal fentanyl.

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Hayashi, Norihito; Kanai, Akifumi; Suzuki, Asaha; Nagahara, Yuki; Okamoto, Hirotsugu

2016-04-01

Prediction of the response to transdermal fentanyl (FENtd) before its use for chronic pain is desirable. We tested the hypothesis that the response to intravenous fentanyl infusion (FENiv) can predict the response to FENtd, including the analgesic and adverse effects. The study subjects were 70 consecutive patients with chronic pain. The response to fentanyl at 0.1 mg diluted in 50 ml of physiological saline and infused over 30 min was tested. This was followed by treatment with FENtd (Durotep MT patch 2.1 mg) at a dose of 12.5 µg/h for 2 weeks. Pain intensity before and after FENiv and 2 weeks after FENtd, and the response to treatment, were assessed by the numerical rating scale (NRS), clinical global impression-improvement scale (CGI-I), satisfaction scale (SS), and adverse effects. The NRS score decreased significantly from 7 (4-9) [median (range)] at baseline to 3 (0-8) after FENiv (p 0.04, each). The analgesic and side effects after intravenous fentanyl infusion can be used to predict the response to short-term transdermal treatment with fentanyl.

Male reproductive effects of octylphenol and estradiol in Fischer and Wistar rats

DEFF Research Database (Denmark)

Hossaini, Alireza; Dalgaard, Majken; Vinggaard, Anne

2003-01-01

to vehicle or 400 mg/kg bw of 4-tert-octylphenol administrated orally by gavage. Estradiol benzoate, at a dose of 40 mug/kg bw, was used as positive control agent. Treatment with estradiol benzoate decreased serum levels of testosterone, LH, FSH, inhibin and increased prolactin. Additionally, estradiol...... benzoate decreased the weight of all investigated reproductive organs, decreased sperm production and increased seminiferous tubular degeneration in both strains. More progressive effects on testis weight and histopathology were observed in the Fischer rats. Oral administration of octylphenol at 400 mg....../kg bw to both rat strains increased prolactin levels but had no effect on LH, FSH, testosterone or inhibin. In the octylphenol-treated Fischer rats the weights of the seminal vesicles and the levator ani/bulbocavernosus muscle were significantly decreased, whereas only the levator ani...

Life-threatening coma and full-thickness sunburn in a patient treated with transdermal fentanyl patches: a case report

Directory of Open Access Journals (Sweden)

Sindali Katia

2012-07-01

Full Text Available Abstract Introduction Fentanyl transdermal patches have been widely used in the treatment of chronic pain and in palliative care settings since 1991 in cases where prolonged opioid use is often necessary. Transdermal drug delivery is deemed safe and effective with the advantages of delivering a steady dose of the drug and improving patient compliance due to its ease of use. However, intentional and unintentional misuse and overdose using transdermal opioid patches has been widely reported in the literature. Case presentation We describe the case of a 77-year-old Caucasian woman who developed severe opioid toxicity while sun tanning, likely due to altered fentanyl transdermal patch function in a heated environment. As a result of prolonged sun exposure due to an opioid-induced coma she then sustained hyperthermia and severe burns to her abdomen and lower limbs. This inadvertent fentanyl overdose necessitated initial treatment in intensive care and follow on care in a specialist burn unit. Conclusion Patients who are using fentanyl patches and their relatives should be educated about how to use the patch safely. Healthcare practitioners should warn patients about the possibility of overdosing on transdermally delivered drugs if used incorrectly. They should avoid strenuous activities and external heat sources such as warming blankets, hot water bottles, saunas, hot tubs or sunbathing and should seek medical attention if they develop a fever. Additionally, any burns sustained in the context of altered consciousness levels such as in this case with opioid overdose should raise suspicion about a potential deeper burn injury than is usually observed.

Mixtures of xenoestrogens disrupt estradiol-induced non-genomic signaling and downstream functions in pituitary cells.

Science.gov (United States)

Viñas, René; Watson, Cheryl S

2013-03-26

Our study examines the effects of xenoestrogen mixtures on estradiol-induced non-genomic signaling and associated functional responses. Bisphenol-A, used to manufacture plastic consumer products, and nonylphenol, a surfactant, are estrogenic by a variety of assays, including altering many intracellular signaling pathways; bisphenol-S is now used as a bisphenol-A substitute. All three compounds contaminate the environment globally. We previously showed that bisphenol-S, bisphenol-A, and nonylphenol alone rapidly activated several kinases at very low concentrations in the GH3/B6/F10 rat pituitary cell line. For each assay we compared the response of individual xenoestrogens at environmentally relevant concentrations (10-15 -10-7 M), to their mixture effects on 10-9 M estradiol-induced responses. We used a medium-throughput plate immunoassay to quantify phosphorylations of extracellular signal-regulated kinases (ERKs) and c-Jun-N-terminal kinases (JNKs). Cell numbers were assessed by crystal violet assay to compare the proliferative effects. Apoptosis was assessed by measuring caspase 8 and 9 activities via the release of the fluorescent product 7-amino-4-trifluoromethylcoumarin. Prolactin release was measured by radio-immunoassay after a 1 min exposure to all individual and combinations of estrogens. Individual xenoestrogens elicited phospho-activation of ERK in a non-monotonic dose- (fM-nM) and mostly oscillating time-dependent (2.5-60 min) manner. When multiple xenoestrogens were combined with nM estradiol, the physiologic estrogen's response was attenuated. Individual bisphenol compounds did not activate JNK, while nonylphenol did; however, the combination of two or three xenoestrogens with estradiol generated an enhanced non-monotonic JNK dose-response. Estradiol and all xenoestrogen compounds induced cell proliferation individually, while the mixtures of these compounds with estradiol suppressed proliferation below that of the vehicle control, suggesting a

Prophylaxis of Postoperative Nausea and Vomiting in Adolescent Patients: A Review with Emphasis on Combination of Fixed-Dose Ondansetron and Transdermal Scopolamine

Directory of Open Access Journals (Sweden)

Joseph V. Pergolizzi

2011-01-01

Full Text Available Postoperative nausea and vomiting (PONV is a relatively common occurrence (20–30% that delays discharge and, if persistent, can lead to serious complications. The incidence of PONV is a function of patient characteristics, the type and duration of surgery, the type of anesthesia, and the choice of pre-, intra-, and postoperative pharmacotherapy. There are no completely effective antiemetic agents for this condition, but recommendations for treatment strategies are separately available for pediatric and adult patients. Left unclear is whether adolescents should be guided by the pediatric or the adult recommendations. We review the developmental physiology of the relevant physiological factors (absorption, distribution, metabolism, and elimination. We also review the clinical evidence regarding the safety and efficacy of a fixed-dose combination of ondansetron (4 mg, i.v. and transdermal scopolamine (1.5 mg.

Exploitation of sub-micron cavitation nuclei to enhance ultrasound-mediated transdermal transport and penetration of vaccines.

Science.gov (United States)

Bhatnagar, Sunali; Kwan, James J; Shah, Apurva R; Coussios, Constantin-C; Carlisle, Robert C

2016-09-28

Inertial cavitation mediated by ultrasound has been previously shown to enable skin permeabilisation for transdermal drug and vaccine delivery, by sequentially applying the ultrasound then the therapeutic in liquid form on the skin surface. Using a novel hydrogel dosage form, we demonstrate that the use of sub-micron gas-stabilising polymeric nanoparticles (nanocups) to sustain and promote cavitation activity during simultaneous application of both drug and vaccine results in a significant enhancement of both the dose and penetration of a model vaccine, Ovalbumin (OVA), to depths of 500μm into porcine skin. The nanocups themselves exceeded the penetration depth of the vaccine (up to 700μm) due to their small size and capacity to 'self-propel'. In vivo murine studies indicated that nanocup-assisted ultrasound transdermal vaccination achieved significantly (pultrasound-assisted vaccine delivery in the presence of nanocups demonstrated substantially higher specific anti-OVA IgG antibody levels compared to other transdermal methods. Further optimisation can lead to a viable, safe and non-invasive delivery platform for vaccines with potential use in a primary care setting or personalized self-vaccination at home. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

Characterization of a microDiamond detector in high-dose-per-pulse electron beams for intra operative radiation therapy.

Science.gov (United States)

Di Venanzio, C; Marinelli, Marco; Tonnetti, A; Verona-Rinati, G; Falco, M D; Pimpinella, M; Ciccotelli, A; De Stefano, S; Felici, G; Marangoni, F

2015-12-01

To characterize a synthetic diamond dosimeter (PTW Freiburg microDiamond 60019) in high dose-per-pulse electron beams produced by an Intra Operative Radiation Therapy (IORT) dedicated accelerator. The dosimetric properties of the microDiamond were assessed under 6, 8 and 9 MeV electron beams by a NOVAC11 mobile accelerator (Sordina IORT Technologies S.p.A.). The characterization was carried out with dose-per-pulse ranging from 26 to 105 mGy per pulse. The microDiamond performance was compared with an Advanced Markus ionization chamber and a PTW silicon diode E in terms of dose linearity, percentage depth dose (PDD) curves, beam profiles and output factors. A good linearity of the microDiamond response was verified in the dose range from 0.2 Gy to 28 Gy. A sensitivity of 1.29 nC/Gy was measured under IORT electron beams, resulting within 1% with respect to the one obtained in reference condition under (60)Co gamma irradiation. PDD measurements were found in agreement with the ones by the reference dosimeters, with differences in R50 values below 0.3 mm. Profile measurements evidenced a high spatial resolution of the microDiamond, slightly worse than the one of the silicon diode. The penumbra widths measured by the microDiamond resulted approximately 0.5 mm larger than the ones by the Silicon diode. Output factors measured by the microDiamond were found within 2% with those obtained by the Advanced Markus down to 3 cm diameter field sizes. The microDiamond dosimeter was demonstrated to be suitable for precise dosimetry in IORT applications under high dose-per-pulse conditions. Copyright © 2015 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.

Circulating Estradiol Regulates Brain-Derived Estradiol via Actions at GnRH Receptors to Impact Memory in Ovariectomized Rats.

Science.gov (United States)

Nelson, Britta S; Black, Katelyn L; Daniel, Jill M

2016-01-01

Systemic estradiol treatment enhances hippocampus-dependent memory in ovariectomized rats. Although these enhancements are traditionally thought to be due to circulating estradiol, recent data suggest these changes are brought on by hippocampus-derived estradiol, the synthesis of which depends on gonadotropin-releasing hormone (GnRH) activity. The goal of the current work is to test the hypothesis that peripheral estradiol affects hippocampus-dependent memory through brain-derived estradiol regulated via hippocampal GnRH receptor activity. In the first experiment, intracerebroventricular infusion of letrozole, which prevents the synthesis of estradiol, blocked the ability of peripheral estradiol administration in ovariectomized rats to enhance hippocampus-dependent memory in a radial-maze task. In the second experiment, hippocampal infusion of antide, a long-lasting GnRH receptor antagonist, blocked the ability of peripheral estradiol administration in ovariectomized rats to enhance hippocampus-dependent memory. In the third experiment, hippocampal infusion of GnRH enhanced hippocampus-dependent memory, the effects of which were blocked by letrozole infusion. Results indicate that peripheral estradiol-induced enhancement of cognition is mediated by brain-derived estradiol via hippocampal GnRH receptor activity.

Transfer of estradiol to human milk

International Nuclear Information System (INIS)

Nilsson, S.; Nygren, K.G.; Johansson, E.D.B.

1978-01-01

A radioimmunoassay for the measurement of estradiol in human milk is evaluated. The detection limit was found to be 25 pg of estradiol per milliliter of milk. In milk samples collected from four lactating women during three to four months and from one pregnant and lactating woman, the concentration of estradiol was found to be below the detection limit of the assay. When six lactating women were given vaginal suppositories containing 50 or 100 mg of estradiol, it was possible to estimate the estradiol concentration in milk. A ratio of transfer of estradiol from plasma to milk during physiologic conditions is calculated to be less than 100 : 10

Di-(2-ethylhexyl) phthalate and mono-(2-ethylhexyl) phthalate inhibit growth and reduce estradiol levels of antral follicles in vitro

International Nuclear Information System (INIS)

Gupta, Rupesh K.; Singh, Jeffery M.; Leslie, Tracie C.; Meachum, Sharon; Flaws, Jodi A.; Yao, Humphrey H-C

2010-01-01

Any insult that affects survival of ovarian antral follicles can cause abnormal estradiol production and fertility problems. Phthalate esters (PEs) are plasticizers used in a wide range of consumer and industrial products. Exposure to these chemicals has been linked to reduced fertility in humans and animal models. Di-(2-ethylhexyl) phthalate (DEHP) and mono-(2-ethylhexyl) phthalate (MEHP) decrease serum estradiol levels and aromatase (Arom) expression, prolong estrous cycles, and cause anovulation in animal and culture models. These observations suggest PEs directly target antral follicles. We therefore tested the hypothesis that DEHP (1-100 μg/ml) and MEHP (0.1-10 μg/ml) directly inhibit antral follicular growth and estradiol production. Antral follicles from adult mice were cultured with DEHP or MEHP, and/or estradiol for 96 h. During culture, follicle size was measured every 24 h as a measurement of follicle growth. After culture, media were collected for measurement of estradiol levels and follicles were subjected to measurement of cylin-D-2 (Ccnd2), cyclin-dependant-kinase-4 (Cdk4), and Arom. We found that DEHP and MEHP inhibited growth of follicles and decreased estradiol production compared to controls at the highest doses. DEHP and MEHP also decreased mRNA expression of Ccnd2, Cdk4, and Arom at the highest dose. Addition of estradiol to the culture medium prevented the follicles from DEHP- and MEHP-induced inhibition of growth, reduction in estradiol levels, and decreased Ccnd2 and Cdk4 expression. Collectively, our results indicate that DEHP and MEHP may directly inhibit antral follicle growth via a mechanism that partially includes reduction in levels of estradiol production and decreased expression of cell cycle regulators.

Future of the transdermal drug delivery market--have we barely touched the surface?

Science.gov (United States)

Watkinson, Adam C; Kearney, Mary-Carmel; Quinn, Helen L; Courtenay, Aaron J; Donnelly, Ryan F

2016-01-01

Transdermal drug delivery is the movement of drugs across the skin for absorption into the systemic circulation. Transfer of the drug can occur via passive or active means; passive transdermal products do not disrupt the stratum corneum to facilitate delivery whereas active technologies do. Due to the very specific physicochemical properties necessary for successful passive transdermal drug delivery, this sector of the pharmaceutical industry is relatively small. There are many well-documented benefits of this delivery route however, and as a result there is great interest in increasing the number of therapeutic substances that can be delivered transdermally. This review discusses the various transdermal products that are currently/have been marketed, and the paths that led to their success, or lack of. Both passive and active transdermal technologies are considered with the advantages and limitations of each highlighted. In addition to marketed products, technologies that are in the investigative stages by various pharmaceutical companies are reviewed. Passive transdermal drug delivery has made limited progress in recent years, however with the ongoing intense research into active technologies, there is great potential for growth within the transdermal delivery market. A number of active technologies have already been translated into marketed products, with other platforms including microneedles, rapidly progressing towards commercialisation.

Analyzing polymeric matrix for fabrication of a biodegradable microneedle array to enhance transdermal delivery.

Science.gov (United States)

Hwa, Kuo-Yuan; Chang, Vincent H S; Cheng, Yao-Yi; Wang, Yue-Da; Jan, Pey-Shynan; Subramani, Boopathi; Wu, Min-Ju; Wang, Bo-Kai

2017-09-19

Traditional drug delivery systems, using invasive, transdermal, and oral routes, are limited by various factors, such as the digestive system environment, skin protection, and sensory nerve stimulation. To improve the drug delivery system, we fabricated a polysaccharide-based, dissolvable microneedle-based array, which combines the advantages of both invasive and transdermal delivery systems, and promises to be an innovative solution for minimally invasive drug delivery. In this study, we designed a reusable aluminum mold that greatly improved the efficiency and convenience of microneedle fabrication. Physical characterization of the polysaccharides, individual or mixed at different ratios, was performed to identify a suitable molecule to fabricate the dissolvable microneedle. We used a vacuum deposition-based micro-molding method at low temperature to fabricate the model. Using a series of checkpoints from material into product, a systematic feedback mechanism was built into the "all-in-one" fabrication step, which helped to improve production yields. The physical properties of the fabricated microneedle were assessed. The cytotoxicity analysis and animal testing of the microneedle demonstrated the safety and compatibility of the microneedle, and the successful penetration and effective release of a model protein.

Transdermal drug delivery: feasibility for treatment of superficial bone stress fractures.

Science.gov (United States)

Aghazadeh-Habashi, Ali; Yang, Yang; Tang, Kathy; Lőbenberg, Raimar; Doschak, Michael R

2015-12-01

Transdermal drug delivery offers the promise of effective drug therapy at selective sites of pathology whilst reducing systemic exposure to the pharmaceutical agents in off-target organs and tissues. However, that strategy is often limited to cells comprising superficial tissues of the body (rarely to deeper bony structures) and mostly indicated with small hydrophobic pharmacological agents, such as steroid hormones and anti-inflammatory gels to skin, muscle, and joints. Nonetheless, advances in transdermal liposomal formulation have rendered the ability to readily incorporate pharmacologically active hydrophilic drug molecules and small peptide biologics into transdermal dosage forms to impart the effective delivery of those bioactive agents across the skin barrier to underlying superficial tissue structures including bone, often enhanced by some form of electrical, chemical, and mechanical facilitation. In the following review, we evaluate transdermal drug delivery systems, with a particular focus on delivering therapeutic agents to treat superficial bone pain, notably stress fractures. We further introduce and discuss several small peptide hormones active in bone (such as calcitonins and parathyroid hormone) that have shown potential for transdermal delivery, often under the added augmentation of transdermal drug delivery systems that employ lipo/hydrophilicity, electric charge, and/or microprojection facilitation across the skin barrier.

Estradiol-induced antinociceptive responses on formalin-induced nociception are independent of COX and HPA activation.

Science.gov (United States)

Hunter, Deirtra A; Barr, Gordon A; Amador, Nicole; Shivers, Kai-Yvonne; Kemen, Lynne; Kreiter, Christopher M; Jenab, Shirzad; Inturrisi, Charles E; Quinones-Jenab, Vanya

2011-07-01

Estrogen modulates pain perception but how it does so is not fully understood. The aim of this study was to determine if estradiol reduces nociceptive responses in part via hypothalamic-pituitary-adrenal (HPA) axis regulation of cyclooxygenase (COX)-1/COX-2 activity. The first study examined the effects of estradiol (20%) or vehicle with concurrent injection nonsteroidal antiinflammatory drugs (NSAIDs) on formalin-induced nociceptive responding (flinching) in ovariectomized (OVX) rats. The drugs were ibuprofen (COX-1 and COX-2 inhibitor), SC560 (COX-1 inhibitor), or NS398 (COX-2 inhibitor). In a second study, estradiol's effects on formalin-induced nociception were tested in adrenalectomized (ADX), OVX, and ADX+OVX rats. Serum levels of prostaglandins (PG) PGE(2) and corticosterone were measured. Estradiol significantly decreased nociceptive responses in OVX rats with effects during both the first and the second phase of the formalin test. The nonsteroidal antiinflammatory drugs (NSAIDs) did not alter nociception at the doses used here. Adrenalectomy neither altered flinching responses in female rats nor reversed estradiol-induced antinociceptive responses. Estradiol alone had no effect on corticosterone (CORT) or prostaglandin levels after the formalin test, dissociating the effects of estradiol on behavior and these serum markers. Ibuprofen and NS398 significantly reduced PGE2 levels. CORT was not decreased by OVX surgery or by estradiol below that of ADX. Only IBU significantly increased corticosterone levels. Taken together, our results suggest that estradiol-induced antinociception in female rats is independent of COX activity and HPA axis activation. Copyright © 2010 Wiley-Liss, Inc.

Transdermal deferoxamine prevents pressure-induced diabetic ulcers.

Science.gov (United States)

Duscher, Dominik; Neofytou, Evgenios; Wong, Victor W; Maan, Zeshaan N; Rennert, Robert C; Inayathullah, Mohammed; Januszyk, Michael; Rodrigues, Melanie; Malkovskiy, Andrey V; Whitmore, Arnetha J; Walmsley, Graham G; Galvez, Michael G; Whittam, Alexander J; Brownlee, Michael; Rajadas, Jayakumar; Gurtner, Geoffrey C

2015-01-06

There is a high mortality in patients with diabetes and severe pressure ulcers. For example, chronic pressure sores of the heels often lead to limb loss in diabetic patients. A major factor underlying this is reduced neovascularization caused by impaired activity of the transcription factor hypoxia inducible factor-1 alpha (HIF-1α). In diabetes, HIF-1α function is compromised by a high glucose-induced and reactive oxygen species-mediated modification of its coactivator p300, leading to impaired HIF-1α transactivation. We examined whether local enhancement of HIF-1α activity would improve diabetic wound healing and minimize the severity of diabetic ulcers. To improve HIF-1α activity we designed a transdermal drug delivery system (TDDS) containing the FDA-approved small molecule deferoxamine (DFO), an iron chelator that increases HIF-1α transactivation in diabetes by preventing iron-catalyzed reactive oxygen stress. Applying this TDDS to a pressure-induced ulcer model in diabetic mice, we found that transdermal delivery of DFO significantly improved wound healing. Unexpectedly, prophylactic application of this transdermal delivery system also prevented diabetic ulcer formation. DFO-treated wounds demonstrated increased collagen density, improved neovascularization, and reduction of free radical formation, leading to decreased cell death. These findings suggest that transdermal delivery of DFO provides a targeted means to both prevent ulcer formation and accelerate diabetic wound healing with the potential for rapid clinical translation.

Tamoxifen counteracts estradiol induced effects on striatal and hypophyseal dopamine receptors

International Nuclear Information System (INIS)

Ferretti, C.; Blengio, M.; Ghi, P.; Racca, S.; Genazzani, E.; Portaleone, P.

1988-01-01

We investigated the ability of Tamoxifen (TAM), an antiestrogen drug, to counteract the modification induced by estrogens on dopamine (DA) receptors on striatum and on adenohypophysis of ovex female rats. Subacute treatment with 17β-estradiol (E 2 ) at both low (0.1 μg/kg) and high (20 μg/kg) doses confirmed its ability to increase the number of striatal 3 H-Spiperone ( 3 H-SPI) binding sites in a dose dependent manner. By contrast in the pituitary, only high doses of estrogen were effective in reducing the number of DA receptors. We treated ovex female rats for 15 days with TAM alone or associated with E 2 , to see if these estrogenic effects could be suppressed by an antiestrogenic drug. TAM did not affect the number of striatal DA receptors, but significantly increased the adenohypophy-seal DA binding sites, without varying their affinity. No changes were observed in pituitary and striatal DA receptor density, even when TAM was injected in association with estradiol. In conclusions: TAM is able to counteract the effects estrogens have on DA receptors. However there is some evidence that it could influence the pituitary DA systems independently of it antiestrogenic activity

Effect of endogenous androgens on 17beta-estradiol-mediated protection after spinal cord injury in male rats.

Science.gov (United States)

Kachadroka, Supatra; Hall, Alicia M; Niedzielko, Tracy L; Chongthammakun, Sukumal; Floyd, Candace L

2010-03-01

Several groups have recently shown that 17beta-estradiol is protective in spinal cord injury (SCI). Testosterone can be aromatized to 17beta-estradiol and may increase estrogen-mediated protection. Alternatively, testosterone has been shown to increase excitotoxicity in models of central nervous system (CNS) injury. These experiments test the hypothesis that endogenous testosterone in male rats alters 17beta-estradiol-mediated protection by evaluating a delayed administration over a clinically relevant dose range and manipulating testicular-derived testosterone. Adult male Sprague Dawley rats were either gonadectomized or left gonad-intact prior to SCI. SCI was produced by a midthoracic crush injury. At 30 min post SCI, animals received a subcutaneous pellet of 0.0, 0.05, 0.5, or 5.0 mg of 17beta-estradiol, released over 21 days. Hindlimb locomotion was analyzed weekly in the open field. Spinal cords were collected and analyzed for cell death, expression of Bcl-family proteins, and white-matter sparing. Post-SCI administration of the 0.5- or 5.0-mg pellet improved hindlimb locomotion, reduced urinary bladder size, increased neuronal survival, reduced apoptosis, improved the Bax/Bcl-xL protein ratio, and increased white-matter sparing. In the absence of endogenous testicular-derived androgens, SCI induced greater apoptosis, yet 17beta-estradiol administration reduced apoptosis to the same extent in gonadectomized and gonad-intact male rats. These data suggest that delayed post-SCI administration of a clinically relevant dose of 17beta-estradiol is protective in male rats, and endogenous androgens do not alter estrogen-mediated protection. These data suggest that 17beta-estradiol is an effective therapeutic intervention for reducing secondary damage after SCI in males, which could be readily translated to clinical trials.

Stereomicroscopic imaging technique for the quantification of cold flow in drug-in-adhesive type of transdermal drug delivery systems.

Science.gov (United States)

Krishnaiah, Yellela S R; Katragadda, Usha; Khan, Mansoor A

2014-05-01

Cold flow is a phenomenon occurring in drug-in-adhesive type of transdermal drug delivery systems (DIA-TDDS) because of the migration of DIA coat beyond the edge. Excessive cold flow can affect their therapeutic effectiveness, make removal of DIA-TDDS difficult from the pouch, and potentially decrease available dose if any drug remains adhered to pouch. There are no compendial or noncompendial methods available for quantification of this critical quality attribute. The objective was to develop a method for quantification of cold flow using stereomicroscopic imaging technique. Cold flow was induced by applying 1 kg force on punched-out samples of marketed estradiol DIA-TDDS (model product) stored at 25°C, 32°C, and 40°C/60% relative humidity (RH) for 1, 2, or 3 days. At the end of testing period, dimensional change in the area of DIA-TDDS samples was measured using image analysis software, and expressed as percent of cold flow. The percent of cold flow significantly decreased (p < 0.001) with increase in size of punched-out DIA-TDDS samples and increased (p < 0.001) with increase in cold flow induction temperature and time. This first ever report suggests that dimensional change in the area of punched-out samples stored at 32°C/60%RH for 2 days applied with 1 kg force could be used for quantification of cold flow in DIA-TDDS. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.

In vivo measurement of tumor estradiol and Vascular Endothelial Growth Factor in breast cancer patients

International Nuclear Information System (INIS)

Garvin, Stina; Dabrosin, Charlotta

2008-01-01

Angiogenesis, crucial for tumor progression, is a process regulated in the tissue micro-environment. Vascular endothelial growth factor (VEGF) is a potent stimulatory factor of angiogenesis and a negative prognostic indicator of breast cancer. VEGF is biologically active in the extracellular space and hitherto, there has been a lack of techniques enabling sampling of angiogenic molecules such as VEGF in situ. The majority of breast cancers are estrogen-dependent, and estrogen has been shown to regulate VEGF in normal breast tissue and experimental breast cancer. We investigated if microdialysis may be applicable in human breast cancer for sampling of extracellular VEGF in situ and to explore if there is an association with local estradiol and VEGF levels in normal and cancerous breast tissue. Microdialysis was used to sample VEGF and estradiol in tumors and adjacent normal breast tissue in postmenopausal breast cancer patients. VEGF and estradiol were also measured in plasma, and immunohistochemical staining for VEGF was performed on tumor sections. We show that in vivo levels of extracellular VEGF were significantly higher in breast cancer tumors than in normal adjacent breast tissue. There was a significant positive correlation between estradiol and extracellular VEGF in normal breast tissue. However, no correlation was detected between estradiol and VEGF in tumors or between tumor VEGF and plasma VEGF. We conclude that VEGF and estradiol correlates significantly in normal breast tissue. Microdialysis may be used to provide novel insight in breast tumor biology and the regulation of molecules in the extracellular space of human breast tumors in vivo

Recent trends in challenges and opportunities of Transdermal drug delivery system

OpenAIRE

P.M.Patil; P.D.Chaudhari; Jalpa K.Patel; K.A.Kedar; P.P.Katolkar

2012-01-01

Drug delivery system relates to the production of a drug, its delivery medium, and the way of administration. Drug delivery systems are even used for administering nitroglycerin. Transdermal drug delivery system is the system in which the delivery of the active ingredients of the drug occurs by the means of skin. Various types of transdermal patches are used. There are various methods to enhance the transdermal drug delivery system. But using microfabricated microneedles drugs are delivered v...

Current advances in the fabrication of microneedles for transdermal delivery

NARCIS (Netherlands)

Indermun, S.; Luttge, R.; Choonara, Y.E.; Kumar, Pradeep; Toit, Du L.C.; Modi, G.; Pillay, V.

2014-01-01

The transdermal route is an excellent site for drug delivery due to the avoidance of gastric degradation and hepatic metabolism, in addition to easy accessibility. Although offering numerous attractive advantages, many available transdermal systems are not able to deliver drugs and other compounds

Transdermal fentanyl matrix patches Matrifen and Durogesic DTrans are bioequivalent

DEFF Research Database (Denmark)

Kress, Hans G; Boss, Hildegard; Delvin, Thomas

2010-01-01

AIM: The pharmacokinetic profiles of the two commercially available transdermal fentanyl patches Matrifen (100 microg/h) and Durogesic DTrans (100 microg/h), used to manage severe chronic pain, were compared regarding their systemic exposure, rate of absorption, and safety. METHODS: Transdermal m...

How can lipid nanocarriers improve transdermal delivery of olanzapine?

Science.gov (United States)

Iqbal, Nimra; Vitorino, Carla; Taylor, Kevin M G

2017-06-01

The development of a transdermal nanocarrier drug delivery system with potential for the treatment of psychiatric disorders, such as schizophrenia and bipolar disorder, is described. Lipid nanocarriers (LN), encompassing various solid:liquid lipid compositions were formulated and assessed as potential nanosystems for transdermal delivery of olanzapine. A previously optimized method of hot high pressure homogenization (HPH) was adopted for the production of the LN, which comprised solid lipid nanoparticles (SLN), nanostructured lipid carriers (NLC) and nanoemulsions (NE). Precirol  ® was selected as the solid lipid for progression of studies. SLN exhibited the best performance for transdermal delivery of olanzapine, based on in vitro release and permeation studies, coupled with results from physicochemical characterization of several solid:liquid lipid formulations. Stability tests, performed to give an indication of long-term storage behavior of the formulations, were in good agreement with previous studies for the best choice of solid:liquid lipid ratio. Overall, these findings highlight the SLN-based formulation as promising for the further inclusion in and production of transdermal patches, representing an innovative therapeutic approach.

MicroRNA-424 suppresses estradiol-induced cell proliferation via targeting GPER in endometrial cancer cells.

Science.gov (United States)

Zhang, H; Wang, X; Chen, Z; Wang, W

2015-11-30

Endometrial carcinoma (EC) is the most common gynecologic malignancy with increasing morbidity in recent years. MicroRNAs (miRNAs), a type of non-coding RNA, have been proven to be critical in the process of tumorigenesis. miR-424 has been reported to play a protective role in various type of cancer including endometrial carcinoma. It has been reported that high levels of estrogen increase morbidity of EC by promoting cell growth ability. The current research was designed to delineate the mechanism of miR-424 in regulating E2 (17β-estradiol)-induced cell proliferation in endometrial cancer. In this study, we confirmed that cell proliferation is increased significantly in E2-treated endometrial cancer cell lines. Moreover, miR-424 overexpression dramatically decreased E2-induced cell proliferation, indicating a pivotal role in endometrial cancer cell growth. In addition, the results suggest that miR-424 up-regulation inactivated the PI3K/AKT signaling, which was mediated by G-protein-coupled estrogen receptor-1 (GPER) in endometrial cancer. Furthermore, the luciferase report confirmed the targeting reaction between miR-424 and GPER. After transfection with the GPER overexpression vector into E2-induced endometrial cancer cells, we found that GPER significantly attenuated the inhibition effect of miR-424 in E2-induced cell growth in EC. Taken together, our study suggests that increased miR-424 suppresses E2-induced cell growth, and providing a potential therapeutic target for estrogen-associated endometrial carcinoma.

The folic acid combined with 17-β estradiol produces antidepressant-like actions in ovariectomized rats forced to swim.

Science.gov (United States)

Molina-Hernández, Miguel; Téllez-Alcántara, N Patricia; Olivera-López, Jorge I; Jaramillo, M Teresa

2011-01-15

Folic acid or 17-β estradiol produces antidepressant effects, either alone or combined with several antidepressants. However, the antidepressant-like actions of folic acid combined with 17-β estradiol in the forced swimming test (FST) have not been tested before. Thus, in the present study, ovariectomized female rats received folic acid (5.0 nmol/i.c.v., Pfluoxetine (20.0mg/kg, Pswimming behavior when they were tested in the FST. Combination of subthreshold doses of folic acid (2.5 nmol/i.c.v.; or 25.0mg/kg, p.o.) with subthreshold doses of 17-β estradiol (5.0 μg/rat, Pfluoxetine (15.0mg/kg, Pfluoxetine in the FST reduced immobility in the FST. These antidepressant-like actions probably were due to modifications of the serotonergic system since swimming behavior was increased and these effects were cancelled by ketanserin. Copyright © 2010 Elsevier Inc. All rights reserved.

Transdermal deferoxamine prevents pressure-induced diabetic ulcers

Science.gov (United States)

Duscher, Dominik; Neofytou, Evgenios; Wong, Victor W.; Maan, Zeshaan N.; Rennert, Robert C.; Januszyk, Michael; Rodrigues, Melanie; Malkovskiy, Andrey V.; Whitmore, Arnetha J.; Galvez, Michael G.; Whittam, Alexander J.; Brownlee, Michael; Rajadas, Jayakumar; Gurtner, Geoffrey C.

2015-01-01

There is a high mortality in patients with diabetes and severe pressure ulcers. For example, chronic pressure sores of the heels often lead to limb loss in diabetic patients. A major factor underlying this is reduced neovascularization caused by impaired activity of the transcription factor hypoxia inducible factor-1 alpha (HIF-1α). In diabetes, HIF-1α function is compromised by a high glucose-induced and reactive oxygen species-mediated modification of its coactivator p300, leading to impaired HIF-1α transactivation. We examined whether local enhancement of HIF-1α activity would improve diabetic wound healing and minimize the severity of diabetic ulcers. To improve HIF-1α activity we designed a transdermal drug delivery system (TDDS) containing the FDA-approved small molecule deferoxamine (DFO), an iron chelator that increases HIF-1α transactivation in diabetes by preventing iron-catalyzed reactive oxygen stress. Applying this TDDS to a pressure-induced ulcer model in diabetic mice, we found that transdermal delivery of DFO significantly improved wound healing. Unexpectedly, prophylactic application of this transdermal delivery system also prevented diabetic ulcer formation. DFO-treated wounds demonstrated increased collagen density, improved neovascularization, and reduction of free radical formation, leading to decreased cell death. These findings suggest that transdermal delivery of DFO provides a targeted means to both prevent ulcer formation and accelerate diabetic wound healing with the potential for rapid clinical translation. PMID:25535360

[Matrix transdermal systems for caffeine delivery based on polymer and emulsion compounds].

Science.gov (United States)

Kuznetsova, E G; Kuryleva, O M; Salomatina, L A; Sevast'ianov, V I

2008-01-01

The goal of this work was to develop and test transdermal therapeutic systems for caffeine delivery. In vitro experiments showed that the rate of caffeine diffusion through untreated rabbit skin from a transdermal therapeutic systems based on polymer compound containing 50 mg medicine was 67.2 (9.1 microg/cm2h; for a system based on emulsion compound it was 173 (19 microg/cm2h. Methods for studying the caffeine release rate and quantitative measurement of caffeine content in the emulsion-based transdermal therapeutic system were developed. These methods are required to obtain data for standard drug documentation. The results of in vivo experiments in rabbits showed the absence of irritating effect of the emulsion-based transdermal therapeutic system. The obtained data on the specific efficiency of the transdermal therapeutic systems for caffeine delivery (50 mg) in healthy volunteers showed that this medicine could be used as a nonnarcotic psychoactivator for improving mental and physical activities and attention concentration.

Estradiol-induced estrogen receptor-alpha trafficking.

Science.gov (United States)

Bondar, Galyna; Kuo, John; Hamid, Naheed; Micevych, Paul

2009-12-02

Estradiol has rapid actions in the CNS that are mediated by membrane estrogen receptors (ERs) and activate cell signaling pathways through interaction with metabotropic glutamate receptors (mGluRs). Membrane-initiated estradiol signaling increases the free cytoplasmic calcium concentration ([Ca(2+)](i)) that stimulates the synthesis of neuroprogesterone in astrocytes. We used surface biotinylation to demonstrate that ERalpha has an extracellular portion. In addition to the full-length ERalpha [apparent molecular weight (MW), 66 kDa], surface biotinylation labeled an ERalpha-immunoreactive protein (MW, approximately 52 kDa) identified by both COOH- and NH(2)-directed antibodies. Estradiol treatment regulated membrane levels of both proteins in parallel: within 5 min, estradiol significantly increased membrane levels of the 66 and 52 kDa ERalpha. Internalization, a measure of membrane receptor activation, was also increased by estradiol with a similar time course. Continuous treatment with estradiol for 24-48 h reduced ERalpha levels, suggesting receptor downregulation. Estradiol also increased mGluR1a trafficking and internalization, consistent with the proposed ERalpha-mGluR1a interaction. Blocking ER with ICI 182,780 or mGluR1a with LY 367385 prevented ERalpha trafficking to and from the membrane. Estradiol-induced [Ca(2+)](i) flux was also significantly increased at the time of peak ERalpha activation/internalization. These results demonstrate that ERalpha is present in the membrane and has an extracellular portion. Furthermore, membrane levels and internalization of ERalpha are regulated by estradiol and mGluR1a ligands. The pattern of trafficking into and out of the membrane suggests that the changing concentration of estradiol during the estrous cycle regulates ERalpha to augment and then terminate membrane-initiated signaling.

Estradiol-induced estrogen receptor-α trafficking

Science.gov (United States)

Bondar, Galyna; Kuo, John; Hamid, Naheed; Micevych, Paul

2010-01-01

Estradiol has rapid actions in the central nervous system, which are mediated by membrane estrogen receptors (ERs) and activate cell signaling pathways through interaction with metabotropic glutamate receptors (mGluRs). Membrane-initiated estradiol signaling increases the free cytoplasmic calcium concentration ([Ca2+]i) that stimulates the synthesis of neuroprogesterone in astrocytes. We used surface biotinylation to demonstrate that ERα has an extracellular portion. In addition to the full length ERα (apparent M.W. 66 kDa), surface biotinylation labeled an ERα-immunoreactive protein (M.W. ~ 52 kDa) identified by both COOH- and NH2-directed antibodies. Estradiol treatment regulated membrane levels of both proteins in parallel: within 5 min, estradiol significantly increased membrane levels of the 66 kDa and 52 kDa ERα. Internalization, a measure of membrane receptor activation, was also increased by estradiol with a similar time course. Continuous treatment with estradiol for 24–48 hr reduced ERα levels, suggesting receptor down-regulation. Estradiol also increased mGluR1a trafficking and internalization, consistent with the proposed ERα-mGluR1a interaction. Blocking ER with ICI 182,780 or mGluR1a with LY 367385 prevented ERα trafficking to and from the membrane. Estradiol-induced [Ca2+]i flux was also significantly increased at the time of peak ERα activation/internalization. These results demonstrate that ERα is present in the membrane and has an extracellular portion. Furthermore, membrane levels and internalization of ERα are regulated by estradiol and mGluR1a ligands. The pattern of trafficking into and out of the membrane suggests that the changing concentration of estradiol during the estrous cycle regulates ERα to augment and then terminate membrane-initiated signaling. PMID:19955385

Transfer of estradiol to human milk. [Radioimmunoassay

Energy Technology Data Exchange (ETDEWEB)

Nilsson, S.; Nygren, K.G.; Johansson, E.D.B.

1978-11-15

A radioimmunoassay for the measurement of estradiol in human milk is evaluated. The detection limit was found to be 25 pg of estradiol per milliliter of milk. In milk samples collected from four lactating women during three to four months and from one pregnant and lactating woman, the concentration of estradiol was found to be below the detection limit of the assay. When six lactating women were given vaginal suppositories containing 50 or 100 mg of estradiol, it was possible to estimate the estradiol concentration in milk. A ratio of transfer of estradiol from plasma to milk during physiologic conditions is calculated to be less than 100 : 10.

The antiaging activity and cerebral protection of rapamycin at micro-doses.

Science.gov (United States)

Qi, Haiyan; Su, Feng-Yun; Wan, Shan; Chen, Yongjie; Cheng, Yan-Qiong; Liu, Ai-Jun

2014-11-01

The immunosuppressant drug rapamycin was reported to have an antiaging activity, which was attributed to the TORC1 inhibition that inhibits cell proliferation and increases autophagy. However, rapamycin also exhibits a number of harmful adverse effects. Whether rapamycin can be developed into an antiaging agent remains unclear. We demonstrated that rapamycin at micro-doses (below the TORC1 inhibiting concentration) exhibits a cell-protective activity: (1) It protects cultured neurons against neurotoxin MPP(+) and H2O2. (2) It increases survival time of neuron in culture. (3) It maintains the nonproliferative state of cultured senescent human fibroblasts and prevents cell death induced by telomere dysfunction. (4) In animal models, it decreased the cerebral infarct sizes induced by acute ischemia and dramatically extended the life span of stroke prone spontaneously hypertensive rats (SHR-SPs). We propose that rapamycin at micro-dose can be developed into an antiaging agent with a novel mechanism. © 2014 John Wiley & Sons Ltd.

Gamma dose effects valuation on micro computing components; Evaluation des effets de la dose gamma sur les composants micro-informatiques

Energy Technology Data Exchange (ETDEWEB)

Joffre, F

1996-12-31

Robotics in hostile environment raises the problem of micro computing components resistance with gamma radiation cumulated dose. The current aim is to reach a dose of 3000 grays with industrial components. A methodology and an instrumentation adapted to test this type of components have been developed. The aim of this work is to present the advantages and disadvantages bound to the use of industrial components in the presence of gamma radiation. After an analysis of the criteria allowing to justify the technological choices, the different steps which characterize the selection and the assessment methodology used are explained. The irradiation and measures means now operational are mentioned. Moreover, the supply aspects of the chosen components for the design of an industrialized system is taken into account. These selection and assessment components contribute to the development and design of computers for civil nuclear robotics. (O.M.). 7 refs.

An open-label, two-period comparative study on pharmacokinetics and safety of a combined ethinylestradiol/gestodene transdermal contraceptive patch

Directory of Open Access Journals (Sweden)

Zhang C

2017-03-01

Full Text Available Chao Zhang,1 Haiyan Li,2 Xin Xiong,1 Suodi Zhai,1 Yudong Wei,2 Shuang Zhang,2 Yuanyuan Zhang,1 Lin Xu,2 Li Liu1 1Department of Pharmacy, 2Institute of Clinical Trial, Peking University Third Hospital, Beijing, People’s Republic of China Abstract: We investigated the pharmacokinetics and safety profiles of a newly developed combined ethinylestradiol (EE/gestodene (GSD transdermal contraceptive patch after a single-dose administration and compared with the market available tablet formulation in healthy adult subjects. An open-label, two-period comparative study was conducted in 12 healthy women volunteers. A single dose of the study combined EE/GE transdermal contraceptive patch and oral tablet (Milunet® were administered. Blood samples at different time points after dose were collected, and concentrations were analyzed. A reliable, highly sensitive and accurate high-performance liquid chromatography coupled with tandem mass spectrometry (HPLC/MS/MS assay method was developed in this study to determine the plasma concentrations of EE and GSD. Compared to the tablet, the study patch had a significantly decreased maximum plasma concentration (Cmax, extended time to reach the Cmax and half-life, as well as increased clearance and apparent volume of distribution. The half-lives of EE and GSD of the patch were 3.3 and 2.2 times, respectively, than the half-life of the tablet. The areas under the plasma concentration–time curve (AUCs of EE and GSD of the patch were 8.0 and 16.2 times, respectively, than the AUC of the tablet. No severe adverse event was observed during the whole study, and the general safety was acceptable. In conclusion, compared to the oral tablet Milunet, the study contraceptive patch was well tolerated and showed potent drug exposure, significant extended half-life and stable drug concentrations. Keywords: pharmacokinetics, safety, ethinylestradiol/gestodene, transdermal contraceptive patch

Effectiveness and tolerability of transdermal rivastigmine in the treatment of Alzheimer’s disease in daily practice

Directory of Open Access Journals (Sweden)

Seibert J

2012-04-01

Full Text Available Johannes Seibert1, Ferenc Tracik2,3, Konstantin Articus2, Stefan Spittler41Outpatient Clinic, Heidelberg, Germany; 2Novartis Pharma, Nürnberg, Germany; 3Department of Neurology, Heinrich-Heine University, Düsseldorf, Germany; 4Alexianer Krefeld, Maria Hilf Clinic, Krefeld, GermanyBackground: Oral cholinesterase inhibitors at doses efficacious for the treatment of Alzheimer’s disease (AD are often prematurely discontinued due to gastrointestinal side effects. In controlled clinical trials, transdermal rivastigmine demonstrated less such effects at similar efficacy. The current study aimed to verify the validity of this data in daily practice.Methods: This was a prospective, multicenter, observational study on transdermal rivastigmine in Germany. Eligible patients were those with AD who had not yet been treated with rivastigmine. Outcome measures were changes in clock-drawing test, Mini-Mental State Examination (MMSE, Caregiver Burden Scale, Clinical Global Impression (CGI, physicians’ assessments of tolerability, and the incidence of adverse events (AEs over 4 months of treatment.Results: In 257 centers 1113 patients were enrolled; 614 women and 499 men, mean age 76.5 years. In 58% of patients AD was treated for the first time and in 42% therapy was switched to transdermal rivastigmine, mostly due to lack of tolerability (13.6% or effectiveness (26.9%. After 4 months, 67.4% of patients were on the target dose of 9.5 mg/day and 21.8% were still on 4.6 mg/day. MMSE significantly improved in patients with and without pretreatment (ΔMMSE, 0.9 ± 3.4 and 0.8 ± 3.4, respectively, both P < 0.001; the CGI score improved in 60.9% and 61.3% of patients, respectively. Overall 11.7% of patients had AEs, mainly affecting the skin or the gastrointestinal tract; in 1.1% of cases AEs were serious; 14.7% of patients discontinued therapy, 6.0% due to AEs. With rivastigmine treatment the percentage of patients taking psychotropic comedication decreased

Relative Biological Effectiveness of HZE Fe Ions for Induction ofMicro-Nuclei at Low Doses

Energy Technology Data Exchange (ETDEWEB)

Groesser, Torsten; Chun, Eugene; Rydberg, Bjorn

2007-01-16

Dose-response curves for induction of micro-nuclei (MN) was measured in Chinese hamster V79 and xrs6 (Ku80-) cells and in human mammary epithelial MCF10A cells in the dose range of 0.05-1 Gy. The Chinese Hamster cells were exposed to 1 GeV/u Fe ions, 600 MeV/u Fe ions, and 300 MeV/u Fe ions (LETs of 151, 176 and 235 keV/{micro}m respectively) as well as with 320 kVp X-rays as reference. Second-order polynomials were fitted to the induction curves and the initial slopes (the alpha values) were used to calculate RBE. For the repair proficient V79 cells the RBE at these low doses increased with LET. The values obtained were 3.1 (LET=151 keV/{micro}m), 4.3 (LET = 176 keV/{micro}m) and 5.7 (LET = 235 keV/{micro}m), while the RBE was close to 1 for the repair deficient xrs6 cells regardless of LET. For the MCF10A cells the RBE was determined for 1 GeV/u Fe ions and found to be 5.4, slightly higher than for V79 cells. To test the effect of shielding, the 1 GeV/u Fe ion beam was intercepted by various thickness of high-density polyethylene plastic absorbers, which resulted in energy loss and fragmentation. It was found that the MN yield for V79 cells placed behind the absorbers decreased in proportion to the decrease in dose both before and after the Fe ion Bragg peak (excluding the area around the Fe-ion Bragg peak itself), indicating that RBE did not change significantly due to shielding. At the Bragg peak the effectiveness for MN formation per unit dose was decreased, indicating an 'overkill' effect by low-energy very high-LET Fe ions.

Engineering approaches to transdermal drug delivery: a tribute to contributions of prof. Robert Langer.

Science.gov (United States)

Mitragotri, S

2013-01-01

Transdermal drug delivery continues to provide an advantageous route of drug administration over injections. While the number of drugs delivered by passive transdermal patches has increased over the years, no macromolecule is currently delivered by the transdermal route. Substantial research efforts have been dedicated by a large number of researchers representing varied disciplines including biology, chemistry, pharmaceutics and engineering to understand, model and overcome the skin's barrier properties. This article focuses on engineering contributions to the field of transdermal drug delivery. The article pays tribute to Prof. Robert Langer, who pioneered the engineering approach towards transdermal drug delivery. Over a period spanning nearly 25 years since his first publication in the field of transdermal drug delivery, Bob Langer has deeply impacted the field by quantitative analysis and innovative engineering. At the same time, he has inspired several generations of engineers by collaborations and mentorship. His scientific insights, innovative technologies, translational efforts and dedicated mentorship have transformed the field. © 2013 S. Karger AG, Basel.

Epoxiconazole-induced degeneration in rat placenta and the effects of estradiol supplementation.

Science.gov (United States)

Rey Moreno, Maria Cecilia; Fussell, Karma C; Gröters, Sibylle; Schneider, Steffen; Strauss, Volker; Stinchcombe, Stefan; Fegert, Ivana; Veras, Mariana; van Ravenzwaay, Bennard

2013-06-01

Epoxiconazole (CAS-No. 133855-98-8) was recently shown to cause both a marked depletion of maternal estradiol blood levels and a significantly increased incidence of late fetal mortality when administered to pregnant rats throughout gestation (GD 7-18 or 21); estradiol supplementation prevented this epoxiconazole effect in rats (Stinchcombe et al., 2013), indicating that epoxiconazole-mediated estradiol depletion is a critical key event for induction of late fetal resorptions in rats. For further elucidation of the mode of action, the placentas from these modified prenatal developmental toxicity experiments with 23 and 50 mg/kg bw/d epoxiconazole were subjected to a detailed histopathological examination. This revealed dose-dependent placental degeneration characterized by cystic dilation of maternal sinuses in the labyrinth, leading to rupture of the interhemal membrane. Concomitant degeneration occurred in the trophospongium. Both placentas supporting live fetuses and late fetal resorptions were affected; the highest degree of severity was observed in placentas with late resorptions. Placental degeneration correlated with a severe decline in maternal serum estradiol concentration. Supplementation with 0.5 and 1.0 μg of the synthetic estrogen estradiol cyclopentylpropionate per day reduced the severity of the degeneration in placentas with live fetuses. The present study demonstrates that both the placental degeneration and the increased incidence of late fetal resorptions are due to decreased levels of estrogen, since estrogen supplementation ameliorates the former and abolishes the latter. © 2013 Wiley Periodicals, Inc.

Sex-specific effects of low-dose gestational estradiol-17β exposure on bone development in porcine offspring

International Nuclear Information System (INIS)

Flöter, Veronika L.; Galateanu, Gabriela; Fürst, Rainer W.; Seidlová-Wuttke, Dana; Wuttke, Wolfgang; Möstl, Erich; Hildebrandt, Thomas B.

2016-01-01

Highlights: • Sex-specific effects and non-monotonic dose responses were demonstrated after low-dose in utero E2 treatment in offspring. • Alterations in bone parameters were found in prepubertal male but not female offspring. • In postpubertal female offspring, cortical and total cross-sectional area were higher at the femoral midpoint. • In utero E2 treatment did neither significantly affect hormone concentrations nor puberty onset in offspring. • The results substantiate the high sensitivity of developing organisms to exogenous estrogens. - Abstract: Estrogens are important for the bone development and health. Exposure to endocrine disrupting chemicals during the early development has been shown to affect the bone phenotype later in life. Several studies have been performed in rodents, while in larger animals that are important to bridge the gap to humans there is a paucity of data. To this end, the pig as large animal model was used in the present study to assess the influence of gestational estradiol-17β (E2) exposure on the bone development of the prepubertal and adult offspring. Two low doses (0.05 and 10 μg E2/kg body weight) referring to the ‘acceptable daily intake’ (ADI) and the ‘no observed effect level’ (NOEL) as stated for humans, and a high-dose (1000 μg E2/kg body weight), respectively, were fed to the sows every day from insemination until delivery. In the male prepubertal offspring, the ADI dose group had a lower strength strain index (p = 0.002) at the proximal tibia compared to controls, which was determined by peripheral quantitative computed tomography. Prepubertal females were not significantly affected. However, there was a higher cortical cross-sectional area (CSA) (p = 0.03) and total CSA (p = 0.02) at the femur midpoint in the adult female offspring of the NOEL dose group as measured by computed tomography. These effects were independent from plasma hormone concentrations (leptin, IGF1, estrogens), which remained

Tamoxifen counteracts estradiol induced effects on striatal and hypophyseal dopamine receptors

Energy Technology Data Exchange (ETDEWEB)

Ferretti, C.; Blengio, M.; Ghi, P.; Racca, S.; Genazzani, E.; Portaleone, P.

1988-01-01

We investigated the ability of Tamoxifen (TAM), an antiestrogen drug, to counteract the modification induced by estrogens on dopamine (DA) receptors on striatum and on adenohypophysis of ovex female rats. Subacute treatment with 17..beta..-estradiol (E/sub 2/) at both low (0.1 ..mu..g/kg) and high (20 ..mu..g/kg) doses confirmed its ability to increase the number of striatal /sup 3/H-Spiperone (/sup 3/H-SPI) binding sites in a dose dependent manner. By contrast in the pituitary, only high doses of estrogen were effective in reducing the number of DA receptors. We treated ovex female rats for 15 days with TAM alone or associated with E/sub 2/, to see if these estrogenic effects could be suppressed by an antiestrogenic drug. TAM did not affect the number of striatal DA receptors, but significantly increased the adenohypophy-seal DA binding sites, without varying their affinity. No changes were observed in pituitary and striatal DA receptor density, even when TAM was injected in association with estradiol. In conclusions: TAM is able to counteract the effects estrogens have on DA receptors. However there is some evidence that it could influence the pituitary DA systems independently of it antiestrogenic activity.

Pharmacokinetics of a granisetron transdermal system for the treatment of chemotherapy-induced nausea and vomiting.

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Howell, Julian; Smeets, Jean; Drenth, Henk-Jan; Gill, David

2009-12-01

To determine the pharmacokinetic (PK) profile of granisetron transdermal formulation and examine its possible relationship with age, gender, and renal function. This article describes a Phase I PK study and a post hoc pooled population PK analysis. The Phase I study was a randomized, cross-over study that assessed PK parameters of three granisetron patch sizes and oral granisetron. The pooled population PK analysis included data from three trials in healthy subjects (n = 48) and from Phase II and III studies in patients with cancer (n = 793). The population PK model was used to investigate granisetron exposure and its possible relationship with age, gender, and renal function. Following oral dosing, plasma granisetron concentration was quantifiable at 1 h, and maximal mean concentration (4.7 ng/mL) was reached 2 h after administration. With transdermal application, maximal concentration was reached 48 h post-application; t(1/2) was 36 h. With oral dosing, overall exposure after 5 days was 306 ng/mL.h, and C(avg) 2.6 ng/mL. This corresponded to an AUC(0-infinity) for the 52 cm(2) patch of 420 ng/mL.h and C(avg) 2.2 ng/mL over 6 days. Clearance was not affected by age, gender, weight, or renal function. The 52 cm( 2) granisetron patch achieves a similar exposure to that of a 2 mg oral dose and provides continuous delivery of granisetron over 6 days. The patch may have utility in treating chemotherapy-induced nausea and vomiting where prolonged drug delivery is advantageous. No dose adjustments would be needed based on age or renal function.

Transdermal microneedles for drug delivery applications

International Nuclear Information System (INIS)

Teo, Ai Ling; Shearwood, Christopher; Ng, Kian Chye; Lu Jia; Moochhala, Shabbir

2006-01-01

Transdermal drug delivery (TDD) has many advantages, the main one being the ability to maintain the prolonged release of drugs to attain optimal blood concentrations. Unfortunately, nature has provided a very effective protective barrier, the stratum corneum (sc), which limits TDD to certain types of drugs with specific properties. In order to enhance TDD, the idea of using microneedles to painlessly penetrate the sc barrier has previously been proposed. In this paper, we will review the different microneedles that are currently being developed as well as our own efforts in this area. Based on our experiences, we will offer our view on the key parameters for effective transdermal microneedle design as well as future directions in this area

Transdermal microneedles for drug delivery applications

Energy Technology Data Exchange (ETDEWEB)

Teo, Ai Ling [Defence Medical and Environmental Research Institute, DSO National Laboratories (Kent Ridge), 27 Medical Drive, 12-00, Singapore 117510 (Singapore); Shearwood, Christopher [School of Mechanical and Aerospace Engineering, 50 Nanyang Avenue, Singapore 639798 (Singapore); Ng, Kian Chye [Defence Medical and Environmental Research Institute, DSO National Laboratories (Kent Ridge), 27 Medical Drive, 12-00, Singapore 117510 (Singapore); Lu Jia [Defence Medical and Environmental Research Institute, DSO National Laboratories (Kent Ridge), 27 Medical Drive, 12-00, Singapore 117510 (Singapore); Moochhala, Shabbir [Defence Medical and Environmental Research Institute, DSO National Laboratories (Kent Ridge), 27 Medical Drive, 12-00, Singapore 117510 (Singapore)]. E-mail: mshabbir@dso.org.sg

2006-07-25

Transdermal drug delivery (TDD) has many advantages, the main one being the ability to maintain the prolonged release of drugs to attain optimal blood concentrations. Unfortunately, nature has provided a very effective protective barrier, the stratum corneum (sc), which limits TDD to certain types of drugs with specific properties. In order to enhance TDD, the idea of using microneedles to painlessly penetrate the sc barrier has previously been proposed. In this paper, we will review the different microneedles that are currently being developed as well as our own efforts in this area. Based on our experiences, we will offer our view on the key parameters for effective transdermal microneedle design as well as future directions in this area.

Estradiol-induced increase in the magnitude of long-term potentiation is prevented by blocking NR2B-containing receptors.

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Smith, Caroline C; McMahon, Lori L

2006-08-16

Estradiol, through activation of genomic estrogen receptors, induces changes in synaptic morphology and function in hippocampus, a brain region important for memory acquisition. Specifically, this hormone increases CA1 pyramidal cell dendritic spine density, NMDA receptor (NMDAR)-mediated transmission, and the magnitude of long-term potentiation (LTP) at CA3-CA1 synapses. We recently reported that the estradiol-induced increase in LTP magnitude occurs only when there is a simultaneous increase in the fractional contribution of NMDAR-mediated transmission relative to AMPA receptor transmission, suggesting a direct role for the increase in NMDAR transmission to the heightened LTP magnitude. Estradiol has been shown to increase expression of the NMDAR subunit NR2B, but whether this translates into an increase in function of NR2B-containing receptors remains to be determined. Here we show that not only is the estradiol-induced increase in NMDAR transmission mediated by NR2B-containing receptors, but blocking these receptors using RO25-6981 [R-(R,S)-alpha-(4-hydroxyphenyl)-beta-methyl-4-(phenylmethyl)-1-piperidine propranol] (0.5 microM), an NR2B selective antagonist, prevents the estradiol-induced increase in LTP magnitude. Thus, our data show a causal link between the estradiol-induced increase in transmission mediated by NR2B-containing NMDARs and the increase in LTP magnitude.

Systemic delivery of atropine sulfate by the MicroDose Dry-Powder Inhaler.

Science.gov (United States)

Corcoran, T E; Venkataramanan, R; Hoffman, R M; George, M P; Petrov, A; Richards, T; Zhang, S; Choi, J; Gao, Y Y; Oakum, C D; Cook, R O; Donahoe, M

2013-02-01

Inhaled atropine is being developed as a systemic and pulmonary treatment for the extended recovery period after chemical weapons exposure. We performed a pharmacokinetics study comparing inhaled atropine delivery using the MicroDose Therapeutx Dry Powder Inhaler (DPIA) with intramuscular (IM) atropine delivery via auto-injector (AUTO). The MicroDose DPIA utilizes a novel piezoelectric system to aerosolize drug and excipient from a foil dosing blister. Subjects inhaled a 1.95-mg atropine sulfate dose from the dry powder inhaler on one study day [5 doses × 0.4 mg per dose (nominal) delivered over 12 min] and received a 2-mg IM injection via the AtroPen® auto-injector on another. Pharmacokinetics, pharmacodynamic response, and safety were studied for 12 hr. A total of 17 subjects were enrolled. All subjects completed IM dosing. One subject did not perform inhaled delivery due to a skin reaction from the IM dose. Pharmacokinetic results were as follows: area under the curve concentration, DPIA=20.1±5.8, AUTO=23.7±4.9 ng hr/mL (means±SD); maximum concentration reached, DPIA=7.7±3.5, AUTO=11.0±3.8 ng/mL; time to reach maximum concentration, DPIA=0.25±0.47, AUTO=0.19±0.23 hr. Pharmacodynamic results were as follows: maximum increase in heart rate, DPIA=18±12, AUTO=23±13 beats/min; average change in 1-sec forced expiratory volume at 30 min, DPIA=0.16±0.22 L, AUTO=0.11±0.29 L. The relative bioavailability for DPIA was 87% (based on output dose). Two subjects demonstrated allergic responses: one to the first dose (AUTO), which was mild and transient, and one to the second dose (DPIA), which was moderate in severity, required treatment with oral and intravenous (IV) diphenhydramine and IV steroids, and lasted more than 7 days. Dry powder inhalation is a highly bioavailable route for attaining rapid and consistent systemic concentrations of atropine.

Transdermal delivery of gentamicin using dissolving microneedle arrays for potential treatment of neonatal sepsis.

Science.gov (United States)

González-Vázquez, Patricia; Larrañeta, Eneko; McCrudden, Maelíosa T C; Jarrahian, Courtney; Rein-Weston, Annie; Quintanar-Solares, Manjari; Zehrung, Darin; McCarthy, Helen; Courtenay, Aaron J; Donnelly, Ryan F

2017-11-10

Neonatal infections are a leading cause of childhood mortality in low-resource settings. World Health Organization guidelines for outpatient treatment of possible serious bacterial infection (PSBI) in neonates and young infants when referral for hospital treatment is not feasible include intramuscular gentamicin (GEN) and oral amoxicillin. GEN is supplied as an aqueous solution of gentamicin sulphate in vials or ampoules and requires health care workers to be trained in dose calculation or selection of an appropriate dose based on the patient's weight band and to have access to safe injection supplies and appropriate sharps disposal. A simplified formulation, packaging, and delivery method to treat PSBI in low-resource settings could decrease user error and expand access to lifesaving outpatient antibiotic treatment for infants with severe infection during the neonatal period. We developed dissolving polymeric microneedles (MN) arrays to deliver GEN transdermally. MN arrays were produced from aqueous blends containing 30% (w/w) of GEN and two polymers approved by the US Food and Drug Administration: sodium hyaluronate and poly(vinylpyrrolidone). The arrays (19×19 needles and 500μm height) were mechanically strong and were able to penetrate a skin simulant to a depth of 378μm. The MN arrays were tested in vitro using a Franz Cell setup delivering approximately 4.45mg of GEN over 6h. Finally, three different doses (low, medium, and high) of GEN delivered by MN arrays were tested in an animal model. Maximum plasma levels of GEN were dose-dependent and ranged between 2 and 5μg/mL. The time required to reach these levels post-MN array application ranged between 1 and 6h. This work demonstrated the potential of dissolving MN arrays to deliver GEN transdermally at therapeutic levels in vivo. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

Gamma dose effects valuation on micro computing components

International Nuclear Information System (INIS)

Joffre, F.

1995-01-01

Robotics in hostile environment raises the problem of micro computing components resistance with gamma radiation cumulated dose. The current aim is to reach a dose of 3000 grays with industrial components. A methodology and an instrumentation adapted to test this type of components have been developed. The aim of this work is to present the advantages and disadvantages bound to the use of industrial components in the presence of gamma radiation. After an analysis of the criteria allowing to justify the technological choices, the different steps which characterize the selection and the assessment methodology used are explained. The irradiation and measures means now operational are mentioned. Moreover, the supply aspects of the chosen components for the design of an industrialized system is taken into account. These selection and assessment components contribute to the development and design of computers for civil nuclear robotics. (O.M.)

Population pharmacokinetic model of transdermal nicotine delivered from a matrix-type patch.

Science.gov (United States)

Linakis, Matthew W; Rower, Joseph E; Roberts, Jessica K; Miller, Eleanor I; Wilkins, Diana G; Sherwin, Catherine M T

2017-12-01

Nicotine addiction is an issue faced by millions of individuals worldwide. As a result, nicotine replacement therapies, such as transdermal nicotine patches, have become widely distributed and used. While the pharmacokinetics of transdermal nicotine have been extensively described using noncompartmental methods, there are few data available describing the between-subject variability in transdermal nicotine pharmacokinetics. The aim of this investigation was to use population pharmacokinetic techniques to describe this variability, particularly as it pertains to the absorption of nicotine from the transdermal patch. A population pharmacokinetic parent-metabolite model was developed using plasma concentrations from 25 participants treated with transdermal nicotine. Covariates tested in this model included: body weight, body mass index, body surface area (calculated using the Mosteller equation) and sex. Nicotine pharmacokinetics were best described with a one-compartment model with absorption based on a Weibull distribution and first-order elimination and a single compartment for the major metabolite, cotinine. Body weight was a significant covariate on apparent volume of distribution of nicotine (exponential scaling factor 1.42). After the inclusion of body weight in the model, no other covariates were significant. This is the first population pharmacokinetic model to describe the absorption and disposition of transdermal nicotine and its metabolism to cotinine and the pharmacokinetic variability between individuals who were administered the patch. © 2017 The British Pharmacological Society.

A randomized, open-label, crossover study comparing the effects of oral versus transdermal estrogen therapy on serum androgens, thyroid hormones, and adrenal hormones in naturally menopausal women.

Science.gov (United States)

Shifren, Jan L; Desindes, Sophie; McIlwain, Marilyn; Doros, Gheorghe; Mazer, Norman A

2007-01-01

To compare the changes induced by oral versus transdermal estrogen therapy on the total and free serum concentrations of testosterone (T), thyroxine (T4), and cortisol (C) and the concentrations of their serum binding globulins sex hormone-binding globulin, thyroxine-binding globulin, and cortisol-binding globulin in naturally menopausal women. Randomized, open-label, crossover. Interventions included a 6-week withdrawal from previous hormone therapy (baseline), followed in randomized order by 12 weeks of oral conjugated equine estrogens (CEE) (0.625 mg/d) and 12 weeks of transdermal estradiol (TD E2) (0.05 mg/d), with oral micronized progesterone (100 mg/d) given continuously during both transdermal estrogen therapy regimens. Twenty-seven women were enrolled in the study, and 25 completed both treatment periods. The mean(SD) percentage changes from baseline of sex hormone-binding globulin, total T, and free T with oral CEE were +132.1% (74.5%), +16.4% (43.8%), and -32.7% (25.9%), respectively, versus +12.0% (25.1%), +1.2% (43.7%), and +1.0% (45.0%) with TD E2. The mean (SD) percentage changes of thyroxine-binding globulin, total T4, and free T4 with oral CEE were +39.9% (20.1%), +28.4% (29.2%), and -10.4% (22.3%), respectively, versus +0.4% (11.1%), -0.7% (16.5%), and +0.2% (26.6%) with TD E2. The mean (SD) percentage changes of cortisol-binding globulin, total C, and free C with oral CEE were +18.0% (19.5%), +29.2% (46.3%), and +50.4% (126.5%), respectively, versus -2.2% (11.3%), -6.7% (30.8%), and +1.8% (77.1%) with TD E2. Concentrations of all hormones and binding globulins were significantly different (P < or = 0.003) during administration of oral versus transdermal estrogen therapy, except for free T4 and free C. Compared with oral CEE, TD E2 exerts minimal effects on the total and free concentrations of T, T4, and C and their binding proteins.

Transdermal nitroglycerine enhances postoperative analgesia of intrathecal neostigmine following abdominal hysterectomies

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Fareed Ahmed

2010-01-01

Full Text Available This study was carried out to assess the effect of nitroglycerine (transdermal on intrathecal neostigmine with bupivacaine on postoperative analgesia and note the incidence of adverse effects, if any. After taking informed consent, 120 patients of ASA Grade I and II were systematically randomised into four groups of 30 each. Patients were premedicated with midazolam 0.05 mg/kg intravenously and hydration with Ringer′s lactate solution 10ml/kg preoperatively in the holding room. Group I patients received Intrathecal injection of 15 mg bupivacaine with 1ml of normal saline and transdermal placebo patch. Group II patients received Intrathecal injection of 15 mg bupivacaine with 5 mcg of neostigmine and transdermal placebo patch. Group III patients received Intrathecal injection of 15 mg bupivacaine with 1ml of normal saline with transdermal nitroglycerine patch (5 mg/24 hours. Group IV patients received Intrathecal injection of 15 mg bupivacaine with 5mcg of neostigmine and transdermal nitroglycerine patch (5 mg/24 hours, applied on a non anaesthetised area after 20 minutes. Groups were demographically similar and did not differ in intraoperative characteristics like sensory block, motor block, haemodynamic parameters and SpO 2 . The mean duration of analgesia was 202.17 minutes, 407.20 minutes, 207.53 minutes and 581.63 minutes in control group (I, neostigmine group (II, nitroglycerine group (III and nitroglycerine neostigmine group (IV respectively (P< 0.01. To conclude, our results show that transdermal nitroglycerine itself does not show any analgesic potential but it enhances the analgesic potential of intrathecal neostigmine.

Synthesis of 123I-16 iodo estradiol

International Nuclear Information System (INIS)

Therain, F.; Gros, J.; Souchu, A.

1982-01-01

16α iodo estradiol has been demonstrated to have as good an affinity as estradiol for estrogen-receptors and, labeled with iodine 123, may provide a good scanning agent fot visualisation of tissues containing estrogen-repectors, especially mammary tumors. 123 I-16α iodo estradiol has been synthesized by an halogen exchange of 16ν bromo estradiol according to the procedure described by Hochberg for 125 I-16α iodo estradiol labeling. Radiochemical yields are much lower than with iodine 125 (1 to 30%) and extremely variable. Specific activity range from 1,000 to 2,000 Ci/mmole [fr

Nomegestrol acetate-17b-estradiol for oral contraception

Directory of Open Access Journals (Sweden)

Burke A

2013-06-01

Full Text Available Anne Burke Johns Hopkins University School of Medicine, Baltimore, MD, USAAbstract: Oral contraceptives remain a popular method of contraception over 50 years after their introduction. While safe and effective for many women, the failure rate of oral contraception is about 8%. Concerns about the risk of venous thromboembolism continue to drive the search for the safest oral contraceptive formulations. The oral contraceptive NOMAC-E2 contains nomegestrol acetate (NOMAC 2.5 mg + 17b-estradiol (E2 1.5 mg. The approved dosing regimen is 24 days of active hormone, followed by a 4-day hormone-free interval. NOMAC is a progestin derived from testosterone, which has high bioavailability, rapid absorption, and a long half-life. Estradiol, though it has a lower bioavailability, has been successfully combined with NOMAC in a monophasic oral contraceptive. Two recently published randomized controlled trials demonstrate that NOMAC-E2 is an effective contraceptive, with a Pearl Index less than one pregnancy per 100 woman-years. The bleeding pattern on NOMAC-E2 is characterized by fewer bleeding/spotting days, shorter withdrawal bleeds, and a higher incidence of amenorrhea than the comparator oral contraceptive containing drospirenone and ethinyl estradiol. The adverse event profile appears to be acceptable. Few severe adverse events were reported in the randomized controlled trials. The most common adverse events were irregular bleeding, acne, and weight gain. Preliminary studies suggest that NOMAC-E2 does not seem to have negative effects on hemostatic and metabolic parameters. While no one oral contraceptive formulation is likely to be the optimum choice for all women, NOMAC-E2 is a formulation with effectiveness comparable with that of other oral contraceptives, and a reassuring safety profile.Keywords: oral contraception, nomegestrol acetate, estradiol

Transdermal rotigotine causes impulse control disorders in patients with restless legs syndrome.

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Schreglmann, S R; Gantenbein, A R; Eisele, G; Baumann, C R

2012-02-01

Dopaminergic drugs are the mainstay of treatment for restless legs syndrome (RLS). We analyzed the frequency and clinical characteristics of impulse control disorders (ICD) in patients with RLS on transdermal rotigotine treatment. Retrospective case series at a university movement disorder clinic (n = 28, 17 women). Symptoms of ICD were assessed via detailed history taking and scoring with the Zurich Screening Questionnaire for ICD (ZICD) prior to and after initiation of treatment. None of the patients had a history of ICD prior to treatment. Baseline mean scores for patients who did (8.0 ± 2.5) and did not (6.2 ± 2.7) develop ICD under treatment did not differ. Six male patients (21%) developed various symptoms of ICD (mean ZICD scores 20.7 ± 10.2) on rotigotine treatment (mean dose: 3.8 mg/d), including binge eating, hypersexuality, compulsive shopping, pathological gambling, and punding, equaling a prevalence rate of 21%. Also in the non-ICD group, ZICD scores increased (7.5 ± 2.8). This is the first report of ICD in patients treated with transdermal rotigotine for RLS. In contrast to literature, even low doses of rotigotine (mean 3.8 mg/d) can cause ICD. Therefore every prescribing physician should be aware that ICD may emerge in both RLS and PD patients on any dopaminergic treatment, and should actively ask for such symptoms. The ZICD questionnaire not only replicated the findings of detailed history taking but also showed an increased tendency towards impulsive behaviour in subjects that did not develop ICD. Copyright © 2011 Elsevier Ltd. All rights reserved.

Poly(lactic-co-glycolic) acid drug delivery systems through transdermal pathway: an overview.

Science.gov (United States)

Naves, Lucas; Dhand, Chetna; Almeida, Luis; Rajamani, Lakshminarayanan; Ramakrishna, Seeram; Soares, Graça

2017-05-01

In past few decades, scientists have made tremendous advancement in the field of drug delivery systems (DDS), through transdermal pathway, as the skin represents a ready and large surface area for delivering drugs. Efforts are in progress to design efficient transdermal DDS that support sustained drug release at the targeted area for longer duration in the recommended therapeutic window without producing side-effects. Poly(lactic-co-glycolic acid) (PLGA) is one of the most promising Food and Drug Administration approved synthetic polymers in designing versatile drug delivery carriers for different drug administration routes, including transdermal drug delivery. The present review provides a brief introduction over the transdermal drug delivery and PLGA as a material in context to its role in designing drug delivery vehicles. Attempts are made to compile literatures over PLGA-based drug delivery vehicles, including microneedles, nanoparticles, and nanofibers and their role in transdermal drug delivery of different therapeutic agents. Different nanostructure evaluation techniques with their working principles are briefly explained.

Behavioral effects of endogenous or exogenous estradiol and progesterone on cocaine sensitization in female rats

Energy Technology Data Exchange (ETDEWEB)

Souza, M.F. [Universidade Federal de Ciências da Saúde de Porto Alegre, Laboratório de Neurociência Comportamental, Porto Alegre, RS, Brasil, Laboratório de Neurociência Comportamental, Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre, RS (Brazil); Couto-Pereira, N.S. [Universidade Federal do Rio Grande do Sul, Instituto de Ciências Básicas da Saúde, Departamento de Bioquímica, Porto Alegre, RS, Brasil, Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS (Brazil); Freese, L.; Costa, P.A.; Caletti, G.; Bisognin, K.M. [Universidade Federal de Ciências da Saúde de Porto Alegre, Laboratório de Neurociência Comportamental, Porto Alegre, RS, Brasil, Laboratório de Neurociência Comportamental, Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre, RS (Brazil); Nin, M.S. [Universidade Federal de Ciências da Saúde de Porto Alegre, Laboratório de Neurociência Comportamental, Porto Alegre, RS, Brasil, Laboratório de Neurociência Comportamental, Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre, RS (Brazil); Instituto Porto Alegre, Centro Metodista do Sul, Curso de Farmácia, Porto Alegre, RS, Brasil, Curso de Farmácia, Centro Metodista do Sul, Instituto Porto Alegre, Porto Alegre, RS (Brazil); Gomez, R. [Universidade Federal do Rio Grande do Sul, Instituto de Ciências Básicas da Saúde, Departamento de Farmacologia, Porto Alegre, RS, Brasil, Departamento de Farmacologia, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS (Brazil); Barros, H.M.T. [Universidade Federal de Ciências da Saúde de Porto Alegre, Laboratório de Neurociência Comportamental, Porto Alegre, RS, Brasil, Laboratório de Neurociência Comportamental, Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre, RS (Brazil)

2014-05-09

Cocaine sensitization is a marker for some facets of addiction, is greater in female rats, and may be influenced by their sex hormones. We compared the modulatory effects of endogenous or exogenous estradiol and progesterone on cocaine-induced behavioral sensitization in 106 female rats. Ovariectomized female rats received progesterone (0.5 mg/mL), estradiol (0.05 mg/mL), progesterone plus estradiol, or the oil vehicle. Sham-operated control females received oil. Control and acute subgroups received injections of saline, while the repeated group received cocaine (15 mg/kg, ip) for 8 days. After 10 days, the acute and repeated groups received a challenge dose of cocaine, after which locomotion and stereotypy were monitored. The estrous cycle phase was evaluated and blood was collected to verify hormone levels. Repeated cocaine treatment induced overall behavioral sensitization in female rats, with increased locomotion and stereotypies. In detailed analysis, ovariectomized rats showed no locomotor sensitization; however, the sensitization of stereotypies was maintained. Only females with endogenous estradiol and progesterone demonstrated increased locomotor activity after cocaine challenge. Estradiol replacement enhanced stereotyped behaviors after repeated cocaine administration. Cocaine sensitization of stereotyped behaviors in female rats was reduced after progesterone replacement, either alone or concomitant with estradiol. The behavioral responses (locomotion and stereotypy) to cocaine were affected differently, depending on whether the female hormones were of an endogenous or exogenous origin. Therefore, hormonal cycling appears to be an important factor in the sensitization of females. Although estradiol increases the risk of cocaine sensitization, progesterone warrants further study as a pharmacological treatment in the prevention of psychostimulant abuse.

Behavioral effects of endogenous or exogenous estradiol and progesterone on cocaine sensitization in female rats

International Nuclear Information System (INIS)

Souza, M.F.; Couto-Pereira, N.S.; Freese, L.; Costa, P.A.; Caletti, G.; Bisognin, K.M.; Nin, M.S.; Gomez, R.; Barros, H.M.T.

2014-01-01

Cocaine sensitization is a marker for some facets of addiction, is greater in female rats, and may be influenced by their sex hormones. We compared the modulatory effects of endogenous or exogenous estradiol and progesterone on cocaine-induced behavioral sensitization in 106 female rats. Ovariectomized female rats received progesterone (0.5 mg/mL), estradiol (0.05 mg/mL), progesterone plus estradiol, or the oil vehicle. Sham-operated control females received oil. Control and acute subgroups received injections of saline, while the repeated group received cocaine (15 mg/kg, ip) for 8 days. After 10 days, the acute and repeated groups received a challenge dose of cocaine, after which locomotion and stereotypy were monitored. The estrous cycle phase was evaluated and blood was collected to verify hormone levels. Repeated cocaine treatment induced overall behavioral sensitization in female rats, with increased locomotion and stereotypies. In detailed analysis, ovariectomized rats showed no locomotor sensitization; however, the sensitization of stereotypies was maintained. Only females with endogenous estradiol and progesterone demonstrated increased locomotor activity after cocaine challenge. Estradiol replacement enhanced stereotyped behaviors after repeated cocaine administration. Cocaine sensitization of stereotyped behaviors in female rats was reduced after progesterone replacement, either alone or concomitant with estradiol. The behavioral responses (locomotion and stereotypy) to cocaine were affected differently, depending on whether the female hormones were of an endogenous or exogenous origin. Therefore, hormonal cycling appears to be an important factor in the sensitization of females. Although estradiol increases the risk of cocaine sensitization, progesterone warrants further study as a pharmacological treatment in the prevention of psychostimulant abuse

Effect of components (polymer, plasticizer and solvent as a variable in fabrication of diclofenac transdermal patch

Directory of Open Access Journals (Sweden)

Chetna Modi

2012-01-01

Full Text Available Transdermal drug delivery influence consumer acceptance and marked increase in bioavailability of some drugs which undergoes hepatic first-pass metabolism. Fabrication of transdermal patch requires lots of attention regarding the amount of components used for it. Because of varied nature of polymer and plasticizer, transdermal patches have different properties and different drug release. This study is on the basis to evaluate the amount to be needed for fabrication of diclofenac transdermal patch. Study shows that Hydroxy Propyl Methyl Cellulose has great influence on transdermal patch, if it is used alone in combination with glycerin or PEG-4000 plasticizer.

Negative effect of 17-beta-estradiol on growth parameters of goldfish (Carassius auratus

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Reza Tarkhani

2015-03-01

Full Text Available Objective: To evaluate the effects of 17-beta-estradiol on growth factors of goldfish (Carassius auratus. Methods: To perform the test, 17-beta-estradiol was given 3 months period to fish at different doses as followed: control group, Group 1: 10 mg/kg food, Group 2: 25 mg/kg food and Group 3: 50 mg/kg food. For this purpose, a solution of hormone in pure ethanol used to spray on food. Feeding was done 3 times daily as an appetite. Comparing the mean values measured for length and weight using ANOVA. Results: Indicated with increase length and weight, the effects of the hormone get more distinct, so that with increase concentration of hormone, reduce weight and length. Conclusions: Estradiol along with testosterone and progesterone regulates final stages of oocyte maturation and ovulation. Various studies have proven the different concentrations of this hormone has different effects on the growth of different fishes.

Efficient Transdermal Delivery of Benfotiamine in an Animal Model

OpenAIRE

Varadi, Gyula; Zhu, Zhen; G. Carter, Stephen

2015-01-01

We designed a transdermal system to serve as a delivery platform for benfotiamine utilizing the attributes of passive penetration enhancing molecules to penetrate through the outer layers of skin combined with the advance of incorporating various peripherally-acting vasodilators to enhance drug uptake.  Benfotiamine, incorporated into this transdermal formulation, was applied to skin in an animal model in order to determine the ability to deliver this thiamine pro-drug effectively to the sub-...

Nanoethosomal transdermal delivery of vardenafil for treatment of erectile dysfunction: optimization, characterization, and in vivo evaluation

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Fahmy UA

2015-11-01

Full Text Available Usama A Fahmy Department of Pharmaceutics & Industrial Pharmacy, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia Abstract: Vesicular drug delivery systems have recently gained attention as a way of improving dosing accuracy for drugs with poor transdermal permeation. The current study focuses on utilization of the natural biocompatible vesicles to formulate vardenafil nanoethosomes (VRD-NE, for the enhancement of their transdermal permeation and bioavailability. Fifteen formulations were prepared by thin-layer evaporation technique according to Box–Behnken design to optimize formulation variables. The effects of lipid composition, sonication time, and ethanol concentration on particle size and encapsulation efficiency were studied. The diffusion of vardenafil (VRD from the prepared nanoethosomes specified by the design was carried out using automated Franz diffusion cell apparatus. The optimized formula was investigated for in vivo pharmacokinetic parameters compared with oral VRD suspension. Confocal laser scanning microscopy images were used to confirm enhanced diffusion release of VRD in rat skin. The results showed that the optimized formula produced nanoethosomes with an average size of 128 nm and an entrapment efficiency of 76.23%. VRD-NE provided a significant improvement in permeation with an enhancement ratio of 3.05-fold for a film made with optimally formulated VRD-NE compared with a film made with VRD powder. The transdermal bioavailability of VRD from the nanoethosome film was approximately twofold higher than the oral bioavailability from an aqueous suspension. VRD-NE thus provide a promising transdermal drug delivery system. As a result, management of impotence for a longer duration could be achieved with a reduced dosage rate that improves patient tolerability and compliance for the treatment of erectile dysfunction.Keywords: Box–Behnken design, impotence, vesicles, nanoparticles

Development, characterization & invivo evaluation of proniosomal based transdermal delivery system of Atenolol

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S. Ramkanth

2018-06-01

Full Text Available The potential of proniosomes as a transdermal drug delivery system for Atenolol was investigated by encapsulating the drug in various formulations of proniosomal gel composed of various ratios of sorbitan fatty acid esters, cholesterol, lecithin prepared by Coacervation-phase separation method. The objectives of the present study were to define effects on the antihypertension activity and pharmacokinetics of a novel transdermal Proniosomal gel incorporating Atenolol. The formulated systems were characterized in vitro for size, drug entrapment, In vitro and in vivo drug permeation profiles and vesicular stability at different storage conditions. The optimized Atenolol proniosomes (AT8 showed nanometric vesicle size, high entrapment efficiency and marked enhancement in transdermal permeation. The prepared Proniosomal gel showed the relative bioavailability of 365.38 fold increased for AT8 than oral. The maximal concentrations (Cmax, of drug were significantly reduced while the areas under the plasma concentration–time curve (AUC, and mean residence times (MRT, t1/2 were evidently increased and extended, respectively. The results suggest that proniosomes can act as promising carrier which offers an alternative approach for transdermal delivery of Atenolol. Keywords: Proniosomes, Atenolol, Niosomes, Pharmacokinetic study, Transdermal delivery

Recent Advances in Skin Penetration Enhancers for Transdermal Gene and Drug Delivery.

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Amjadi, Morteza; Mostaghaci, Babak; Sitti, Metin

2017-01-01

There is a growing interest in transdermal delivery systems because of their noninvasive, targeted, and on-demand delivery of gene and drugs. However, efficient penetration of therapeutic compounds into the skin is still challenging largely due to the impermeability of the outermost layer of the skin, known as stratum corneum. Recently, there have been major research activities to enhance the skin penetration depth of pharmacological agents. This article reviews recent advances in the development of various strategies for skin penetration enhancement. We show that approaches such as ultrasound waves, laser, and microneedle patches have successfully been employed to physically disrupt the stratum corneum structure for enhanced transdermal delivery. Rather than physical approaches, several non-physical route have also been utilized for efficient transdermal delivery across the skin barrier. Finally, we discuss some clinical applications of transdermal delivery systems for gene and drug delivery. This paper shows that transdermal delivery devices can potentially function for diverse healthcare and medical applications while further investigations are still necessary for more efficient skin penetration of gene and drugs. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Transdermal carbamate poisoning – a case of misuse

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Lalit Kumar Rajbanshi

2017-01-01

Full Text Available Acute pesticide poisoning is a common mode of intentional self harm. Oral ingestion is the usual mode of poisoning. However, inhalation, accidental or occupational transdermal exposure leading to acute or chronic poisoning can be the other route of poisoning. It has been seen that the purpose of poising is suicidal intensity in most of the cases. We report an unusual case where the victim had acute pesticide poisoning through transdermal route that was intended for non suicidal purpose. The patient was managed successfully with immediate decontamination and adequate antidote.

Effects of estradiol and FSH on maturation of the testis in the hypogonadal (hpg mouse

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Mayhew Terry M

2008-01-01

Full Text Available Abstract Background The hypogonadal (hpg mouse is widely used as an animal model with which to investigate the endocrine regulation of spermatogenesis. Chronic treatment of these GnRH-deficient mice with estradiol is known to induce testicular maturation and restore qualitatively normal spermatogenesis. The aim of the current studies was to investigate whether these effects of estradiol are direct effects in the testis, or indirect actions via paradoxical stimulation of FSH secretion from the pituitary gland. Methods Initially, Western blot and immunohistochemistry were used to analyse tissues from hpg mice to identify potential sites of action of estradiol. In the main study, hpg mice were treated for 50 days with either an estradiol implant or daily injections of recombinant human FSH, or a combination of both, to determine whether estradiol would have an additive or synergistic effect with FSH on testis development, as assessed by histological analysis and stereological quantification of Leydig, Sertoli and germ cell proliferation. Results Western blot analysis revealed ERα immunoreactive bands of appropriate molecular weight in extracts of testis and pituitary glands from hpg mice, and immunohistochemical studies confirmed ERα in nuclei of anterior pituitary cells and Leydig and peritubular cells in hpg mice. Histological and morphometric analyses revealed that estradiol treatment alone was as effective as FSH in promoting Sertoli cell production and proliferation of the seminiferous epithelium, resulting in the production of elongating spermatids. Combined estradiol and FSH treatment did not produce a greater effect than either treatment alone, though an increased dose of FSH significantly increased seminiferous tubule volume and testis weight and increase Sertoli cell numbers further within the same time frame. In contrast, estradiol caused substantial increases in the wet weight of the seminal vesicles, whereas FSH was without effect on

Regenerated cellulose micro-nano fiber matrices for transdermal drug release

International Nuclear Information System (INIS)

Liu, Yue; Nguyen, Andrew; Allen, Alicia; Zoldan, Janet; Huang, Yuxiang; Chen, Jonathan Y.

2017-01-01

In this work, biobased fibrous membranes with micro- and nano-fibers are fabricated for use as drug delivery carries because of their biocompatibility, eco-friendly approach, and potential for scale-up. The cellulose micro-/nano-fiber (CMF) matrices were prepared by electrospinning of pulp in an ionic liquid, 1-butyl-3-methylimidazolium chloride. A model drug, ibuprofen (IBU), was loaded on the CMF matrices by a simple immersing method. The amount of IBU loading was about 6% based on the weight of cellulose membrane. The IBU-loaded CMF matrices were characterized by Fourier-transform infrared spectroscopy, thermal gravimetric analysis, and scanning electron microscopy. The test of ibuprofen release was carried out in an acetate buffer solution of pH 5.5 and examined by UV–Vis spectroscopy. Release profiles from the CMF matrices indicated that the drug release rate could be determined by a Fickian diffusion mechanism. - Highlights: • Cellulose micro-nano fiber matrix was prepared by dry-wet electrospinning. • Ibuprofen was loaded on the matrix by a simple immersing method. • The drug loaded matrix showed a biphasic release profile. • The drug release was determined by a Fickian diffusion mechanism.

Regenerated cellulose micro-nano fiber matrices for transdermal drug release

Energy Technology Data Exchange (ETDEWEB)

Liu, Yue [School of Human Ecology, The University of Texas at Austin, Austin, TX (United States); Department of Chemistry, School of Science, Tianjin University, Tianjin (China); Nguyen, Andrew; Allen, Alicia; Zoldan, Janet [Department of Biomedical Engineering, The University of Texas at Austin, Austin, TX (United States); Huang, Yuxiang [School of Human Ecology, The University of Texas at Austin, Austin, TX (United States); Chen, Jonathan Y., E-mail: jychen2@austin.utexas.edu [School of Human Ecology, The University of Texas at Austin, Austin, TX (United States)

2017-05-01

In this work, biobased fibrous membranes with micro- and nano-fibers are fabricated for use as drug delivery carries because of their biocompatibility, eco-friendly approach, and potential for scale-up. The cellulose micro-/nano-fiber (CMF) matrices were prepared by electrospinning of pulp in an ionic liquid, 1-butyl-3-methylimidazolium chloride. A model drug, ibuprofen (IBU), was loaded on the CMF matrices by a simple immersing method. The amount of IBU loading was about 6% based on the weight of cellulose membrane. The IBU-loaded CMF matrices were characterized by Fourier-transform infrared spectroscopy, thermal gravimetric analysis, and scanning electron microscopy. The test of ibuprofen release was carried out in an acetate buffer solution of pH 5.5 and examined by UV–Vis spectroscopy. Release profiles from the CMF matrices indicated that the drug release rate could be determined by a Fickian diffusion mechanism. - Highlights: • Cellulose micro-nano fiber matrix was prepared by dry-wet electrospinning. • Ibuprofen was loaded on the matrix by a simple immersing method. • The drug loaded matrix showed a biphasic release profile. • The drug release was determined by a Fickian diffusion mechanism.

Radionuclide decorporation: matching the biokinetics of actinides by transdermal delivery of pro-chelators.

Science.gov (United States)

Zhang, Yong; Sadgrove, Matthew P; Mumper, Russell J; Jay, Michael

2013-10-01

The threat of nuclear terrorism by the deliberate detonation of a nuclear weapon or radiological dispersion device ("dirty bomb") has made emergency response planning a priority. The only FDA-approved treatments for contamination with isotopes of the transuranic elements Am, Pu, and Cm are the Ca and Zn salts of diethylenetriaminepentaacetic acid (DTPA). These injectable products are not well suited for use in a mass contamination scenario as they require skilled professionals for their administration and are rapidly cleared from the circulation. To overcome the mismatch in the pharmacokinetics of the DTPA and the biokinetics of these transuranic elements, which are slowly released from contamination sites, the penta-ethyl ester of DTPA (C2E5) was prepared and formulated in a nonaqueous gel for transdermal administration. When gels comprised of 40% C2E5, 40-45% Miglyol® 840, and 15-20% ethyl cellulose were spiked with [(14)C]-C2E5 and applied to rat skin; over 60% of the applied dose was absorbed within a 24-h period. Radioactivity was observed in urinary and fecal excretions for over 3 days after removal of the gel. Using an (241)Am wound contamination model, transdermal C2E5 gels were able to enhance total body elimination and reduce the liver and skeletal burden of (241)Am in a dose-dependent manner. The efficacy achieved by a single 1,000 mg/kg dose to contaminated rats was statistically comparable to intravenous Ca-DTPA at 14 mg/kg. The effectiveness of this treatment, favorable sustained release profile of pro-chelators, and ease of administration support its use following radiological emergencies and for its inclusion in the Strategic National Stockpile.

Monte Carlo simulations of the dose from imaging with GE eXplore 120 micro-CT using GATE

Energy Technology Data Exchange (ETDEWEB)

Bretin, Florian; Bahri, Mohamed Ali; Luxen, André; Phillips, Christophe; Plenevaux, Alain; Seret, Alain, E-mail: aseret@ulg.ac.be [Cyclotron Research Centre, University of Liège, Sart Tilman B30, Liège 4000 (Belgium)

2015-10-15

Purpose: Small animals are increasingly used as translational models in preclinical imaging studies involving microCT, during which the subjects can be exposed to large amounts of radiation. While the radiation levels are generally sublethal, studies have shown that low-level radiation can change physiological parameters in mice. In order to rule out any influence of radiation on the outcome of such experiments, or resulting deterministic effects in the subjects, the levels of radiation involved need to be addressed. The aim of this study was to investigate the radiation dose delivered by the GE eXplore 120 microCT non-invasively using Monte Carlo simulations in GATE and to compare results to previously obtained experimental values. Methods: Tungsten X-ray spectra were simulated at 70, 80, and 97 kVp using an analytical tool and their half-value layers were simulated for spectra validation against experimentally measured values of the physical X-ray tube. A Monte Carlo model of the microCT system was set up and four protocols that are regularly applied to live animal scanning were implemented. The computed tomography dose index (CTDI) inside a PMMA phantom was derived and multiple field of view acquisitions were simulated using the PMMA phantom, a representative mouse and rat. Results: Simulated half-value layers agreed with experimentally obtained results within a 7% error window. The CTDI ranged from 20 to 56 mGy and closely matched experimental values. Derived organ doses in mice reached 459 mGy in bones and up to 200 mGy in soft tissue organs using the highest energy protocol. Dose levels in rats were lower due to the increased mass of the animal compared to mice. The uncertainty of all dose simulations was below 14%. Conclusions: Monte Carlo simulations proved a valuable tool to investigate the 3D dose distribution in animals from microCT. Small animals, especially mice (due to their small volume), receive large amounts of radiation from the GE eXplore 120

Contraception containing estradiol valerate and dienogest--advantages, adherence and user satisfaction.

Science.gov (United States)

Graziottin, A

2014-10-01

The contraceptive pill containing estradiol valerate and dienogest meets women's requests for: a more natural contraceptive, that is reliable and easy to use, with positive cosmetic effects; less intense and shorter bleeding, reduced anaemia and increased vital energy; reduced dysmenorrhoea and all the specific cycle-related symptoms linked to a drop in oestrogen and the related systemic inflammation, the result of a hormone free interval (HFI) of just two days; with a good impact on sexuality and overall well-being, all associated with a high level of efficacy: (uncorrected Pearl Index: 0.79; corrected: 0.42). Women would prefer more natural hormonal contraception, with high reliability, good tolerability, a simple dosing schedule and possibly some health advantages. To evaluate what the pill containing estradiol valerate and dienogest can offer women and the best way to communicate this opportunity, after 4 years of growing clinical use. A review of literature plus the Author's clinical experience. The new pill containing estradiol valerate and dienogest may satisfy women's need for: a more natural hormonal contraceptive with a low hormone dosage, high reliability and good tolerability; a simple dosing schedule (one pill per day for 28 days); a positive cosmetic effect on the skin; lighter and shorter withdrawal bleeding, improved anaemia, less fatigue and higher vital energy; reduced dysmenorrhoea and a dramatic reduction in all symptoms thanks to a shorter Hormone Free Interval (HFI) of just two days. The new pill is an option for all women taking hormonal contraception who would like a more natural choice; for those who have never used hormonal contraception and may consider this new opportunity positively, for those who suffer from various menstrual symptoms, related inflammation ("a shorter HFI means much fewer or no symptoms") and, possibly for pre-menopausal women, an opportunity to combine excellent contraception with a definite improvement in their well

Transdermal Delivery of Drugs with Microneedles—Potential and Challenges

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Kevin Ita

2015-06-01

Full Text Available Transdermal drug delivery offers a number of advantages including improved patient compliance, sustained release, avoidance of gastric irritation, as well as elimination of pre-systemic first-pass effect. However, only few medications can be delivered through the transdermal route in therapeutic amounts. Microneedles can be used to enhance transdermal drug delivery. In this review, different types of microneedles are described and their methods of fabrication highlighted. Microneedles can be fabricated in different forms: hollow, solid, and dissolving. There are also hydrogel-forming microneedles. A special attention is paid to hydrogel-forming microneedles. These are innovative microneedles which do not contain drugs but imbibe interstitial fluid to form continuous conduits between dermal microcirculation and an attached patch-type reservoir. Several microneedles approved by regulatory authorities for clinical use are also examined. The last part of this review discusses concerns and challenges regarding microneedle use.

Enhanced Transdermal Delivery by Combined Application of Dissolving Microneedle Patch on Serum-Treated Skin.

Science.gov (United States)

Kim, Suyong; Dangol, Manita; Kang, Geonwoo; Lahiji, Shayan F; Yang, Huisuk; Jang, Mingyu; Ma, Yonghao; Li, Chengguo; Lee, Sang Gon; Kim, Chang Hyun; Choi, Young Wook; Kim, So Jeong; Ryu, Ja Hyun; Baek, Ji Hwoon; Koh, Jaesuk; Jung, Hyungil

2017-06-05

Dissolving microneedle (DMN), a transdermal drug delivery system in which drugs are encapsulated in a biodegradable polymeric microstructure, is designed to dissolve after skin penetration and release the encapsulated drugs into the body. However, because of limited loading capacity of drugs within microsized structures, only a small dosage can be delivered, which is often insufficient for patients. We propose a novel DMN application that combines topical and DMN application simultaneously to improve skin permeation efficiency. Drugs in pretreated topical formulation and encapsulated drugs in DMN patch are delivered into the skin through microchannels created by DMN application, thus greatly increasing the delivered dose. We used 4-n-butylresorcinol to treat human hyperpigmentation and found that sequential application of serum formulation and DMNs was successful. In skin distribution experiments using Alexa Fluor 488 and 568 dyes as model drugs, we confirmed that the pretreated serum formulation was delivered into the skin through microchannels created by the DMNs. In vitro skin permeation and retention experiments confirmed that this novel combined application delivered more 4-n-butylresorcinol into the skin than traditional DMN-only and serum-only applications. Moreover, this combined application showed a higher efficacy in reducing patients' melanin index and hyperpigmented regions compared with the serum-only application. As combined application of DMNs on serum-treated skin can overcome both dose limitations and safety concerns, this novel approach can advance developments in transdermal drug delivery.

Development and evaluation of transdermal organogels containing nicorandil.

Science.gov (United States)

Madan, J R; Sagar, Banode; Chellappan, Dinesh K; Dua, Kamal

2013-01-01

The objective of the study was to formulate a transdermal product containing Nicorandil as a model drug, because it has been first drug of choice to treat angina and hypertension. A further objective was to reduce its side effects. The transdermal product was prepared using various synthetic and natural gelling agents such as Carbopol 934p, Carbopol 974p, HPMC K15M and HPMC K100M. Various penetration enhancers were incorporated to enhance the diffusion across the rat skin. A further objective was to formulate organogels and minimize the concentration of penetration enhancer to 50% of the concentration used in gels and yet to achieve the maximum drug release. The prepared formulations were evaluated for their physical appearance, viscosity, spreadability, drug content and freeze thaw cycle. Based on in vitro studies across rat skin and human cadaver skin it was concluded that Nicrorandil transdermal organogel formulation using HPMC K100M with 2% w/w Transcutol-P shows increase in cumulative diffusion of Nicorandil amongst all other formulations.

Transdermal Spray in Hormone Delivery

African Journals Online (AJOL)

market for the delivery system and ongoing development of transdermal sprays for hormone ... (DOAJ), African Journal Online, Bioline International, Open-J-Gate and Pharmacy Abstracts ... patches and gels have been very popular owing ... This product was developed for ... In a safety announcement, the US Food and.

Behavioral effects of endogenous or exogenous estradiol and progesterone on cocaine sensitization in female rats

Directory of Open Access Journals (Sweden)

M.F. Souza

2014-06-01

Full Text Available Cocaine sensitization is a marker for some facets of addiction, is greater in female rats, and may be influenced by their sex hormones. We compared the modulatory effects of endogenous or exogenous estradiol and progesterone on cocaine-induced behavioral sensitization in 106 female rats. Ovariectomized female rats received progesterone (0.5 mg/mL, estradiol (0.05 mg/mL, progesterone plus estradiol, or the oil vehicle. Sham-operated control females received oil. Control and acute subgroups received injections of saline, while the repeated group received cocaine (15 mg/kg, ip for 8 days. After 10 days, the acute and repeated groups received a challenge dose of cocaine, after which locomotion and stereotypy were monitored. The estrous cycle phase was evaluated and blood was collected to verify hormone levels. Repeated cocaine treatment induced overall behavioral sensitization in female rats, with increased locomotion and stereotypies. In detailed analysis, ovariectomized rats showed no locomotor sensitization; however, the sensitization of stereotypies was maintained. Only females with endogenous estradiol and progesterone demonstrated increased locomotor activity after cocaine challenge. Estradiol replacement enhanced stereotyped behaviors after repeated cocaine administration. Cocaine sensitization of stereotyped behaviors in female rats was reduced after progesterone replacement, either alone or concomitant with estradiol. The behavioral responses (locomotion and stereotypy to cocaine were affected differently, depending on whether the female hormones were of an endogenous or exogenous origin. Therefore, hormonal cycling appears to be an important factor in the sensitization of females. Although estradiol increases the risk of cocaine sensitization, progesterone warrants further study as a pharmacological treatment in the prevention of psychostimulant abuse.

Effect of sub-optimal doses of fluoxetine plus estradiol on antidepressant-like behavior and hippocampal neurogenesis in ovariectomized rats.

Science.gov (United States)

Vega-Rivera, Nelly M; Fernández-Guasti, Alonso; Ramírez-Rodríguez, Gerardo; Estrada-Camarena, Erika

2015-07-01

Estrogens and antidepressants synergize to reduce depressive symptoms and stimulate neurogenesis and neuroplastic events. The aim of this study was to explore whether the antidepressant-like effect induced by the combination of low doses of estradiol (E2) and fluoxetine (FLX) involves changes in cell proliferation, early survival, morphology and dendrite complexity of hippocampal new-immature neurons. The antidepressant-like effects of E2 and/or FLX were evaluated by the forced swimming test (FST), cell proliferation was determined with the endogenous marker Ki67, survival of newborn cells was established with bromo-deoxiuridine (BrdU) and immature neurons were ascertained by doublecortin (DCX) labeling while their dendrite complexity was evaluated with Sholl analysis. Ovariectomized Wistar rats were randomly assigned to one of the following groups: Vehicle (saline/14 days+Oil/-8h before FST); E2 (saline/14 days + E2 2.5 or 10 μg/rat; -8 h before FST); FLX (1.25 or 10 mg/kg for 14 days + oil -8h before FST), and FLX plus E2 (FLX 1.25 mg/kg for 14 days + E2 2.5 μg/rat -8 h before FST). The combination of sub-threshold doses of FLX plus E2 produced antidepressant-like actions similar to those induced by FLX or E2 given independently at optimal doses. Only FLX at an optimal dose and the combination of FLX plus E2 increased cell proliferation, the number of DCX-labeled immature neurons and the complexity of their dendritic tree, suggesting that these events may be responsible for their antidepressant-like effect. Copyright © 2015 Elsevier Ltd. All rights reserved.

Effects of Sizes and Conformations of Fish-Scale Collagen Peptides on Facial Skin Qualities and Transdermal Penetration Efficiency

Directory of Open Access Journals (Sweden)

Huey-Jine Chai

2010-01-01

Full Text Available Fish-scale collagen peptides (FSCPs were prepared using a given combination of proteases to hydrolyze tilapia (Oreochromis sp. scales. FSCPs were determined to stimulate fibroblast cells proliferation and procollagen synthesis in a time- and dose-dependent manner. The transdermal penetration capabilities of the fractionationed FSCPs were evaluated using the Franz-type diffusion cell model. The heavier FSCPs, 3500 and 4500 Da, showed higher cumulative penetration capability as opposed to the lighter FSCPs, 2000 and 1300 Da. In addition, the heavier seemed to preserve favorable coiled structures comparing to the lighter that presents mainly as linear under confocal scanning laser microscopy. FSCPs, particularly the heavier, were concluded to efficiently penetrate stratum corneum to epidermis and dermis, activate fibroblasts, and accelerate collagen synthesis. The heavier outweighs the lighter in transdermal penetration likely as a result of preserving the given desired structure feature.

Dissolving polymeric microneedle arrays for electrically assisted transdermal drug delivery.

Science.gov (United States)

Garland, Martin J; Caffarel-Salvador, Ester; Migalska, Katarzyna; Woolfson, A David; Donnelly, Ryan F

2012-04-10

It has recently been proposed that the combination of skin barrier impairment using microneedles (MNs) coupled with iontophoresis (ITP) may broaden the range of drugs suitable for transdermal delivery, as well as enabling the rate of delivery to be achieved with precise electronic control. However, no reports exist on the combination of ITP with in situ drug loaded polymeric MN delivery systems. Furthermore, although a number of studies have highlighted the importance of MN design for transdermal drug delivery enhancement, to date, there has been no systematic investigation of the influence of MN geometry on the performance of polymeric MN arrays which are designed to remain in contact with the skin during the period of drug delivery. As such, for the first time, this study reports on the effect of MN heigth and MN density upon the transdermal delivery of small hydrophilic compounds (theophylline, methylene blue, and fluorescein sodium) across neonatal porcine skin in vitro, with the optimised MN array design evaluated for its potential in the electrically faciliatated delivery of peptide (bovine insulin) and protein (fluorescein isothiocyanate-labelled bovine serum albumin (FTIC-BSA)) macromolecules. The results of the in vitro drug release investigations revealed that the extent of transdermal delivery was dependent upon the design of the MN array employed, whereby an increase in MN height and an increase in MN density led to an increase in the extent of transdermal drug delivery achieved 6h after MN application. Overall, the in vitro permeation studies revealed that the MN design containing 361 MNs/cm(2) of 600 μm height resulted in the greatest extent of transdermal drug delivery. As such, this design was evaluated for its potential in the MN mediated iontophoretic transdermal delivery. Whilst the combination of MN and ITP did not further enhance the extent of small molecular weight solute delivery, the extent of peptide/protein release was significantly

Effects of Sizes and Conformations of Fish-Scale Collagen Peptides on Facial Skin Qualities and Transdermal Penetration Efficiency

OpenAIRE

Chai, Huey-Jine; Li, Jing-Hua; Huang, Han-Ning; Li, Tsung-Lin; Chan, Yi-Lin; Shiau, Chyuan-Yuan; Wu, Chang-Jer

2010-01-01

Fish-scale collagen peptides (FSCPs) were prepared using a given combination of proteases to hydrolyze tilapia (Oreochromis sp.) scales. FSCPs were determined to stimulate fibroblast cells proliferation and procollagen synthesis in a time- and dose-dependent manner. The transdermal penetration capabilities of the fractionationed FSCPs were evaluated using the Franz-type diffusion cell model. The heavier FSCPs, 3500 and 4500?Da, showed higher cumulative penetration capability as opposed to the...

Conductive polymer nanotube patch for fast and controlled ex vivo transdermal drug delivery.

Science.gov (United States)

Nguyen, Thao M; Lee, Sebin; Lee, Sang Bok

2014-10-01

To uptake and release hydrophilic model drugs and insulin in a novel conductive polymer (CP) nanotube transdermal patch. The externally controlled transdermal delivery of model drugs and insulin were tested ex vivo and results were compared with CP films. The unique intrinsic properties of CPs provide electrostatic interaction between the model drugs and polymer backbone. When a pulsed potential was applied, the drug delivery release profile mimics that of injection delivery. With a constant potential applied, the release rate constants of the patch system were up to three-times faster than the control (0 V) and released approximately 80% more drug molecules over 24 h. The CP nanotube transdermal patch represents a new and promising drug method, specifically for hydrophilic molecules, which have been a large obstacle for conventional transdermal drug delivery systems.

Estradiol modulates the anorexic response to central glucagon-like peptide 1.

Science.gov (United States)

Maske, Calyn B; Jackson, Christine M; Terrill, Sarah J; Eckel, Lisa A; Williams, Diana L

2017-07-01

Estrogens suppress feeding in part by enhancing the response to satiation signals. Glucagon-like peptide 1 (GLP-1) acts on receptor populations both peripherally and centrally to affect food intake. We hypothesized that modulation of the central GLP-1 system is one of the mechanisms underlying the effects of estrogens on feeding. We assessed the anorexic effect of 0, 1, and 10μg doses of GLP-1 administered into the lateral ventricle of bilaterally ovariectomized (OVX) female rats on a cyclic regimen of either 2μg β-estradiol-3-benzoate (EB) or oil vehicle 30min prior to dark onset on the day following hormone treatment. Central GLP-1 treatment significantly suppressed food intake in EB-treated rats at both doses compared to vehicle, whereas only the 10μg GLP-1 dose was effective in oil-treated rats. To follow up, we examined whether physiologic-dose cyclic estradiol treatment influences GLP-1-induced c-Fos in feeding-relevant brain areas of OVX females. GLP-1 significantly increased c-Fos expression in the area postrema (AP) and nucleus of the solitary tract (NTS), and the presence of estrogens may be required for this effect in the paraventricular nucleus of the hypothalamus (PVN). Together, these data suggest that modulation of the central GLP-1 system may be one of the mechanisms by which estrogens suppress food intake, and highlight the PVN as a region of interest for future investigation. Copyright © 2017 Elsevier Inc. All rights reserved.

Rhodamine B triggers ovarian toxicity through oxidative stress, decreases in the number of follicles, 17B-estradiol level, and thickness of endometrium

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Syiska Atik Maryanti

2014-06-01

Full Text Available Objective: The purpose of this study was to analyze the effects of exposure to rhodamine B on ovarian oxidative stress, ovarian follicles, hormone 17beta-estradiol and thickness of endometrium. Methods: A total of 28 female rats were divided into four groups consisting of control; groups treated with rhodamine B at doses of 4.5; 9, and 18 milligram/200 gram body weight. Rhodamine B was administered orally for 36 days with the probe. Analysis of MDA level was done spectrophotometrically. Analysis of the number of ovarian follicles and thickness of endometrium was done histopathologically by hematoxylin eosin staining. Analysis of 17-estradiol level was done by ELISA. Results: Rhodamine B administered in different doses in female rats can increase ovarian MDA levels significantly than the control (P 0.05. Administration of rhodamine B of the second and third doses in female rats can reduce the number of primary, secondary, and De Graaf follicles significantly compared to the control (P 0.05. Administration of rhodamine B of the second and third doses in female rats can reduce 17-estradiol level significantly compared to the control (P 0.05. The administration of rhodamine B could reduce thickness of endometrium significantly compared to the control (P 0.05. Conclusion: It was concluded that administration of rhodamine B triggered ovarian toxicity through oxidative stress, a decrease in the number of follicles, and decreased level of 17-estradiol which ultimately lowered the thickness of endometrium. [Cukurova Med J 2014; 39(3.000: 451-457

[The influence of estradiol on histomorphology of skin flaps with ischemia reperfusion injury].

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Jianlong, Wu; Ruixing, Hou; Guangliang, Zhou; Jihui, Ju

2015-09-01

To study the influence of estradiol on histomorphology of skin flaps with ischemia reperfusion injury. 48 adult male Wistar rats aged 12-14 weeks old, were randomly divided into control group (group I), ischemia-reperfusion group (group II), saline group (group III), estradiol group (group IV). Superficial epigastric artery axial flap, 3 cm x 6 cm in size, was made in the left lower quadrant abdominal of each rat. Flap model with ischemia-reperfusion injury was established by using the nondestructive micro vascular clamp to clamp the superficial epigastric artery. The general condition of the flap was observed after operation. At 7 days after operation, the survival rate of the flap was detected, the flaps were harvested to receive histology and ultrastructural observation. The neutrophils level of the superficial epigastric vein were tested. 7 days after operation, the survival rate of the flap in group IV was significantly higher than that in group II, III (P organization structure in flap.

Transferosomes - A vesicular transdermal delivery system for enhanced drug permeation

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Reshmy Rajan

2011-01-01

Full Text Available Transdermal administration of drugs is generally limited by the barrier function of the skin. Vesicular systems are one of the most controversial methods for transdermal delivery of active substances. The interest in designing transdermal delivery systems was relaunched after the discovery of elastic vesicles like transferosomes, ethosomes, cubosomes, phytosomes, etc. This paper presents the composition, mechanisms of penetration, manufacturing and characterization methods of transferosomes as transdermal delivery systems of active substances. For a drug to be absorbed and distributed into organs and tissues and eliminated from the body, it must pass through one or more biological membranes/barriers at various locations. Such a movement of drug across the membrane is called as drug transport. For the drugs to be delivered to the body, they should cross the membranous barrier. The concept of these delivery systems was designed in an attempt to concentrate the drug in the tissues of interest, while reducing the amount of drug in the remaining tissues. Hence, surrounding tissues are not affected by the drug. In addition, loss of drug does not happen due to localization of drug, leading to get maximum efficacy of the medication. Therefore, the phospholipid based carrier systems are of considerable interest in this era.

The effect of 17β-estradiol on gene expression of calcitonin gene-related peptide and some pro-inflammatory mediators in peripheral blood mononuclear cells from patients with pure menstrual migraine

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Azam Karkhaneh

2015-09-01

Results:Treatment with 17β-estradiol had a biphasic effect on expression of CGRP. We found that 17β-estradiol treatment at pharmacological dose significantly increases mRNA expression of CGRP in both groups (P

Radiosensitization dependent on p53 function in bronchial carcinoma cells by the isoflavone genistein and estradiol in vitro

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Hermann, R.M.; Fest, J.; Christiansen, H.; Hille, A.; Rave-Fraenk, M.; Nitsche, M.; Gruendker, C.; Viereck, V.; Jarry, H.; Schmidberger, H.

2007-01-01

Background and Purpose: Simultaneous radiotherapy with chemotherapy is a standard treatment for inoperable non-small cell lung cancer (NSCLC), but the clinical outcome still remains poor. To further intensify treatment, substances need to be identified, which increase the effect of radiation on tumor cells without further enhancing toxicity to normal tissue. Hormones have a different toxicity profile than radiation or cytostatic drugs. As NSCLC often express estrogen receptors (ERs), the combination of genistein or estradiol and radiation in vitro was investigated. Material and Methods: A549 NSCLC cells with an inducible expression of a mutated TP53 and fibroblasts of a male donor (DF-18) were examined. ER expression was immunocytologically confirmed in all studied cell lines. Clonogenic survival was measured after incubation of the cells with genistein or estradiol (0.01 μM and 10 μM as maximum clinically applicable dose) and irradiation with different doses (0-4 Gy). The differentiation state of fibroblasts after combined therapy was analyzed. Results: A549 cells expressing mutated TP53 were more radioresistant than TP53 wild-type cells. Incubation of nonfunctional TP53 cells with genistein or estradiol increased radiosensitivity in both tested concentrations. By contrast, radiosensitivity of A549 with wild-type TP53 and DF-18 was not altered by hormonal incubation. In DF-18 radiation induced growth arrest that was not increased by additional hormonal incubation. Conclusion: NSCLC cells with nonfunctional TP53 might be sensitized against radiation by genistein or estradiol. As genistein is better tolerable than estradiol in patients, additional studies are warranted to assess potential gains of this combination therapy

Development and evaluation of polymer nanoparticles for oral delivery of estradiol to rat brain in a model of Alzheimer's pathology.

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Mittal, G; Carswell, H; Brett, R; Currie, S; Kumar, M N V Ravi

2011-03-10

The purpose of this study was to develop tween 80 (T-80) coated polylactide-co-glycolide (PLGA) nanoparticles that can deliver estradiol to the brain upon oral administration. Estradiol containing nanoparticles were made by a single emulsion technique and T-80 coating was achieved by incubating the re-constituted nanoparticles at different concentrations of T-80. The process of T-80 coating on the nanoparticles was optimized and the pharmacokinetics of estradiol nanoparticles was studied as a function of T-80 coating. The nanoparticles were then evaluated in an ovariectomized (OVX) rat model of Alzheimer's disease (AD) that mimics the postmenopausal conditions. The nanoparticles bound T-80 were found to proportionally increase from 9.72 ± 1.07 mg to 63.84 ± 3.59 mg with an increase in the initial concentration T-80 from 1% to 5% and were stable in simulated gastric fluid (SGF) and simulated intestinal fluid (SIF). Orally administered T-80 coated nanoparticles resulted in significantly higher brain estradiol levels after 24h (1.969 ± 0.197 ng/g tissue) as compared to uncoated ones (1.105 ± 0.136 ng/g tissue) at a dose of 0.2mg/rat, suggesting a significant role of surface coating. Moreover, these brain estradiol levels were almost similar to those obtained after administration of the same dose of drug suspension via 100% bioavailable intramuscular route (2.123 ± 0.370 ng/g tissue), indicating the increased fraction of bioavailable drug reaching the brain when administered orally. Also, the nanoparticle treated group was successful in preventing the expression of amyloid beta-42 (Aβ42) immunoreactivity in the hippocampus region of brain. Together, the results indicate the potential of nanoparticles for oral delivery of estradiol to brain. Copyright © 2010 Elsevier B.V. All rights reserved.

Transdermal granisetron: a guide to its use in preventing nausea and vomiting induced by chemotherapy.

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Keating, Gillian M; Duggan, Sean T; Curran, Monique P

2012-09-01

Transdermal granisetron (Sancuso®) is effective in the prevention of nausea and vomiting in patients with cancer who are receiving moderately or highly emetogenic chemotherapy for 3-5 days. Transdermal granisetron is noninferior to oral granisetron in this indication, and is generally well tolerated in this indication. Thus, transdermal granisetron provides a convenient option for the prevention of chemotherapy-induced nausea and vomiting, with the potential to improve patient compliance.

Low dose bisphenol S or ethinyl estradiol exposures during the perinatal period alter female mouse mammary gland development.

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Kolla, SriDurgaDevi; Morcos, Mary; Martin, Brian; Vandenberg, Laura N

2018-03-08

Throughout life, mammary tissue is strongly influenced by hormones. Scientists have hypothesized that synthetic chemicals with hormonal activities could disrupt mammary gland development and contribute to breast diseases and dysfunction. Bisphenol S (BPS) is an estrogenic compound used in many consumer products. In this study, CD-1 mice were exposed to BPS (2 or 200 μg/kg/day) during pregnancy and lactation. Mice exposed to 0.01 or 1 μg/kg/day ethinyl estradiol (EE2), a pharmaceutical estrogen, were also evaluated. Mammary glands from female offspring were collected prior to the onset of puberty, during puberty, and in early adulthood. Growth parameters, histopathology, cell proliferation and expression of hormone receptors were quantified. Our evaluations revealed age- and dose-specific effects of BPS that were different from the effects of EE2, and distinct from the effects of BPA that have been reported previously. These assessments suggest that individual xenoestrogens may have unique effects on this sensitive tissue. Copyright © 2018 Elsevier Inc. All rights reserved.

Transdermal optogenetic peripheral nerve stimulation

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Maimon, Benjamin E.; Zorzos, Anthony N.; Bendell, Rhys; Harding, Alexander; Fahmi, Mina; Srinivasan, Shriya; Calvaresi, Peter; Herr, Hugh M.

2017-06-01

Objective: A fundamental limitation in both the scientific utility and clinical translation of peripheral nerve optogenetic technologies is the optical inaccessibility of the target nerve due to the significant scattering and absorption of light in biological tissues. To date, illuminating deep nerve targets has required implantable optical sources, including fiber-optic and LED-based systems, both of which have significant drawbacks. Approach: Here we report an alternative approach involving transdermal illumination. Utilizing an intramuscular injection of ultra-high concentration AAV6-hSyn-ChR2-EYFP in rats. Main results: We demonstrate transdermal stimulation of motor nerves at 4.4 mm and 1.9 mm depth with an incident laser power of 160 mW and 10 mW, respectively. Furthermore, we employ this technique to accurately control ankle position by modulating laser power or position on the skin surface. Significance: These results have the potential to enable future scientific optogenetic studies of pathologies implicated in the peripheral nervous system for awake, freely-moving animals, as well as a basis for future clinical studies.

Study on Coagulant Dosing Control System of Micro Vortex Water Treatment

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Fengping, Hu; Qi, Fan; Wenjie, Hu; Xizhen, He; Hongling, Dai

2018-03-01

In view of the characteristics of nonlinearity, large time delay and multi disturbance in the process of coagulant dosing in water treatment, it is difficult to control the dosage of coagulant. According to the four indexes of raw water quality parameters (raw water flow, turbidity, pH value) and turbidity of sedimentation tank, the micro vortex coagulation dosing control model is constructed based on BP neural network and GA. The forecast results of BP neural network model are ideal, and after the optimization of GA, the prediction accuracy of the model is partly improved. The prediction error of the optimized network is ±0.5 mg/L, and has a better performance than non-optimized network.

Comparative enhancing effects of electret with chemical enhancers on transdermal delivery of meloxicam in vitro

International Nuclear Information System (INIS)

Cui, L L; Hou, X M; Li, G D; Jiang, J; Liang, Y Y; Xin, X

2008-01-01

Electret offers enhancing effect in transdermal drug delivery for altering of the arrangement of lipid molecules in the stratum corneum, forming many transient permeable apertures and enhancing the transdermal drug delivery. In this paper, meloxicam patch formulations were developed to make the comparative study of transdermal drug delivery between electret and chemical enhancers. Patches were made into control, electret, chemical enhancer and electret with chemical enhancer ones, according to the preparation procedure. The electret combined with chemical enhancer patch was designed to probe the incorporation between electret and chemical enhancer in transdermal drug delivery. The meloxicam release from the patch was found to increase in order of blank, chemical enhancer, electret and electret with chemical enhancer patch, in general.

MICRONEEDLES AS A WAY TO INCREASE THE TRANSDERMAL INSULIN DELIVERY

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E. G. Kuznetsova

2016-01-01

Full Text Available Aim: to prove the possibility of increasing the diffusion of insulin through the skin in vitro with pre-applying microneedles.Materials and methods. Microemulsion for transdermal therapeutic system of insulin has been used in vitro studies. Genetically engineered human insulin has been used in this research. Applicators with silicon microneedles (40 and 150 microns long have been used to enhance the diffusion fl ux of drug substance. The dynamics of insulin release from the transdermal therapeutic systems through the rabbit skin has been studied in glass Franz diffusion cells in analyzer diffusion of drugs HDT 1000 (Copley Scientifi c Ltd., UK. Insulin has been labeled with fl uorescein isothiocyanate to separate the insulin absorption spectrum from the spectra of native skin proteins at spectrophotometer measurements.Results. The amounts of insulin delivered through the skin in vitro after previous application of microneedles of 40 and 150 microns are 282.5 ± 61.1 and 372.3 ± 7.0 microgram, respectively. This is 1.4 and 1.9 times more than in the transdermal system without microneedles.Conclusion. The conditions for increasing the diffusion of insulin through the skin in a model transdermal therapeutic system with microneedles (length – 150 microns, duration of pre-application – 1 hour have been found.

Laminated chemical and physical micro-jet actuators based on conductive media

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Gadiraju, Priya D.

2008-04-01

This dissertation presents the development of electrically-powered, lamination-based microactuators for the realization of large arrays of high impulse and short duration micro-jets with potential applications in the field of micro-electro-mechanical systems (MEMS). Microactuators offer unique control opportunities by converting the input electrical or chemical energy stored in a propellant into useful mechanical energy. This small and precise control obtained can potentially be applied towards aerodynamic control and transdermal drug delivery applications. This thesis work discusses the feasibility of using microactuators for two such applications: Control of the motion of a spinning projectile by utilizing the chemically-driven microjets ejected from the actuators, and enhancement of the permeability properties of skin by selectively ablating the stratum corneum layer of skin using the physical microjets ejected from the actuators. This enhanced permeability of skin can later be used for the delivery of high molecular weight drugs for transdermal drug delivery. The development of electrically powered microactuators starts by fabricating an array of radially firing microactuators using lamination-based microfabrication techniques that potentially enable batch fabrication at low cost. The microactuators of this thesis consist of three main parts: a micro chamber in which the propellant is stored; two electrode structures through which electrical energy is supplied to the propellant; and a micro nozzle through which the propellant or released gases from the propellant are expanded as a jet. Once the actuators are fabricated, they are integrated with MEMS-process-compatible propellants and optimized so as to produce instantaneous ignition of the propellant. This instantaneous ignition is achieved either by making the propellant itself conductive, thus, passing an electric current directly through the propellant; or by discharging an arc across the propellant by

Estradiol upregulates voltage-gated sodium channel 1.7 in trigeminal ganglion contributing to hyperalgesia of inflamed TMJ.

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Rui-Yun Bi

Full Text Available Temporomandibular disorders (TMDs have the highest prevalence in women of reproductive age. The role of estrogen in TMDs and especially in TMDs related pain is not fully elucidated. Voltage-gated sodium channel 1.7 (Nav1.7 plays a prominent role in pain perception and Nav1.7 in trigeminal ganglion (TG is involved in the hyperalgesia of inflamed Temporomandibular joint (TMJ. Whether estrogen could upregulate trigeminal ganglionic Nav1.7 expression to enhance hyperalgesia of inflamed TMJ remains to be explored.Estrous cycle and plasma levels of 17β-estradiol in female rats were evaluated with vaginal smear and enzyme linked immunosorbent assay, respectively. Female rats were ovariectomized and treated with 17β-estradiol at 0 μg, 20 μg and 80 μg, respectively, for 10 days. TMJ inflammation was induced using complete Freund's adjuvant. Head withdrawal thresholds and food intake were measured to evaluate the TMJ nociceptive responses. The expression of Nav1.7 in TG was examined using real-time PCR and western blot. The activity of Nav1.7 promoter was examined using luciferase reporter assay. The locations of estrogen receptors (ERα and ERβ, the G protein coupled estrogen receptor (GPR30, and Nav1.7 in TG were examined using immunohistofluorescence.Upregulation of Nav1.7 in TG and decrease in head withdrawal threshold were observed with the highest plasma 17β-estradiol in the proestrus of female rats. Ovariectomized rats treated with 80 μg 17β-estradiol showed upregulation of Nav1.7 in TG and decrease in head withdrawal threshold as compared with that of the control or ovariectomized rats treated with 0 μg or 20 μg. Moreover, 17β-estradiol dose-dependently potentiated TMJ inflammation-induced upregulation of Nav1.7 in TG and also enhanced TMJ inflammation-induced decrease of head withdrawal threshold in ovariectomized rats. In addition, the estrogen receptor antagonist, ICI 182,780, partially blocked the 17β-estradiol effect on Nav1

Formulation, in vitro and in vivo evaluation of transdermal patches containing risperidone.

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Aggarwal, Geeta; Dhawan, Sanju; Hari Kumar, S L

2013-01-01

The efficacy of oral risperidone treatment in prevention of schizophrenia is well known. However, oral side effects and patient compliance is always a problem for schizophrenics. In this study, risperidone was formulated into matrix transdermal patches to overcome these problems. The formulation factors for such patches, including eudragit RL 100 and eudragit RS 100 as matrix forming polymers, olive oil, groundnut oil and jojoba oil in different concentrations as enhancers and amount of drug loaded were investigated. The transdermal patches containing risperidone were prepared by solvent casting method and characterized for physicochemical and in vitro permeation studies through excised rat skin. Among the tested preparations, formulations with 20% risperidone, 3:2 ERL 100 and ERS 100 as polymers, mixture of olive oil and jojoba oil as enhancer, exhibited greatest cumulative amount of drug permeated (1.87 ± 0.09 mg/cm(2)) in 72 h, so batch ROJ was concluded as optimized formulation and assessed for pharmacokinetic, pharmacodynamic and skin irritation potential. The pharmacokinetic characteristics of the optimized risperidone patch were determined using rabbits, while orally administered risperidone in solution was used for comparison. The calculated relative bioavailability of risperidone transdermal patch was 115.20% with prolonged release of drug. Neuroleptic efficacy of transdermal formulation was assessed by rota-rod and grip test in comparison with control and marketed oral formulations with no skin irritation. This suggests the transdermal application of risperidone holds promise for improved bioavailability and better management of schizophrenia in long-term basis.

Assessment of estradiol-induced gene regulation and proliferation in an immortalized mouse immature Sertoli cell line.

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Kumar, Narender; Srivastava, Swati; Burek, Malgorzata; Förster, Carola Y; Roy, Partha

2016-03-01

The number of Sertoli cells during proliferative phase determines the fate of the germ cells in male reproductive system. A well-characterized cell line may help in better understanding of Sertoli cell biology. Hence, the present study assessed estradiol signaling in a mouse immature Sertoli cell line (MSC-1) as an alternative model in place of primary culture of Sertoli cells. In this study, we used MSC-1 cell line, derived from 10-day old mice. The cell cycle parameters were assessed, and the expression and regulation of Sertoli cell-specific secretory genes (ABP; androgen-binding protein) and tight junction genes (claudin-5, occludin, and vimentin) in response to estradiol was studied. The results obtained suggested the presence of both estrogen receptors (ERα and ERβ) in MSC-1 cells. In vitro scratch assay and cell-cycle analysis suggested the proliferative effects of estradiol in both time- and dose-dependent manner. The gene expression profiles of ABP, claudin-5, and occludin showed biphasic regulation at low and high doses of estradiol. Analysis of signaling pathways suggested the activation of extracellular signal-regulated kinase (ERK) pathway with significantly increased pERK/ERK ratio (p<0.05). The results also suggested down regulation in the expression of mir-17 family members (mir-17, mir-20b, and mir-106a) (p<0.05). Considering the limited number of Sertoli cell lines and long-term survival inability of primary culture of Sertoli cells, MSC-1 cells could be a potential cell line for understanding the mechanisms of various cellular events in Sertoli cells. Copyright © 2016 Elsevier Inc. All rights reserved.

Percutaneous 17ß-estradiol replacement therapy in hypertensive postmenopausal women

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M.C. Osório-Wender

1997-09-01

Full Text Available The present study evaluated the short-term effects of percutaneous 17ß-estradiol on blood pressure, metabolic profile and hormonal levels in postmenopausal women with systemic arterial hypertension. After a wash-out period of 15 days, 10 hypertensive patients were treated with guanabenz acetate to control blood pressure, followed by 17ß-estradiol in the form of hydroalcoholic gel administered for 21 of 28 days of each cycle, for 3 cycles. Patients were evaluated before, during and 2 months after estrogen administration. Systolic and diastolic blood pressure or heart rate did not present any significant change in any patient when compared to those periods with the antihypertensive drug only (pretreatment period and 60 days after estrogen therapy was discontinued. Plasma biological markers of hepatic estrogenic action (plasma renin activity, antithrombin III, triglycerides, total cholesterol and lipoproteins also remained unchanged during the study. Hormone treatment was effective, as indicated by the relief of menopausal symptoms, a decrease in FSH levels (73.48 ± 27.21 to 35.09 ± 20.44 IU/l, P<0.05, and an increase in estradiol levels (15.06 ± 8.76 to 78.7 ± 44.6 pg/ml, P<0.05. There was no effect on LH (18.0 ± 9.5 to 14.05 ± 8.28 IU/l. Hormone levels returned to previous values after estrogen treatment was discontinued. The data indicate that short-term percutaneous 17ß-estradiol replacement therapy, at the dose used, seems to be a safe hormone therapy for hypertensive menopausal women. Nevertheless, a controlled, prospective, randomized clinical assay with a larger number of subjects is needed to definitely establish both the beneficial and harmful effects of hormone replacement therapy in hypertensive women

Status of surfactants as penetration enhancers in transdermal drug delivery

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Iti Som

2012-01-01

Full Text Available Surfactants are found in many existing therapeutic, cosmetic, and agro-chemical preparations. In recent years, surfactants have been employed to enhance the permeation rates of several drugs via transdermal route. The application of transdermal route to a wider range of drugs is limited due to significant barrier to penetration across the skin which is associated with the outermost stratum corneum layer. Surfactants have effects on the permeability characteristics of several biological membranes including skin. They have the potential to solubilize lipids within the stratum corneum. The penetration of the surfactant molecule into the lipid lamellae of the stratum corneum is strongly dependent on the partitioning behavior and solubility of surfactant. Surfactants ranging from hydrophobic agents such as oleic acid to hydrophilic sodium lauryl sulfate have been tested as permeation enhancer to improve drug delivery. This article reviews the status of surfactants as permeation enhancer in transdermal drug delivery of various drugs.

Pharmacokinetics of the transdermal delivery of benfotiamine.

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Zhu, Zhen; Varadi, Gyula; Carter, Stephen G

2016-04-01

Accumulation of advanced glycation endpoints is a trigger to the development of diabetic peripheral neuropathy, which is a common complication of diabetes. Oral administration of benfotiamine (BFT) has shown some preclinical and clinical promise as a treatment for diabetic peripheral neuropathy. The purpose of this study was to evaluate the method of transdermal delivery of BFT as a possible, viable route of administration for the treatment of diabetic peripheral neuropathy. A single application of 10 mg of BFT was given to guinea pigs topically. The levels of thiamine (T), thiamine monophosphate, thiamine diphosphate, S-benzoylthiamine and BFT were measured in the blood, skin and muscle at different time points within 24 h. At the 24-h time point, following the single BFT dose, the T level was increased 10× in the blood, more than 7× in the skin and almost 4× in the muscle compared to the untreated animals. The total T content (total) was increased 7× in the blood, 17× in the skin and 3× in the muscle compared to the untreated animals. This strong increase in the tissue levels of T and the associated metabolic derivatives levels found in the blood and local tissues following a single dose indicate that topically applied BFT may be a viable and advantageous delivery method for the treatment of diabetic peripheral neuropathy.

Estradiol-loaded PLGA nanoparticles for improving low bone mineral density of cancellous bone caused by osteoporosis: Application of enhanced charged nanoparticles with iontophoresis.

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Takeuchi, Issei; Kobayashi, Shiori; Hida, Yukari; Makino, Kimiko

2017-07-01

Postmenopausal osteoporosis among older women, which occurs by an ovarian hormone deficiency, is one of the major public health problems. 17 β-estradiol (E2) is used to prevent and treat this disease as a drug of hormone replacement therapy. In oral administration, E2 is significantly affected by first-pass hepatic metabolism, and high dose administration must be needed to obtain drug efficacy. Therefore, alternative administration route is needed, and we have focused on the transdermal drug delivery system. In this study, we have prepared E2-loaded poly(DL-lactide-co-glycolide) (PLGA) nanoparticles for osteoporosis by using a combination of an antisolvent diffusion method with preferential solvation. The average particle diameter of the nanoparticles was 110.0±41.0nm and the surface charge number density was 82 times higher than that of conventional E2-loaded PLGA nanoparticles. Therapeutic evaluation of E2-loaded PLGA nanoparticles was carried out using ovariectomized female rats. Therapeutic efficacy was evaluated to measure bone mineral density of cancellous bone using an X-ray CT system. When the E2-loaded PLGA nanoparticles were administrated once a week, bone mineral density was significantly higher than that of the non-treated group at 60days after the start of treatment. Also, in the group administered this nanoparticle twice a week, the bone mineral density increased significantly at 45days after the start of treatment. From these results, it was revealed that E2-loaded PLGA nanoparticles with iontophoresis were useful to recover bone mineral density of cancellous bone, and it was also suggested that they extend the dosing interval of E2. Copyright © 2017 Elsevier B.V. All rights reserved.

Use of granisetron transdermal system in the prevention of chemotherapy-induced nausea and vomiting: a review

International Nuclear Information System (INIS)

Tuca, Albert

2009-01-01

Until now only intravenous and oral formulations of 5HT 3 receptor antagonists have been available. Recently a new formulation of a 5HT 3 receptor antagonist, transdermal granisetron, has been developed, and approved by the FDA. Three phase I studies to evaluate its pharmacokinetic profile have shown that granisetron administered by a transdermal delivery system is absorbed by passive diffusion and maximal concentration is reached 48 hours after patch application. The patch of 52 cm 2 , which contains 34.3 mg of granisetron, releases 3.3 mg of the drug every day and maintains a stable average plasma concentration of 2.2 ng/mL over 6 days, similar to levels obtained with 2 mg of oral granisetron, administered every day during the same period of time. Two randomized as yet unpublished clinical trials (phase II/III) have been conducted to evaluate the antiemetic efficacy of transdermal granisetron in chemotherapy-induced nausea and vomiting, in patients receiving moderately and highly emetogenic chemotherapy, compared with 2 mg of oral granisetron. More than 800 cancer patients were included in the trials. The rate of complete control of acute emesis was 49% for the phase II trial and 60% for the phase III trial. Neither trial showed a statistically significant difference between transdermal and oral granisetron. The control of delayed emesis was observed in 46% of patients, and there were no statistically significant differences between transdermal and oral granisetron. The most common adverse effects in both trials were constipation (<7%) and headache (<1%); there were no statistically significant differences between transdermal and oral granisetron. These data show that transdermal granisetron is effective and safe in controlling acute emesis induced by chemotherapy with both moderate and high emetogenic potential. Efficacy and safety of transdermal granisetron are fully comparable with that of oral granisetron. More clinical trials using regimens of 2 or 3 drugs

Pharmacokinetics of a Transdermal Fentanyl Solution in Suffolk Sheep (Ovis aries).

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Jen, Kimberly Y; Dyson, Melissa C; Lester, Patrick A; Nemzek, Jean A

2017-09-01

Sheep used as surgical models require appropriate pain management, and the commonly used transdermal fentanyl patches require a long predosing period to achieve adequate plasma concentrations. The aim of this study was to assess the pharmacokinetic parameters of an FDA-approved transdermal fentanyl solution (TFS) that has yet to be tested in sheep. In this study, we compared TFS at 2.7 mg/kg (n = 2), 1.7 mg/kg (n = 3), and 0.5 mg/kg (n = 3) with the control fentanyl patch at 2 μg/kg/h (n = 1); both products were applied topically to the intrascapular region. Plasma concentrations showed significant interanimal variability. Severe adverse effects occurred at both 2.7 and 1.7 mg/kg TFS and mild to moderate adverse effects were noted at 0.5 mg/kg. At all 3 doses, TFS had greater maximal concentration, clearance rate, and volume of distribution; shorter time to maximal concentration; and similar half-lives to those of the patch. In addition, we validated the use of a commercial human fentanyl ELISA kit, which positively correlated with the liquid chromatography-mass spectroscopy data, but absolute values did not match. Overall, at all 3 dosages tested (0.5, 1.7, and 2.7 mg/kg), TFS delivered fentanyl plasma concentrations that exceeded the minimal effective concentration; however, adverse effects were noted at all 3 dosages. Caution and further study are required before the use of TFS in sheep can be recommended fully.

Comparison of an Additional Transdermal Fentanyl Patch Compared to Intravenous NSAID and Opioid Analgesics within 24 Hours of an Uterine Artery Embolization for Myoma and Adenomyosis

International Nuclear Information System (INIS)

Song, Suk Yun; Kang, Byung Chul; Rho, Kyung Min

2011-01-01

To evaluate the effectiveness of an additional transdermal fentanyl patch compared to intravenous analgesics in pain control during the 24-hour period following uterine artery embolization (UAE) for myoma and adenomyosis. Between September 2009 and August 2010, 42 patients underwent UAE for myoma or adenomyosis. Of these, 21 received an intravenous opioid (pethidine) and a nonsteroidal anti-inflammatory drug (group A), and 21 received an additional transdermal fentanyl patch (group B). Pain perception levels were established verbally on a 0-10 scale during the 24-hour period following UAE. Differences in pain trends, mean dose of intravenous pethidine, and adverse effects were compared between the two groups. Pain perception was most severe at 6 hours after UAE and the mean pain level of group B at that time was 6.3 ± 0.7, which was significantly lower than that of group A, 8.2 ± 0.7 (p 0.05), and no evidence of respiratory distress was demonstrated. The addition of a transdermal fentanyl patch to intravenous analgesics is effective in reducing post-embolization pain during the 24-hour period after UAE.

Comparison of an Additional Transdermal Fentanyl Patch Compared to Intravenous NSAID and Opioid Analgesics within 24 Hours of an Uterine Artery Embolization for Myoma and Adenomyosis

Energy Technology Data Exchange (ETDEWEB)

Song, Suk Yun; Kang, Byung Chul; Rho, Kyung Min [Dept. of Radiology, Mokdong Hospital, Ewha Womans University School of Medicine, Seoul (Korea, Republic of)

2011-05-15

To evaluate the effectiveness of an additional transdermal fentanyl patch compared to intravenous analgesics in pain control during the 24-hour period following uterine artery embolization (UAE) for myoma and adenomyosis. Between September 2009 and August 2010, 42 patients underwent UAE for myoma or adenomyosis. Of these, 21 received an intravenous opioid (pethidine) and a nonsteroidal anti-inflammatory drug (group A), and 21 received an additional transdermal fentanyl patch (group B). Pain perception levels were established verbally on a 0-10 scale during the 24-hour period following UAE. Differences in pain trends, mean dose of intravenous pethidine, and adverse effects were compared between the two groups. Pain perception was most severe at 6 hours after UAE and the mean pain level of group B at that time was 6.3 {+-} 0.7, which was significantly lower than that of group A, 8.2 {+-} 0.7 (p<0.05). The mean dose of intravenous pethidine was 114.3 {+-} 59.5 mg in group A and 90.5 {+-} 49.0 mg in group B, while the incidence of nausea was 67% in group A and 77% in group B. In both cases, the differences were not significantly different (p>0.05), and no evidence of respiratory distress was demonstrated. The addition of a transdermal fentanyl patch to intravenous analgesics is effective in reducing post-embolization pain during the 24-hour period after UAE.

Topical and transdermal drug delivery: principles and practice

National Research Council Canada - National Science Library

Benson, Heather A. E; Watkinson, Adam C

2012-01-01

.... Providing an overview of the current science in drug and cosmetic application to and through the skin, Topical and Transdermal Drug Delivery includes treatment of skin conditions, skin permeation...

Microneedle-assisted transdermal delivery of Zolmitriptan: effect of microneedle geometry, in vitro permeation experiments, scaling analyses and numerical simulations.

Science.gov (United States)

Uppuluri, Chandra Teja; Devineni, Jyothirmayee; Han, Tao; Nayak, Atul; Nair, Kartik J; Whiteside, Benjamin R; Das, Diganta B; Nalluri, Buchi N

2017-08-01

The present study was aimed to investigate the effect of salient microneedle (MN) geometry parameters like length, density, shape and type on transdermal permeation enhancement of Zolmitriptan (ZMT). Two types of MN devices viz. AdminPatch ® arrays (ADM) (0.6, 0.9, 1.2 and 1.5 mm lengths) and laboratory fabricated polymeric MNs (PM) of 0.6 mm length were employed. In the case of PMs, arrays were applied thrice at different places within a 1.77 cm 2 skin area (PM-3) to maintain the MN density closer to 0.6 mm ADM. Scaling analyses was done using dimensionless parameters like concentration of ZMT (C t /C s ), thickness (h/L) and surface area of the skin (Sa/L 2 ). Micro-injection molding technique was employed to fabricate PM. Histological studies revealed that the PM, owing to their geometry/design, formed wider and deeper microconduits when compared to ADM of similar length. Approximately 3.17- and 3.65-fold increase in ZMT flux values were observed with 1.5 mm ADM and PM-3 applications when compared to the passive studies. Good correlations were observed between different dimensionless parameters with scaling analyses. Numerical simulations, using MATLAB and COMSOL software, based on experimental data and histological images provided information regarding the ZMT skin distribution after MN application. Both from experimental studies and simulations, it was inferred that PM were more effective in enhancing the transdermal delivery of ZMT when compared to ADM. The study suggests that MN application enhances the ZMT transdermal permeation and the geometrical parameters of MNs play an important role in the degree of such enhancement.

Enhanced Transdermal Permeability via Constructing the Porous Structure of Poloxamer-Based Hydrogel

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Wen-Yi Wang

2016-11-01

Full Text Available A major concern for transdermal drug delivery systems is the low bioavailability of targeted drugs primarily caused by the skin’s barrier function. The resistance to the carrier matrix for the diffusion and transport of drugs, however, is routinely ignored. This study reports a promising and attractive approach to reducing the resistance to drug transport in the carrier matrix, to enhance drug permeability and bioavailability via enhanced concentration-gradient of the driving force for transdermal purposes. This approach simply optimizes and reconstructs the porous channel structure of the carrier matrix, namely, poloxamer 407 (P407-based hydrogel matrix blended with carboxymethyl cellulose sodium (CMCs. Addition of CMCs was found to distinctly improve the porous structure of the P407 matrix. The pore size approximated to normal distribution as CMCs were added and the fraction of pore number was increased by over tenfold. Transdermal studies showed that P407/CMCs saw a significant increase in drug permeability across the skin. This suggests that P407/CMC with improved porous structure exhibits a feasible and promising way for the development of transdermal therapy with high permeability and bioavailability, thereby avoiding or reducing use of any chemical enhancers.

Does estradiol have an impact on the dipeptidyl peptidase IV enzyme activity of the Prevotella intermedia group bacteria?

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Fteita, Dareen; Könönen, Eija; Gürsoy, Mervi; Söderling, Eva; Gürsoy, Ulvi Kahraman

2015-12-01

Initiation and development of pregnancy-associated gingivitis is seemingly related to the microbial shift towards specific gram-negative anaerobes in subgingival biofilms. It is known that Prevotella intermedia sensu lato is able to use estradiol as an alternative source of growth instead of vitamin K. The aim of the present study was to investigate the impact of estradiol on the bacterial dipeptidyl peptidase IV (DPPIV) enzyme activity in vitro as a virulent factor of the Prevotella intermedia group bacteria, namely P. intermedia, Prevotella nigrescens, Prevotella pallens, and Prevotella aurantiaca. In all experiments, 2 strains of each Prevotella species were used. Bacteria were incubated with the concentrations of 0, 30, 90, and 120 nmol/L of estradiol and were allowed to build biofilms at an air-solid interface. DPPIV activities of biofilms were measured kinetically during 20 min using a fluorometric assay. The enzyme activity was later related to the amount of protein produced by the same biofilm, reflecting the biofilm mass. Estradiol significantly increased DPPIV activities of the 8 Prevotella strains in a strain- and dose-dependent manner. In conclusion, our in vitro experiments indicate that estradiol regulates the DPPIV enzyme activity of P. intermedia, P. nigrescens, P. pallens, and P. aurantiaca strains differently. Our results may, at least partly, explain the role of estradiol to elicit a virulent state which contributes to the pathogenesis of pregnancy-related gingivitis. Copyright © 2015 Elsevier Ltd. All rights reserved.

Estradiol receptors mediate estradiol-induced inhibition of mitochondrial Ca^{2+} efflux in rat caudate nucleus and brain stem

OpenAIRE

PETROVIC, SNJEZANA; MILOSEVIC, MAJA; RISTIC-MEDIC, DANIJELA; VELICKOVIC, NATASA; DRAKULIC, DUNJA; GRKOVIC, IVANA; HORVAT, ANICA

2015-01-01

Our earlier studies found that in vitro estradiol modulates mitochondrial Ca2+ transport in discrete brain regions. The present study examined the role of estradiol receptors (ERs) in estradiol-induced inhibition of Ca^{2+} efflux from synaptosomal mitochondria isolated from rat caudate nuclei and brain stems. Radioactively labeled CaCl_2 (0.6?0.75 µCi ^45CaCl_{2}) was used for Ca^{2+} transport monitoring. The results revealed that in the presence of ER antagonist 7\\alpha,17ß-[9[(4,4,5,5,5-...

Estradiol RIA kit in clinical practice

International Nuclear Information System (INIS)

Friedrich, W.; Lisse, K.; Bienert, R.; Flentje, H.; Koerner, H.; Wilken, T.; Akademie der Wissenschaften der DDR, Berlin-Buch. Zentralinstitut fuer Isotopen- und Strahlenforschung)

1985-01-01

First clinical experience with a estradiol RIA kit developed in the Central Institute for Isotope- and Radiation Research is reported. The kit was used for the daily control of estradiol level in patients, which were treated within the program for in vitro fertilization and embryo transfer. The time of incubation could be shortened by means of a double antibody technique and by use of a precipitation mixture to 2 h. The intraassay variation is 9.2%, the interassay variation is 15.1%, the recovery rate is 94%. The sensitivity of the test (B 0 -3SD) is about 120 pmol/l. The estradiol RIA kit satisfies clinical requirements. (author)

CONCENTRATION OF ESTRADIOL IN DOGS (BITCHES IN SPRINGTIME

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Edina Hajdarević

2013-09-01

Full Text Available Measuring of estradiol level in the peripheral blood in dog is important for the precise estrus detection. In proestrus, estradiol dominates. In estrus, however, estradiol progressively decreases while progesterone and LH increase, the latter shortly and abruptly. The research of Feldman and Nelson (7 indicates that the beginning of the sexual cycle of the female dog is the result of complex interaction of the environment, general health condition, condition of the ovaries, condition of the uterus, animal age, and some unidentified factors. Estradiol level in the peripheral circulation is starting to rise before the beginning of the proestrus, and during the proestrus the female dog is under the influence of estradiol (4. Our research included 30 female dogs on the territory of Tuzla Municipality, in the springtime. The female dogs were divided in three groups according to the breeding and living conditions: group A (female dogs living in the house environment; group B (female dogs living in the shelter; group C (female stray dogs. For the researched groups, estradiol level varied between 6,265 pg\\ml and 69,734 pg\\ml over the springtime. Of importance is the results can be applied in the evaluation of estrus in the female dogs, and when considering factors crucial for their sustainable reproduction potential.Key words: dogs, estradiol, spring

Transdermal testosterone replacement therapy in men

Science.gov (United States)

Ullah, M Iftekhar; Riche, Daniel M; Koch, Christian A

2014-01-01

Androgen deficiency syndrome in men is a frequently diagnosed condition associated with clinical symptoms including fatigue, decreased libido, erectile dysfunction, and metabolic syndrome. Serum testosterone concentrations decline steadily with age. The prevalence of androgen deficiency syndrome in men varies depending on the age group, known and unknown comorbidities, and the respective study group. Reported prevalence rates may be underestimated, as not every man with symptoms of androgen deficiency seeks treatment. Additionally, men reporting symptoms of androgen deficiency may not be correctly diagnosed due to the vagueness of the symptom quality. The treatment of androgen deficiency syndrome or male hypogonadism may sometimes be difficult due to various reasons. There is no consensus as to when to start treating a respective man or with regards to the best treatment option for an individual patient. There is also lack of familiarity with treatment options among general practitioners. The formulations currently available on the market are generally expensive and dose adjustment protocols for each differ. All these factors add to the complexity of testosterone replacement therapy. In this article we will discuss the general indications of transdermal testosterone replacement therapy, available formulations, dosage, application sites, and recommended titration schedule. PMID:24470750

Build-up and surface dose measurements on phantoms using micro-MOSFET in 6 and 10 MV x-ray beams and comparisons with Monte Carlo calculations

International Nuclear Information System (INIS)

Xiang, Hong F.; Song, Jun S.; Chin, David W. H.; Cormack, Robert A.; Tishler, Roy B.; Makrigiorgos, G. Mike; Court, Laurence E.; Chin, Lee M.

2007-01-01

This work is intended to investigate the application and accuracy of micro-MOSFET for superficial dose measurement under clinically used MV x-ray beams. Dose response of micro-MOSFET in the build-up region and on surface under MV x-ray beams were measured and compared to Monte Carlo calculations. First, percentage-depth-doses were measured with micro-MOSFET under 6 and 10 MV beams of normal incidence onto a flat solid water phantom. Micro-MOSFET data were compared with the measurements from a parallel plate ionization chamber and Monte Carlo dose calculation in the build-up region. Then, percentage-depth-doses were measured for oblique beams at 0 deg. - 80 deg. onto the flat solid water phantom with micro-MOSFET placed at depths of 2 cm, 1 cm, and 2 mm below the surface. Measurements were compared to Monte Carlo calculations under these settings. Finally, measurements were performed with micro-MOSFET embedded in the first 1 mm layer of bolus placed on a flat phantom and a curved phantom of semi-cylindrical shape. Results were compared to superficial dose calculated from Monte Carlo for a 2 mm thin layer that extends from the surface to a depth of 2 mm. Results were (1) Comparison of measurements with MC calculation in the build-up region showed that micro-MOSFET has a water-equivalence thickness (WET) of 0.87 mm for 6 MV beam and 0.99 mm for 10 MV beam from the flat side, and a WET of 0.72 mm for 6 MV beam and 0.76 mm for 10 MV beam from the epoxy side. (2) For normal beam incidences, percentage depth dose agree within 3%-5% among micro-MOSFET measurements, parallel-plate ionization chamber measurements, and MC calculations. (3) For oblique incidence on the flat phantom with micro-MOSFET placed at depths of 2 cm, 1 cm, and 2 mm, measurements were consistent with MC calculations within a typical uncertainty of 3%-5%. (4) For oblique incidence on the flat phantom and a curved-surface phantom, measurements with micro-MOSFET placed at 1.0 mm agrees with the MC

Transdermal rivastigmine: management of cutaneous adverse events and review of the literature.

Science.gov (United States)

Greenspoon, Jill; Herrmann, Nathan; Adam, David N

2011-07-01

Alzheimer's disease is a chronic neurodegenerative disorder resulting in part from the degeneration of cholinergic neurons in the brain. Rivastigmine, a cholinesterase inhibitor, is commonly used as a treatment for dementia due to its ability to moderate cholinergic neurotransmission; however, treatment with oral rivastigmine can lead to gastrointestinal adverse effects such as nausea and vomiting. Transdermal administration of rivastigmine can minimize these adverse effects by providing continuous delivery of the medication, while maintaining the effectiveness of the oral treatment. While the transdermal form of rivastigmine has been found to have fewer systemic adverse effects compared with the oral form, cutaneous reactions, such as contact dermatitis, can lead to discontinuation of the drug in its transdermal form. Lack of patient compliance with regard to applying the patch to the designated site, applying the patch for the correct length of time or rotating patch application sites increases the risk of cutaneous adverse reactions. This article outlines the diagnosis and management of irritant contact dermatitis and allergic contact dermatitis secondary to transdermal rivastigmine. The large majority of reactions to transdermal patches are of an irritant type, which can be diagnosed clinically by the presence of a pruritic, erythematous, eczematous plaque strictly confined to the borders of the patch. In contrast, an allergic reaction can be differentiated by the presence of vesicles and/or oedema, erythema beyond the boundaries of the transdermal patch and lack of improvement of the lesion 48 hours after removal of the offending treatment. By encouraging the patient to follow a regular rotation schedule for the patch, and using lipid-based emollients for irritant dermatitis and pre- and post-treatment topical corticosteroids for allergic dermatitis, cutaneous reactions can often be alleviated and patients can continue with their medication regimen. Other

Synthesis and characterization of modified starch/polybutadiene as novel transdermal drug delivery system.

Science.gov (United States)

Saboktakin, Mohammad Reza; Akhyari, Shahab; Nasirov, Fizuli A

2014-08-01

Transdermal drug delivery systems are topically administered medicaments in the form of patches that deliver drugs for systemic effects at a predetermined and controlled rate. It works very simply in which drug is applied inside the patch and it is worn on skin for long period of time. Polymer matrix, drug, permeation enhancers are the main components of transdermal drug delivery systems. The objective of the present study was to develop the modified starch and 1,4-cis polybutadiene nanoparticles as novel polymer matrix system. We have been studied the properties of a novel transdermal drug delivery system with clonidine as drug model. Copyright © 2014 Elsevier B.V. All rights reserved.

Optimization of Biopolymer Based Transdermal Films of Metoclopramide as an Alternative Delivery Approach

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Betül Aktar

2014-05-01

Full Text Available The objectives of this study were to develop and to characterize sodium alginate based matrix-type transdermal films of metoclopramide hydrochloride (MTC in order to improve patient compliance to treatment. The suitability of sodium alginate was shown to be a natural film former in terms of the physicochemical, mechanical, and bioadhesive features of the MTC loaded transdermal films. Terpinolene provided the highest drug release among the different terpenes (nerolidol, eucalyptol, dl-limonene, or terpinolene assessed as enhancer. Attenuated Total Reflectance Infrared (ATR-FTIR spectroscopy analysis performed to evaluate the effect of the transdermal films on skin barrier confirmed enhancer induced lipid bilayer disruption in stratum corneum, indicating its permeation enhancement effect.

Recent trends in the transdermal delivery of therapeutic agents used for the management of neurodegenerative diseases.

Science.gov (United States)

Ita, Kevin

2017-06-01

With the increasing proportion of the global geriatric population, it becomes obvious that neurodegenerative diseases will become more widespread. From an epidemiological standpoint, it is necessary to develop new therapeutic agents for the management of Alzheimer's disease, Parkinson's disease, multiple sclerosis and other neurodegenerative disorders. An important approach in this regard involves the use of the transdermal route. With transdermal drug delivery systems (TDDS), it is possible to modulate the pharmacokinetic profiles of these medications and improve patient compliance. Transdermal drug delivery has also been shown to be useful for drugs with short half-life and low or unpredictable bioavailability. In this review, several transdermal drug delivery enhancement technologies are being discussed in relation to the delivery of medications used for the management of neurodegenerative disorders.

Use of granisetron transdermal system in the prevention of chemotherapy-induced nausea and vomiting: a review

Directory of Open Access Journals (Sweden)

Albert Tuca

2009-12-01

Full Text Available Albert TucaPalliative Care Hospital Team, Palliative Care Department, Institut Català d’Oncologia, L’Hospitalet de Llobregat, Barcelona, SpainAbstract: Until now only intravenous and oral formulations of 5HT3 receptor antagonists have been available. Recently a new formulation of a 5HT3 receptor antagonist, transdermal granisetron, has been developed, and approved by the FDA. Three phase I studies to evaluate its pharmacokinetic profile have shown that granisetron administered by a transdermal delivery system is absorbed by passive diffusion and maximal concentration is reached 48 hours after patch application. The patch of 52 cm2, which contains 34.3 mg of granisetron, releases 3.3 mg of the drug every day and maintains a stable average plasma concentration of 2.2 ng/mL over 6 days, similar to levels obtained with 2 mg of oral granisetron, administered every day during the same period of time. Two randomized as yet unpublished clinical trials (phase II/III have been conducted to evaluate the antiemetic efficacy of transdermal granisetron in chemotherapy-induced nausea and vomiting, in patients receiving moderately and highly emetogenic chemotherapy, compared with 2 mg of oral granisetron. More than 800 cancer patients were included in the trials. The rate of complete control of acute emesis was 49% for the phase II trial and 60% for the phase III trial. Neither trial showed a statistically significant difference between transdermal and oral granisetron. The control of delayed emesis was observed in 46% of patients, and there were no statistically significant differences between transdermal and oral granisetron. The most common adverse effects in both trials were constipation (<7% and headache (<1%; there were no statistically significant differences between transdermal and oral granisetron. These data show that transdermal granisetron is effective and safe in controlling acute emesis induced by chemotherapy with both moderate and high

Low-dose cardio-respiratory phase-correlated cone-beam micro-CT of small animals.

Science.gov (United States)

Sawall, Stefan; Bergner, Frank; Lapp, Robert; Mronz, Markus; Karolczak, Marek; Hess, Andreas; Kachelriess, Marc

2011-03-01

Micro-CT imaging of animal hearts typically requires a double gating procedure because scans during a breath-hold are not possible due to the long scan times and the high respiratory rates, Simultaneous respiratory and cardiac gating can either be done prospectively or retrospectively. True five-dimensional information can be either retrieved with retrospective gating or with prospective gating if several prospective gates are acquired. In any case, the amount of information available to reconstruct one volume for a given respiratory and cardiac phase is orders of magnitud lower than the total amount of information acquired. For example, the reconstruction of a volume from a 10% wide respiratory and a 20% wide cardiac window uses only 2% of the data acquired. Achieving a similar image quality as a nongated scan would therefore require to increase the amount of data and thereby the dose to the animal by up to a factor of 50. To achieve the goal of low-dose phase-correlated (LDPC) imaging, the authors propose to use a highly efficient combination of slightly modified existing algorithms. In particular, the authors developed a variant of the McKinnon-Bates image reconstruction algorithm and combined it with bilateral filtering in up to five dimensions to significantly reduce image noise without impairing spatial or temporal resolution. The preliminary results indicate that the proposed LDPC reconstruction method typically reduces image noise by a factor of up to 6 (e.g., from 170 to 30 HU), while the dose values lie in a range from 60 to 500 mGy. Compared to other publications that apply 250-1800 mGy for the same task [C. T. Badea et al., "4D micro-CT of the mouse heart," Mol. Imaging 4(2), 110-116 (2005); M. Drangova et al., "Fast retrospectively gated quantitative four-dimensional (4D) cardiac micro computed tomography imaging of free-breathing mice," Invest. Radiol. 42(2), 85-94 (2007); S. H. Bartling et al., "Retrospective motion gating in small animal CT of mice

Turning theory into practice: the development of modern transdermal drug delivery systems and future trends.

Science.gov (United States)

Perumal, O; Murthy, S N; Kalia, Y N

2013-01-01

Despite its remarkable barrier function, the skin remains an attractive site for systemic drug delivery given its easy accessibility, large surface area and the possibility to bypass the gastrointestinal tract and the liver and so modify drug absorption kinetics. The pioneering work of Scheuplein, Higuchi and others in the 1960s helped to explain the processes involved in passive percutaneous absorption and led to the development of mathematical models to describe transdermal drug delivery. The intervening years have seen these theories turned to practice and a significant number of transdermal systems are now available including some that employ active drug delivery. This review briefly discusses the evolution of transdermal therapeutic systems over the years and the potential of newer transdermal technologies to deliver hydrophilic drugs and macromolecules through the skin. © 2013 S. Karger AG, Basel.

Targeted nanoparticle delivery of therapeutic antisense microRNAs presensitizes glioblastoma cells to lower effective doses of temozolomide in vitro and in a mouse model.

Science.gov (United States)

Malhotra, Meenakshi; Sekar, Thillai Veerapazham; Ananta, Jeyarama S; Devulapally, Rammohan; Afjei, Rayhaneh; Babikir, Husam A; Paulmurugan, Ramasamy; Massoud, Tarik F

2018-04-20

Temozolomide (TMZ) chemotherapy for glioblastoma (GBM) is generally well tolerated at standard doses but it can cause side effects. GBMs overexpress microRNA-21 and microRNA-10b, two known oncomiRs that promote cancer development, progression and resistance to drug treatment. We hypothesized that systemic injection of antisense microRNAs (antagomiR-21 and antagomiR-10b) encapsulated in cRGD-tagged PEG-PLGA nanoparticles would result in high cellular delivery of intact functional antagomiRs, with consequent efficient therapeutic response and increased sensitivity of GBM cells to lower doses of TMZ. We synthesized both targeted and non-targeted nanoparticles, and characterized them for size, surface charge and encapsulation efficiency of antagomiRs. When using targeted nanoparticles in U87MG and Ln229 GBM cells, we showed higher uptake-associated improvement in sensitivity of these cells to lower concentrations of TMZ in medium. Co-inhibition of microRNA-21 and microRNA-10b reduced the number of viable cells and increased cell cycle arrest at G2/M phase upon TMZ treatment. We found a significant increase in expression of key target genes for microRNA-21 and microRNA-10b upon using targeted versus non-targeted nanoparticles. There was also significant reduction in tumor volume when using TMZ after pre-treatment with loaded nanoparticles in human GBM cell xenografts in mice. In vivo targeted nanoparticles plus different doses of TMZ showed a significant therapeutic response even at the lowest dose of TMZ, indicating that preloading cells with antagomiR-21 and antagomiR-10b increases cellular chemosensitivity towards lower TMZ doses. Future clinical applications of this combination therapy may result in improved GBM response by using lower doses of TMZ and reducing nonspecific treatment side effects.

Transport efficiency in transdermal drug delivery: What is the role of fluid microstructure?

Science.gov (United States)

Liuzzi, Roberta; Carciati, Antonio; Guido, Stefano; Caserta, Sergio

2016-03-01

Interaction of microstructured fluids with skin is ubiquitous in everyday life, from the use of cosmetics, lotions, and drugs, to personal care with detergents or soaps. The formulation of microstructured fluids is crucial for the control of the transdermal transport. In biomedical applications transdermal delivery is an efficient approach, alternative to traditional routes like oral and parenteral administration, for local release of drugs. Poor skin permeability, mainly due to its outer layer, which acts as the first barrier against the entry of external compounds, greatly limits the applicability of transdermal delivery. In this review, we focus on recent studies on the improvement of skin transport efficiency by using microemulsions (ME). Quantitative techniques, which are able to investigate both skin morphology and penetration processes, are also reviewed. ME are increasingly used as transdermal systems due to their low preparation cost, stability and high bioavailability. ME may act as penetration enhancers for many active principles, but ME microstructure should be chosen appropriately considering several factors such as ratio and type of ingredients and physic-chemical properties of the active components. ME microstructure is strongly affected by the flow conditions applied during processing, or during spreading and rubbing onto skin. Although the role played by ME microstructure has been generally recognized, the skin transport mechanisms associated with different ME microstructures are still to be elucidated and further investigations are required to fully exploit the potential of ME in transdermal delivery. Copyright © 2015 Elsevier B.V. All rights reserved.

Estradiol coupling to human monocyte nitric oxide release is dependent on intracellular calcium transients: evidence for an estrogen surface receptor.

Science.gov (United States)

Stefano, G B; Prevot, V; Beauvillain, J C; Fimiani, C; Welters, I; Cadet, P; Breton, C; Pestel, J; Salzet, M; Bilfinger, T V

1999-10-01

We tested the hypothesis that estrogen acutely stimulates constitutive NO synthase (cNOS) activity in human peripheral monocytes by acting on an estrogen surface receptor. NO release was measured in real time with an amperometric probe. 17beta-estradiol exposure to monocytes stimulated NO release within seconds in a concentration-dependent manner, whereas 17alpha-estradiol had no effect. 17beta-estradiol conjugated to BSA (E2-BSA) also stimulated NO release, suggesting mediation by a membrane surface receptor. Tamoxifen, an estrogen receptor inhibitor, antagonized the action of both 17beta-estradiol and E2-BSA, whereas ICI 182,780, a selective inhibitor of the nuclear estrogen receptor, had no effect. We further showed, using a dual emission microfluorometry in a calcium-free medium, that the 17beta-estradiol-stimulated release of monocyte NO was dependent on the initial stimulation of intracellular calcium transients in a tamoxifen-sensitive process. Leeching out the intracellular calcium stores abolished the effect of 17beta-estradiol on NO release. RT-PCR analysis of RNA obtained from the cells revealed a strong estrogen receptor-alpha amplification signal and a weak beta signal. Taken together, a physiological dose of estrogen acutely stimulates NO release from human monocytes via the activation of an estrogen surface receptor that is coupled to increases in intracellular calcium.

Statistically optimized fast dissolving microneedle transdermal patch of meloxicam: A patient friendly approach to manage arthritis.

Science.gov (United States)

Amodwala, Sejal; Kumar, Praveen; Thakkar, Hetal P

2017-06-15

The long term administration of Meloxicam for the management of arthritis, a chronic disorder, results in gastrointestinal disturbances leading to poor patient compliance. Considering the favorable molecular weight, therapeutic dose, biological half-life and log P value of meloxicam for transdermal delivery, its fast dissolving microneedle patch, with an ability to breach the stratum corneum and efficiently deliver the cargo to deeper skin layers, were developed. Microneedle patch of low molecular weight polyvinyl alcohol and polyvinylpyrrolidone was prepared using Polydimethylsiloxane micromolds. The ratio of polyvinyl alcohol to polyvinyl pyrrolidone and solid content of matrix solution was optimized to achieve maximum needle strength. The optimized batch was extensively evaluated for in vitro dissolution, drug release, stability, ex vivo skin permeation/deposition, histopathology and in vivo pharmacodynamic study. The patch containing 9:1 polyvinyl alcohol to polyvinylpyrrolidone ratio with 50% solid content had shown maximum axial needle fracture force (0.9N) suitable for penetrating the skin. The optimized batch was found to be fast dissolving and released almost 100% drug in 60min following dissolution controlled kinetics. The formulation showed a significant drug deposition within skin (63.37%) and an improved transdermal flux (1.60μg/cm 2 /h) with a 2.58 fold enhancement in permeation as compared to plain drug solution. The formulation showed a comparable anti-inflammatory activity in rats when compared to its existing approved marketed oral tablet. Histopathology and stability evaluations demonstrated acceptable safety and shelf-life of the developed formulation. The successful verification of safety, efficacy and stability of microneedle patch advocated the suitability of the formulation for transdermal use. Copyright © 2017 Elsevier B.V. All rights reserved.

Promotion of the transdermal delivery of protein drugs by N-trimethyl chitosan nanoparticles combined with polypropylene electret.

Science.gov (United States)

Tu, Ye; Wang, Xinxia; Lu, Ying; Zhang, He; Yu, Yuan; Chen, Yan; Liu, Junjie; Sun, Zhiguo; Cui, Lili; Gao, Jing; Zhong, Yanqiang

We recently reported that electret, which was prepared by a corona charging system with polypropylene film, could enhance the transdermal delivery of several drugs of low molecular weight. The aim of this study was to investigate whether electret could enhance the transdermal delivery of protein drugs by N -trimethyl chitosan nanoparticles (TMC NPs) prepared by an ionic gelation method. A series of experiments were performed, including in vitro skin permeation assays and anti-inflammatory effects, to evaluate the transdermal delivery of protein drugs by TMC NPs in the presence of electret. The results showed that in the presence of electret, the transdermal delivery of protein drugs in TMC NPs was significantly enhanced, as demonstrated by in vitro permeation studies and confocal laser scanning microscopy. Notably, superoxide dismutase-loaded TMC NPs combined with electret exhibited the best inhibitory effect on the edema of the mouse ear. TMC NPs combined with electret represent a novel platform for the transdermal delivery of protein drugs.

[11C]diclofenac sodium: synthesis and PET assessment of transdermal penetration

International Nuclear Information System (INIS)

Petroni, Debora; Menichetti, Luca; Sorace, Oreste; Poli, Michela; Vanasia, Massimo; Salvadori, Piero A.

2011-01-01

The aim of this work was to study the feasibility of using Positron Emission Tomography (PET) imaging as a new tool to detect transdermal penetration of topical drugs in human subjects. The compound used in the study is sodium 2-[(2,6-dichlorophenyl)amino]phenyl]acetate, better known as diclofenac sodium. This molecule belongs to the family of non-steroidal anti-inflammatory drugs and is considered one of the first choices among non-steroidal anti-inflammatory drugs for the treatment of inflammatory diseases; it is widely used and commercially present in a large number of pharmaceutical forms and formulations. 11 C-labeled diclofenac has been synthesized and coformulated, as an internal indicator, with a proprietary preparation based on the use of a sprayer. The radiolabeled preparation was topically administered to healthy volunteers, and PET imaging was used to evaluate transdermal penetration. Results obtained have demonstrated the efficacy of PET and radiolabeled tracers for the evaluation of transdermal penetration of active pharmaceutical ingredients as topical formulations.

Protection against soman and sarin exposure by transdermal physostigmine and scopolamine

Energy Technology Data Exchange (ETDEWEB)

Meshulam, Y.; Davidovici, R.; Levy, A.

1993-05-13

The purpose of this study was to evaluate the prophylactic efficacy of physostigmine (physo), administered via sustained release (SR) methods, with and without scopolamine, against soman and sarin exposure in guinea-pigs. Transdermal physo pad (3 sq cm/kg; 60-80 ug/sq cm), containing a vehicle based on propionic acid, was applied onto the dorsal back of the animals, 24 hours before exposure to the cholinesterase (ChE) inhibitors. At the time of exposure, physo concentrations in brain and plasma were 3.6 ng/g and 4.1 ng/ml respectively. Brain and whole blood ChE activity were inhibited to 70% and 57% of their original activity. Transdermal physo by itself protected up to 70% of the animals exposed to 1.5 LD(50) of soman or sarin (100% mortality was recorded in the control group). Combining transdermal physo with Scopoderm (by Ciba Geigy Inc.) provided full protection against 1.5 LD(50).

Functionalization of Cotton Fabrics with Polycaprolactone Nanoparticles for Transdermal Release of Melatonin

Directory of Open Access Journals (Sweden)

Daniele Massella

2017-12-01

Full Text Available Drug delivery by means of transdermal patches raised great interest as a non-invasive and sustained therapy. The present research aimed to design a patch for transdermal delivery of melatonin, which was encapsulated in polycaprolactone (PCL nanoparticles (NPs by employing flash nanoprecipitation (FNP technique. Melatonin-loaded PCL nanoparticles were successfully prepared with precise control of the particle size by effectively tuning process parameters. The effect of process parameters on the particle size was assessed by dynamic light scattering for producing particles with suitable size for transdermal applications. Quantification of encapsulated melatonin was performed by mean of UV spectrophotometry, obtaining the estimation of encapsulation efficiency (EE% and loading capacity (LC%. An EE% higher than 80% was obtained. Differential scanning calorimetry (DSC analysis of NPs was performed to confirm effective encapsulation in the solid phase. Cotton fabrics, functionalized by imbibition with the nano-suspension, were analyzed by scanning electron microscopy to check morphology, adhesion and distribution of the NPs on the surface; melatonin transdermal release from the functionalized fabric was performed via Franz’s cells by using a synthetic membrane. NPs were uniformly distributed on cotton fibres, as confirmed by SEM observations; the release test showed a continuous and controlled release whose kinetics were satisfactorily described by Baker–Lonsdale model.

Efficacy of transdermal nitroglycerine in idiopathic pre-term labour.

Science.gov (United States)

Shaikh, Shahida; Shaikh, Abdul Hameed; Akhter, Saleem; Isran, Basma

2012-01-01

To determine the efficacy of transdermal Nitroglycerine patch in idiopathic pre-term labour and foetomaternal outcome. This quasi-experimental study was conducted at the Obstetrics Unit-II of Shaikh Zayed Hospital for Women, Chandka Medical College, Shaheed Mohtarma Benazir Bhutto Medical University, Larkana, from Jan 1 to June 30, 2010. Sixtyfive pregnant women at 28-34 weeks of gestation were recruited after they met the selection criteria based on non-probability consecutive sampling. Initially, 73 patients were selected, but 65 of them completed the treatment, while 8 patients refused to continue. Patients diagnosed with pre-term labour were given glyceryl trinitrate (GTN) 5 mg/12 hours transdermal patch which was applied on the anterior abdominal wall. The second patch of same dose was given after 12 hours. Arrest of labour, prolongation of pregnancy in days or weeks along with side effects of the agent were monitored. Patients were followed till delivery to know the foeto-maternal outcome. Dramatic effects were seen in around 60 (92.3%), of the total patients who had felt relief from premature labour pains within the first hour and only 5 (7.6%) patients could not go beyond 24 hours, as among them 3 (4.61%) had previous uterine scar and 2 (3.07%) developed ruptured membranes after 12 hours of admission and their babies also could not survive. Mean pregnancy prolongation was 15.35 +/- 9.45 days (min: 4 max: 35), so delivery was deferred up to 48 hours, 3 to 7 days and more than 7 days in 4 (6.15%), 6 (9.23%) and 50 (76.92%) respectively. Glyceryl trinitrate, trans dermal patch is effective and safe tocolytic in idiopathic preterm labour. By prolonging pregnancy it improves neonatal outcome.

Modular reservoir concept for MEMS-based transdermal drug delivery systems

International Nuclear Information System (INIS)

Cantwell, Cara T; Wei, Pinghung; Ziaie, Babak; Rao, Masaru P

2014-01-01

While MEMS-based transdermal drug delivery device development efforts have typically focused on tightly-integrated solutions, we propose an alternate conception based upon a novel, modular drug reservoir approach. By decoupling the drug storage functionality from the rest of the delivery system, this approach seeks to minimize cold chain storage volume, enhance compatibility with conventional pharmaceutical practices, and allow independent optimization of reservoir device design, materials, and fabrication. Herein, we report the design, fabrication, and preliminary characterization of modular reservoirs that demonstrate the virtue of this approach within the application context of transdermal insulin administration for diabetes management. (technical note)

Modular reservoir concept for MEMS-based transdermal drug delivery systems

Science.gov (United States)

Cantwell, Cara T.; Wei, Pinghung; Ziaie, Babak; Rao, Masaru P.

2014-11-01

While MEMS-based transdermal drug delivery device development efforts have typically focused on tightly-integrated solutions, we propose an alternate conception based upon a novel, modular drug reservoir approach. By decoupling the drug storage functionality from the rest of the delivery system, this approach seeks to minimize cold chain storage volume, enhance compatibility with conventional pharmaceutical practices, and allow independent optimization of reservoir device design, materials, and fabrication. Herein, we report the design, fabrication, and preliminary characterization of modular reservoirs that demonstrate the virtue of this approach within the application context of transdermal insulin administration for diabetes management.

Biomaterials as novel penetration enhancers for transdermal and dermal drug delivery systems.

Science.gov (United States)

Chen, Yang; Wang, Manli; Fang, Liang

2013-01-01

The highly organized structure of the stratum corneum provides an effective barrier to the drug delivery into or across the skin. To overcome this barrier function, penetration enhancers are always used in the transdermal and dermal drug delivery systems. However, the conventional chemical enhancers are often limited by their inability to delivery large and hydrophilic molecules, and few to date have been routinely incorporated into the transdermal formulations due to their incompatibility and local irritation issues. Therefore, there has been a search for the compounds that exhibit broad enhancing activity for more drugs without producing much irritation. More recently, the use of biomaterials has emerged as a novel method to increase the skin permeability. In this paper, we present an overview of the investigations on the feasibility and application of biomaterials as penetration enhancers for transdermal or dermal drug delivery systems.

Transdermal administration of radiolabelled [14C]rotigotine by a patch formulation: A mass balance trial

NARCIS (Netherlands)

Cawello, W.; Wolff, H.M.; Meuling, W.J.A.; Horstmann, R.; Braun, M.

2007-01-01

Background and objective: The dopamine agonist rotigotine has been formulated in a silicone-based transdermal system for once-daily administration. The objective of the present study was to characterise the mass balance of rotigotine in humans after administration of a single transdermal patch

Hybrid electrospun chitosan-phospholipids nanofibers for transdermal drug delivery

DEFF Research Database (Denmark)

Mendes, Ana Carina Loureiro; Gorzelanny, Christian; Halter, Natalia

2016-01-01

Chitosan (Ch) polysaccharide was mixed with phospholipids (P) to generate electrospun hybrid nanofibers intended to be used as platforms for transdermal drug delivery. Ch/P nanofibers exibithed average diameters ranging from 248 +/- 94 nm to 600 +/- 201 nm, depending on the amount of phospholipids...... used. Fourier Transformed Infra-Red (FTIR) spectroscopy and Dynamic Light Scattering (DLS) data suggested the occurrence of electrostatic interactions between amine groups of chitosan with the phospholipid counterparts. The nanofibers were shown to be stable for at least 7 days in Phosphate Buffer...... culture plate (control). The release of curcumin, diclofenac and vitamin B12, as model drugs, from Ch/P hybrid nanofibers was investigated, demonstrating their potential utilization as a transdermal drug delivery system....

[Effect of low-dose or standard-dose conjugated equine estrogen combined with different progesterone on bone density in menopause syndrome women].

Science.gov (United States)

Zuo, H L; Deng, Y; Wang, Y F; Gao, L L; Xue, W; Zhu, S Y; Ma, X; Sun, A J

2018-04-25

Objective: To explore the effect of low-dose or standard-dose conjugated equine estrogen (CEE) combined with natural progesterone or dydrogesterone on bone density in menopause syndrome women. Methods: Totally 123 patients with menopause syndrome were recruited and randomly assigned to 3 treatment groups: group A (low-dose CEE+progesterone) , group B (standard-dose CEE+progesterone) , group C (standard-dose CEE+dydrogesterone) . Using continuous sequential regimen, the duration of intervention was 12 cycles. The bone mineral density of lumbar 2-4 and neck of femur, the bone metabolic markers, the level of FSH and estradiol were examined just before the drug administration and 12 months after the beginning of experiment. Results: There were 107 cases completed the one year trial. (1) Bone density: after 12 cycles of treatment, there was no significant change in bone density in group A ( P> 0.05) ; lumbar vertebrae of group B and C increased significantly, at 3.0% and 2.1%respectively (all Pdensity of left femoral neck of group C significantly increased by 2.9% ( P= 0.029) . There was no significant difference among the treatment groups at the beginning of experiment ( P> 0.05) . (2) Bone metabolic markers: after 12 cycles of treatment, the levels of calcium, phosphorus, alkaline phosphatase, Ca/Cr decreased significantly, the difference were statistically significant (all P 0.05) . (3) Levels of FSH and estradiol: after 12 cycles of treatment, the levels of FSH in three groups were decreased significantly (all P 0.05) . Conclusions: Both low-dose and standard-dose menopause hormone therapy (MHT) could elevate the level of estradiol, reduce bone turnover, prevent bone loss of postmenopausal women effectively. The standard dose of MHT could also increase the density of vertebrae and femoral neck, and generate more clinical benefits.

Penetration Enhancement Effect of Turpentine Oil on Transdermal ...

African Journals Online (AJOL)

inflammation drastically affect the quality of life after SCI. ... inhibitors may reduce spinal cord ischemic injury. [11]. Various .... Healthy male Wistar rats (200-250 g) were used ..... Guy RH. Transdermal science and technology an update.

Detection of sub micro Gray dose levels using OSL phosphor LiMgPO_4:Tb,B

International Nuclear Information System (INIS)

Rawat, N.S.; Dhabekar, Bhushan; Muthe, K.P.; Koul, D.K.; Datta, D.

2017-01-01

Highlights: • LiMgPO4:Tb,B has been studied and shown to possesses minimum measurable dose (MMD) in sub micro Gray region. • MMD as low as 0.49 µGy in readout time of less than 1 s at stimulation intensity of 32 mW/cm"2 has been achieved. • The OSL measurements for low doses has strengthened and validated this claim. • OSL spectrum shows several emission peaks and the prominent peak around 380 nm. - Abstract: Detection of sub micro Gray doses finds application in personnel and environmental monitoring, and nuclear forensics. Recently developed LiMgPO_4:Tb,B (LMP) is highly sensitive Optically Stimulated Luminescence (OSL) phosphor with excellent dosimetric properties. The OSL emission spectrum of LMP consists of several peaks attributed to characteristic Tb"3"+ emission. The OSL emission peak at 380 nm is favorable for bi-alkali PMT used in RISO reader system. It is demonstrated that significant improvement in dose detection threshold can be realized for LMP by optimization of continuous wave (CW–) OSL parameters like stimulation intensity and readout time. The minimum measurable dose (MMD) as low as 0.49 µGy in readout time of less than 1 s at stimulation intensity of 32 mW/cm"2 has been achieved using this phosphor. The recommendations for choice of parameters for personnel and environmental monitoring are also discussed.

Estradiol potentiation of gonadotropin-releasing hormone responsiveness in the anterior pituitary is mediated by an increase in gonadotropin-releasing hormone receptors

International Nuclear Information System (INIS)

Menon, M.; Peegel, H.; Katta, V.

1985-01-01

In order to investigate the mechanism by which 17 beta-estradiol potentiates the action of gonadotropin-releasing hormone on the anterior pituitary in vitro, cultured pituitary cells from immature female rats were used as the model system. Cultures exposed to estradiol at concentrations ranging from 10(-10) to 10(-6) mol/L exhibited a significant augmentation of luteinizing hormone release in response to a 4-hour gonadotropin-releasing hormone (10 mumol/L) challenge at a dose of 10(-9) mol/L compared to that of control cultures. The estradiol augmentation of luteinizing hormone release was also dependent on the duration of estradiol exposure. When these cultures were incubated with tritium-labeled L-leucine, an increase in incorporation of radiolabeled amino acid into total proteins greater than that in controls was observed. A parallel stimulatory effect of estradiol on iodine 125-labeled D-Ala6 gonadotropin-releasing hormone binding was observed. Cultures incubated with estradiol at different concentrations and various lengths of time showed a significant increase in gonadotropin-releasing hormone binding capacity and this increase was abrogated by cycloheximide. Analysis of the binding data showed that the increase in gonadotropin-releasing hormone binding activity was due to a change in the number of gonadotropin-releasing hormone binding sites rather than a change in the affinity. These results suggest that (1) estradiol treatment increases the number of pituitary receptors for gonadotropin-releasing hormone, (2) the augmentary effect of estradiol on luteinizing hormone release at the pituitary level might be mediated, at least in part, by the increase in the number of binding sites of gonadotropin-releasing hormone, and (3) new protein synthesis may be involved in estradiol-mediated gonadotropin-releasing hormone receptor induction

Anti-cancer vaccination by transdermal delivery of antigen peptide-loaded nanogels via iontophoresis.

Science.gov (United States)

Toyoda, Mao; Hama, Susumu; Ikeda, Yutaka; Nagasaki, Yukio; Kogure, Kentaro

2015-04-10

Transdermal vaccination with cancer antigens is expected to become a useful anti-cancer therapy. However, it is difficult to accumulate enough antigen in the epidermis for effective exposure to Langerhans cells because of diffusion into the skin and muscle. Carriers, such as liposomes and nanoparticles, may be useful for the prevention of antigen diffusion. Iontophoresis, via application of a small electric current, is a noninvasive and efficient technology for transdermal drug delivery. Previously, we succeeded in the iontophoretic transdermal delivery of liposomes encapsulating insulin, and accumulation of polymer-based nanoparticle nanogels in the stratum corneum of the skin. Therefore, in the present study, we examined the use of iontophoresis with cancer antigen gp-100 peptide KVPRNQDWL-loaded nanogels for anti-cancer vaccination. Iontophoresis resulted in the accumulation of gp-100 peptide and nanogels in the epidermis, and subsequent increase in the number of Langerhans cells in the epidermis. Moreover, tumor growth was significantly suppressed by iontophoresis of the antigen peptide-loaded nanogels. Thus, iontophoresis of the antigen peptide-loaded nanogels may serve as an effective transdermal delivery system for anti-cancer vaccination. Copyright © 2015 Elsevier B.V. All rights reserved.

Microneedles array with biodegradable tips for transdermal drug delivery

Science.gov (United States)

Iliescu, Ciprian; Chen, Bangtao; Wei, Jiashen; Tay, Francis E. H.

2008-12-01

The paper presented an enhancement solution for transdermal drug delivery using microneedles array with biodegradable tips. The microneedles array was fabricated by using deep reactive ion etching (DRIE) and the biodegradable tips were made to be porous by electrochemical etching process. The porous silicon microneedle tips can greatly enhance the transdermal drug delivery in a minimum invasion, painless, and convenient manner, at the same time; they are breakable and biodegradable. Basically, the main problem of the silicon microneedles consists of broken microneedles tips during the insertion. The solution proposed is to fabricate the microneedle tip from a biodegradable material - porous silicon. The silicon microneedles are fabricated using DRIE notching effect of reflected charges on mask. The process overcomes the difficulty in the undercut control of the tips during the classical isotropic silicon etching process. When the silicon tips were formed, the porous tips were then generated using a classical electrochemical anodization process in MeCN/HF/H2O solution. The paper presents the experimental results of in vitro release of calcein and BSA with animal skins using a microneedle array with biodegradable tips. Compared to the transdermal drug delivery without any enhancer, the microneedle array had presented significant enhancement of drug release.

17β-Estradiol augments antidepressant efficacy of escitalopram in ovariectomized rats: Neuroprotective and serotonin reuptake transporter modulatory effects.

Science.gov (United States)

Ibrahim, Weam W; Safar, Marwa M; Khattab, Mahmoud M; Agha, Azza M

2016-12-01

The prevalence or recurrence of depression is seriously increased in women during the transition to and after menopause. The chronic hypo-estrogenic state of menopause may reduce the response to antidepressants; however the influence of estrogen therapy on their efficacy is still controversial. This study aimed at investigating the effects of combining escitalopram with 17β-estradiol on depression and cognitive impairment induced by ovariectomy, an experimental model of human menopause. Young adult female Wistar rats were subjected to either sham operation or ovariectomy. Ovariectomized animals were treated chronically with escitalopram (10mg/kg/day, i.p) alone or with four doses of 17β-estradiol (40μg/kg, s.c) given prior to the behavioral tests. Co-administration of 17β-estradiol improved escitalopram-induced antidepressant effect in forced swimming test verified as more prominent decrease in the immobility time without opposing its memory enhancing effect in Morris water maze. 17β-estradiol augmented the modulatory effects of escitalopram on the hippocampal levels of brain-derived neurotrophic factor and serotonin reuptake transporter as well as tumor necrosis factor-alpha without altering its effects on the gene expressions of serotonin receptor 1A, estrogen receptors alpha and beta, or acetylcholinestearase content. This combined therapy afforded synergistic protective effects on the brain histopathological architecture, particularly, the hippocampus. The antidepressant effect of 17β-estradiol was abolished by pretreatment with estrogen receptor antagonist, tamoxifen (10mg/kg, p.o). In conclusion, 17β-estradiol-induced antidepressant effect was confined to intracellular estrogen receptors activation. Moreover, 17β-estradiol enhanced escitalopram's efficiency in ameliorating menopausal-like depression, via exerting synergistic neuroprotective and serotonin reuptake transporter modulatory effects, without impeding escitalopram-mediated cognitive

Natural oils as skin permeation enhancers for transdermal delivery of olanzapine: in vitro and in vivo evaluation.

Science.gov (United States)

Aggarwal, Geeta; Dhawan, Sanju; HariKumar, S L

2012-03-01

The feasibility of development of transdermal delivery system of olanzapine utilizing natural oils as permeation enhancers was investigated. Penetration enhancing potential of corn (maize) oil, groundnut oil and jojoba oil on in vitro permeation of olanzapine across rat skin was studied. The magnitude of flux enhancement factor with corn oil, groundnut oil and jojoba oil was 7.06, 5.31 and 1.9 respectively at 5mg/ml concentration in solvent system. On the basis of in vitro permeation studies, eudragit based matrix type transdermal patches of olanzapine were fabricated using optimized concentrations of natural oils as permeation enhancers. All transdermal patches were found to be uniform with respect to physical characteristics. The interaction studies carried out by comparing the results of ultraviolet, HPLC and FTIR analyses for the pure drug, polymers and mixture of drug and polymers indicated no chemical interaction between the drug and excipients. Corn oil containing unsaturated fatty acids was found to be promising natural permeation enhancer for transdermal delivery of olanzapine with greatest cumulative amount of drug permeated (1010.68 μg/cm²/h) up to 24 h and caused no skin irritation. The fabricated transdermal patches were found to be stable. The pharmacokinetic characteristics of the final optimized matrix patch (T2) were determined after transdermal application to rabbits. The calculated relative bioavailability of TDDS was 113.6 % as compared to oral administration of olanzapine. The therapeutic effectiveness of optimized transdermal system was confirmed by tranquillizing activity in rotarod and grip mice model.

Opioids Switching with Transdermal Systems in Chronic Cancer Pain

Directory of Open Access Journals (Sweden)

Barbarisi M

2009-05-01

Full Text Available Abstract Background Due to tolerance development and adverse side effects, chronic pain patients frequently need to be switched to alternative opioid therapy Objective To assess the efficacy and tolerability of an alternative transdermally applied (TDS opioid in patients with chronic cancer pain receiving insufficient analgesia using their present treatment. Methods A total of 32 patients received alternative opioid therapy, 16 were switched from buprenorphine to fentanyl and 16 were switched from fentanyl to buprenorphine. The dosage used was 50% of that indicated in equipotency conversion tables. Pain relief was assessed at weekly intervals for the next 3 weeks Results Pain relief as assessed by VAS, PPI, and PRI significantly improved (p Conclusion Opioid switching at 50% of the calculated equianalgesic dose produced a significant reduction in pain levels and rescue medication. The incidence of side effects decreased and no new side effects were noted. Further studies are required to provide individualized treatment for patients according to their different types of cancer.

Preparation and characterization of metoprolol tartrate containing matrix type transdermal drug delivery system.

Science.gov (United States)

Malipeddi, Venkata Ramana; Awasthi, Rajendra; Ghisleni, Daniela Dal Molim; de Souza Braga, Marina; Kikuchi, Irene Satiko; de Jesus Andreoli Pinto, Terezinha; Dua, Kamal

2017-02-01

The present study aimed to develop matrix-type transdermal drug delivery system (TDDS) of metoprolol tartrate using polyvinyl pyrrolidone (PVP) and polyvinyl alcohol (PVA). The transdermal films were evaluated for physical parameters, Fourier transform infrared spectroscopy analysis (FTIR), differential scanning calorimetry (DSC), in vitro drug release, in vitro skin permeability, skin irritation test and stability studies. The films were found to be tough, non-sticky, easily moldable and possess good tensile strength. As the concentration of PVA was increased, the tensile strength of the films was also increased. Results of FTIR spectroscopy and DSC revealed the absence of any drug-polymer interactions. In vitro release of metoprolol followed zero-order kinetics and the mechanism of release was found to be diffusion rate controlled. In vitro release studies of metoprolol using Keshary-Chein (vertical diffusion cell) indicated 65.5 % drug was released in 24 h. In vitro skin permeation of metoprolol transdermal films showed 58.13 % of the drug was released after 24 h. In vitro skin permeation of metoprolol followed zero-order kinetics in selected formulations. The mechanism of release was found to be diffusion rate controlled. In a 22-day skin irritation test, tested formulation of transdermal films did not exhibit any allergic reactions, inflammation, or contact dermatitis. The transdermal films showed good stability in the 180-day stability study. It can be concluded that the TDDS of MPT can help in bypassing the first-pass effect and will provide patient improved compliance, without sacrificing the therapeutic advantages of the drugs.

Estradiol Valerate-induced Polycystic Ovary Syndrome: An Animal Model Study

Directory of Open Access Journals (Sweden)

F Mesbah

2011-01-01

Full Text Available Introduction & Objective: Polycystic ovary syndrome (PCOS is a complex endocrine and metabolic disorder and one of the most common causes of an ovulation among women in their reproductive age. Presence of cysts in the ovaries alteration in the blood levels of gonadotropine hormones and gaining weight are some of the main characteristics of PCOS among humans. Our goal was to investigate the possible occurrence of such conditions in animal models of PCOS. Materials & Methods: Forty five Sprague Dawely rats were divided into 3 equal groups: the treatment and sham groups were intramuscularly injected by a single dose of Estradiol Valerate (4 mg/rat, dissolved in 0.4 ml and equal volume of olive oil, respectively, and the control group without any injection. During the 12 weeks of study, the animal’s weights were measured once a week. After 8 weeks, serum levels of testosterone, estrogen, progesterone, Follicular Stimulating Hormone (FSH, Latinizing Hormone (LH and glucose were measured. Following 12 weeks, ovaries were removed and prepared for light microscopy. Histological characteristics of ovaries were observed after hematoxylin-eosin staining. Results: Animal weight and serum level of testosterone were significantly reduced among PCOS induced rats while progesterone, LH and glucose levels were elevated. There was no significant difference in estradiol and FSH levels among different group of animals. Many cysts and degenerating follicles were observed in the treatment group. Conclusion: PCOS can be experimentally produced by a single injection of Estradiol Valerate in the rat, but some of the complex aspects of PCOS are not clearly defined.

Effect of exogenous estradiol applied at different embryonic stages on sex determination, growth, and mortality in the leopard gecko (Eublepharis macularius).

Science.gov (United States)

Tousignant, A; Crews, D

1994-01-01

Temperature-dependent sex determination (TSD) occurs in three orders of reptiles. Several studies have examined the ability of estradiol to produce female hatchlings incubated at a male-producing temperature. The results of these experiments support the idea that estradiol could be used as a powerful tool in the conservation of endangered species with TSD by manipulating hatchling sex ratios. However, these experiments have concentrated on the mechanism of determination. This experiment was designed to test the efficacy of various dosages of estradiol applied at two different stages to alter the hatchling sex ratio as well as determining the potential use of such manipulation for conservation efforts by monitoring egg mortality and hatchling growth. The leopard gecko (Eublepharis macularius) exhibits TSD and reaches reproductive maturity in less than one year, making it an excellent model for evaluating the long-term effects of estradiol. The results demonstrate that estradiol has a dose-dependent effect on the hatchling sex ratio while only high dosages applied at the later stage of development showed increased mortality. Estrogen-determined females grew at the same rate as temperature-determined females and have produced viable hatchlings. Estradiol treatment of eggs from endangered species may provide a method of insuring female offspring when the TSD pattern is unknown or equipment for controlled incubation is unavailable.

Predictive value of repeated measurements of luteal progesterone and estradiol levels in patients with intrauterine insemination and controlled ovarian stimulation.

Science.gov (United States)

Bakas, Panagiotis; Simopoulou, Maria; Giner, Maria; Drakakis, Petros; Panagopoulos, Perikles; Vlahos, Nikolaos

2017-10-01

The objective of this study is to assess if the difference of repeated measurements of estradiol and progesterone during luteal phase predict the outcome of intrauterine insemination. Prospective study. Reproductive clinic. 126 patients with infertility. Patients underwent controlled ovarian stimulation with recombinant FSH (50-150 IU/d). The day of IUI patients were given p.o natural micronized progesterone in a dose of 100 mg/tds. The area under the receiver characteristic operating curve (ROC curve) in predicting clinical pregnancy for % change of estradiol level on days 6 and 10 was 0.892 with 95% CI: 0.82-0.94. A cutoff value of change > -29.5% had a sensitivity of 85.7 with a specificity of 90.2. The corresponding ROC curve for % change of progesterone level was 0.839 with 95% CI: 0.76-0.90. A cutoff value of change > -33% had a sensitivity of 85 with a specificity of 75. The % change of estradiol and progesterone between days 6 and 10 has a predictive ability of pregnancy after IUI with COS of 89.2% and 83.4%, respectively. The addition of % of progesterone to % change of estradiol does not improve the predictive ability of % estradiol and should not be used.

Dosage of estradiol, bone and body composition in Turner syndrome: a 5-year randomized controlled clinical trial

DEFF Research Database (Denmark)

Cleemann, Line; Holm, Kirsten; Kobbernagel, Hanne

2017-01-01

OBJECTIVE: Reduced bone mineral density (BMD) is seen in Turner syndrome (TS) with an increased risk of fractures, and body composition is characterized by increased body fat and decreased lean body mass. To evaluate the effect of two different doses of oral 17ß-estradiol in young TS women on bone...

Transdermal and transbuccal drug delivery systems: enhancement using iontophoretic and chemical approaches.

Science.gov (United States)

Hu, Longsheng; Silva, Sérgio M C; Damaj, Bassam B; Martin, Richard; Michniak-Kohn, Bozena B

2011-12-12

We investigated the enhancement effect of chemical enhancers and iontophoresis on the in vitro transdermal and transbuccal delivery of lidocaine HCl (LHCl), nicotine hydrogen tartrate (NHT), and diltiazem HCl (DHCl) using porcine skin and buccal tissues. Dodecyl 2-(N,N-dimethylamino) propionate (DDAIP), dodecyl-2-(N,N-dimethylamino) propionate hydrochloride (DDAIP HCl), N-(4-bromobenzoyl)-S,S-dimethyliminosulfurane (Br-iminosulfurane), and azone (laurocapram) were used as chemical enhancers. The study results showed that the application of iontophoresis at either 0.1 mA or 0.3 mA significantly enhanced transdermal and transmucosal delivery of LHCl, NHT and DHCl. It was also demonstrated that iontophoresis had a more pronounced enhancement effect on transdermal delivery than on transbuccal delivery of LHCl, NHT and DHCl. In addition, DDAIP HCl was found to be the most effective enhancer for transbuccal delivery of LHCl and NHT. Copyright © 2011 Elsevier B.V. All rights reserved.

Estradiol-promoted accumulation of receptor in nuclei of porcine endometrium cells. Immunogold electron microscopy of resting and estradiol-stimulated cells.

Science.gov (United States)

Sierralta, W D; Jakob, F; Thole, H; Engel, P; Jungblut, P W

1992-01-01

Endometrium was collected by curettage from castrated pigs, either untreated or exposed to estradiol in vivo by intrauterine injection, and processed for electron microscopy. The resin LR Gold was used for embedding, and sections were floated on droplets of 10 nm diameter gold particles, coated with the immunoglobulin-G1 (IgG1) fraction or its Fab2 fragment of a monospecific polyclonal antiserum raised in goats against the C-terminal half of the estradiol receptor. On average, only one gold particle per microns 2 became attached in the cytoplasmic area of untreated cells, whereas four were found over the nuclear area. These figures rose to 2-3/microns 2 and 15-26/microns 2, respectively, within 10 min after exposure to estradiol. The labeling intensities of nuclei in cell clusters and of coprocessed nuclei released from cells ruptured during curettage were identical in all situations. Nuclear pores were frequently tagged after estradiol treatment. The proportions of tagging densities in nuclei of untreated and estradiol-exposed cells corresponded to those of receptor contents measured in extracts of isolated nuclei by ligand binding. This correlation was not seen for the cytoplasmic compartment of untreated cells, the scarce tagging of which is interpreted by hidden antigenic determinants. Our morphological analyses support the conclusions drawn from biochemical data (Sierralta et al., 1992) of an estradiol-promoted translocation of receptor from the cytoplasm into the nucleus.

Modified Transdermal Technologies: Breaking the Barriers of Drug ...

African Journals Online (AJOL)

In-depth analysis, formulation approaches, applications, advantages and disadvantages of these newer technologies are discussed. Keywords: Transdermal drug delivery, microneedles, macroflux, iontophoresis, ultrasound, powderject, skin abrasion. > Tropical Journal of Pharmaceutical Research Vol. 6 (1) 2007: pp. 633- ...

Direct radioimmunoassay of 17. beta. -estradiol in ether extracts of bovine

Energy Technology Data Exchange (ETDEWEB)

Medina, M.B.

Anabolic estrogens such as 17..beta..-estradiol or 17..beta..-estradiol benzoate are used to promote growth and increase feed efficiency in food-producing cattle. This paper describes a technique to produce a more specific antibody to 17..beta..-estradiol by intradermal immunization using microquantities of 6-(carboxymethyl)-17..beta..-estradiol oxime bovine serum albumin and the development of a radioimmunoassay (RIA) procedure to measure directly the amounts of 17..beta..-estradiol in ether extracts of bovine serum without using cleanup procedures. Results demonstrated that a specific and sensitive antibody was produced, and a titer of 1:10,000 was used in the RIA procedure. Antibody cross-reactivity with ..beta..-estradiol metabolites and other anabolic estrogens was negligible. The untreated bovine sera showed 0-24 pg of apparent 17..beta..-estradiol/mL, while 0-31 pg/mL total estrogens had been reported in the literature. This assay can measure 5-100 pg in 20-250..mu..L/sample. This method can be used before or immediately after slaughter to monitor the residual amounts of estradiol used in the treatment of cattle.

Direct radioimmunoassay of 17β-estradiol in ether extracts of bovine

International Nuclear Information System (INIS)

Medina, M.B.

1986-01-01

Anabolic estrogens such as 17β-estradiol or 17β-estradiol benzoate are used to promote growth and increase feed efficiency in food-producing cattle. This paper describes a technique to produce a more specific antibody to 17β-estradiol by intradermal immunization using microquantities of 6-(carboxymethyl)-17β-estradiol oxime bovine serum albumin and the development of a radioimmunoassay (RIA) procedure to measure directly the amounts of 17β-estradiol in ether extracts of bovine serum without using cleanup procedures. Results demonstrated that a specific and sensitive antibody was produced, and a titer of 1:10,000 was used in the RIA procedure. Antibody cross-reactivity with β-estradiol metabolites and other anabolic estrogens was negligible. The untreated bovine sera showed 0-24 pg of apparent 17β-estradiol/mL, while 0-31 pg/mL total estrogens had been reported in the literature. This assay can measure 5-100 pg in 20-250μL/sample. This method can be used before or immediately after slaughter to monitor the residual amounts of estradiol used in the treatment of cattle

[Studies on transdermal delivery of ferulic acid through rat skin treated by microneedle arrays].

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Yang, Bing; Du, Shou-ying; Bai, Jie; Shang, Ke-xin; Lu, Yang; Li, Peng-yue

2014-12-01

In order to investigate the characteristics of transdermal delivery of ferulic acid under the treated of microneedle arrays and the influence on permeability of rat skin capillaries, improved Franz-cells were used in the transdermal delivery experiment with the rat skin of abdominal wall and the length of microneedle arrays, different insertion forces, retention time were studied in the influence of characteristics of transdermal delivery of FA. The amount of FA was determined by HPLC system. Intravenous injection Evans blue and FA was added after microneedle arrays treated. Established inflammation model was built by daubing dimethylbenzene. The amount of Evans blue in the rat skin was read at 590 nm wavelength with a Multiskan Go microplate reader. Compared with passive diffusion group the skin pretreated with microneedle arrays had a remarkable enhancement of FA transport (P Microneedle arrays with different length had a remarkable enhancement of FA transport, but was not related to the increase of the length. The research of FA on the reduce of permeability of rat skin capillaries indicated that the skin pretreated with microneedle arrays could reduce the content of Evans blue in the skins of rat significantly compared with the untreated group. The permeation rate of ferulic acid transdermal delivery had remarkable increase under the treated of microneedle arrays and the length of microneedle arrays ,the retention time so as to the insertion force were important to the transdermal delivery of ferulic acid.

Effect of Estradiol-17β Injection on Gonad Development of White Shrimp (Litopenaeus vannamei

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. Tarsim

2007-01-01

Full Text Available The methods for hormonal control of shrimp reproduction are very limited, and only eyestalk ablation is used to induce ovarian development and spawning in shrimp farming. The occurrence of vertebrate-type steroid hormones in crustaceans have been reported, however, their physiological role are not sufficiently understood. The present study analyzed the effect of estradiol-17β injection on gonad development of white shrimp, Litopenaeus vannamei. The estradiol-17β dose 0.10 μg/g body weight were used. The treatments consisted of control, single injection (day 0 and double injection (day 0 and 6. The females broodstock were cultured for 12 days. The result showed that estradiol-17β had positive effect on gonad development. The gonado somatic index (GSI and oocytes diameter in treatment larger than the control. Double injection had highest effect with ∆GSI and oocytes diameter was 0.453  and 23.97 µm, respectively. The only oocytes previtelogenesis was found in gonad. It indicated that estradiol-17β important to induce endogenous vitellogenesis. Gonad development probably affected by gonad inhibiting hormone in the eyestalk. It was inhibited oocyte maturation. The polypeptide sub unit was observed in vitellin of ovari by SDS-PAGE. The molecular weights of approximately 95, 98, 109 and two units higher than 118 kDa of protein marker. Keywords: Gonad, estradiol-17β, oocyte, Litopenaeus vannamei   ABSTRAK Teknologi reproduksi dalam pembenihan udang belum mengalami perkembangan yang signifikan.  Pada umumnya untuk mempercepat kematangan gonad induk udang digunakan teknik ablasi. Mekanisme dan peranan hormon pada proses reproduksi udang belum banyak diketahui. Keberadaan hormon steroid pada krustase telah dikemukaan oleh beberapa peneliti, tetapi peranannya belum banyak diketahui.  Pada penelitian ini dikaji pengaruh penyuntikan hormon estradiol-17β pada perkembangan gonad induk udang putih (Litopenaeus vannamei.  Penelitian ini

Assessment of micro-dose biplanar radiography in lower limb measurements in children

International Nuclear Information System (INIS)

Lerisson, Heloise; Amzallag-Bellenger, Elisa; Cebulski-Delebarre, Aurelie; Boutry, Nathalie; Nectoux, Eric; Herbaux, Bernard; Desmulliez, Geoffrey; Duhamel, Alain; Drumez, Elodie

2018-01-01

To evaluate in children microdose protocol compared with low dose for lower limb alignment (LLA) measurements on biplanar radiography. Children 6 years or older were included. Height, weight and hip width were measured prior to imaging. Hip width allowed classifying children into morphotype M1 (width <25 cm), M2 (25-35 cm) or M3 (>35 cm) corresponding to predefined acquisition parameters (kV, mA, tube speed). Micro- and low-dose protocols were used alternately, with simultaneous acquisition of frontal and lateral radiographs. LLA measurements were performed by two independent observers (n = 526). In 15 children per morphotype, a third observer performed measurements twice (n = 180). Intraclass correlation coefficients and the dose (delivered, absorbed) were calculated. 100 girls and 160 boys (mean age = 11.7 years) were investigated: 74 M1 (mean BMI, 15.7kg/m 2 ), 149 M2 (19.8 kg/m 2 ) and 40 M3 (30.2 kg/m 2 ). With microdose, inter- and intra-observer agreement was >0.90 for lengths whatever the morphotype, 0.75-0.90 (M1) and >0.90 (M2, M3) for valgus/varus and flexion/hyperextension deviations. Dose reduction reached a factor of 8.5 and 5.4 for the delivered and absorbed dose respectively. Microdose could be used for LLA measurements in children and permits a significant dose reduction. (orig.)

ACCEPTABILITY OF ULTRA LOW-DOSE ORAL CONTRACEPTIVES CONTAINING 20 µg ETHINYL ESTRADIOL AND 75 µg GESTODENE IN YOUNG FEMALES IN A MULTICENTER CLINICAL STUDY

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Bojana Pinter

2004-06-01

Full Text Available Background. The acceptability of ultra low-dose oral contraception (OC among young females after three and six cycles of treatment was assessed.Methods. In the clinical prospective study, carried out in 10 outpatient clinics in Slovenia, 240 healthy women aged 16– 30 years choosing ultra low-dose OC (20 µg ethinyl estradiol and 75 µg gestodene were included.Results. The average age was 20.6 (± 3.5 years. After three cycles (N = 228 there were no changes in body weight or blood pressure; one tenth (9.6% of women reported irregular bleeding and 3.9% weight gain while other side effects occurred rarely. After three cycles 88.3% of the women initially included continued OC use (5% discontinued the use due to side effects. After six cycles (N = 195 there were no changes in blood pressure; body weight statistically significantly increased for 0.5 kg providing the weight changes during the time were not considered. Fewer women reported side effects (3.6% irregular bleeding, 2.6% weight gain and rarely other side effects. After six cycles 75.0% of the women initially included continued the OC use (7.5% discontinued the use due to the side effects.Conclusions. The study has shown good clinical acceptability of ultra low-dose OC by young females.

Avanafil Liposomes as Transdermal Drug Delivery for Erectile ...

African Journals Online (AJOL)

Avanafil is slightly soluble in ethanol, practically insoluble in water ... transdermal permeability and bioavailability for the treatment of .... Table 1 shows that the EE had higher values for the MLVs .... reason is the lower solubility of avanafil at pH.

The specific features of using a rivastigmine transdermal formulation in Alzheimer’s disease

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Elena Evgenyevna Vasenina

2012-01-01

Full Text Available Cholinergic deficiency associated mainly with the degeneration of neurons in the nucleus basalis of Meynert is one of the key factors of the development of cognitive impairments in Alzheimer’s disease (AD. Cholinesterase inhibitors are used to treat mild and moderate dementia in AD. However, the wide use of this group of agents is limited by the high incidence of some side effects. The application of a novel rivastigmine transdermal (patch formulation substantially reduces the risk of adverse reactions chiefly associated with a negative effect on the gastrointestinal tract and increases treatment adherence. Thus, there is a rise in the number of patients who may be given the drug in the optimal therapeutic dose for a long time.

Estradiol-Dependent Stimulation and Suppression of Gonadotropin-Releasing Hormone Neuron Firing Activity by Corticotropin-Releasing Hormone in Female Mice.

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Phumsatitpong, Chayarndorn; Moenter, Suzanne M

2018-01-01

Gonadotropin-releasing hormone (GnRH) neurons are the final central regulators of reproduction, integrating various inputs that modulate fertility. Stress typically inhibits reproduction but can be stimulatory; stress effects can also be modulated by steroid milieu. Corticotropin-releasing hormone (CRH) released during the stress response may suppress reproduction independent of downstream glucocorticoids. We hypothesized CRH suppresses fertility by decreasing GnRH neuron firing activity. To test this, mice were ovariectomized (OVX) and either implanted with an estradiol capsule (OVX+E) or not treated further to examine the influence of estradiol on GnRH neuron response to CRH. Targeted extracellular recordings were used to record firing activity from green fluorescent protein-identified GnRH neurons in brain slices before and during CRH treatment; recordings were done in the afternoon when estradiol has a positive feedback effect to increase GnRH neuron firing. In OVX mice, CRH did not affect the firing rate of GnRH neurons. In contrast, CRH exhibited dose-dependent stimulatory (30 nM) or inhibitory (100 nM) effects on GnRH neuron firing activity in OVX+E mice; both effects were reversible. The dose-dependent effects of CRH appear to result from activation of different receptor populations; a CRH receptor type-1 agonist increased firing activity in GnRH neurons, whereas a CRH receptor type-2 agonist decreased firing activity. CRH and specific agonists also differentially regulated short-term burst frequency and burst properties, including burst duration, spikes/burst, and/or intraburst interval. These results indicate that CRH alters GnRH neuron activity and that estradiol is required for CRH to exert both stimulatory and inhibitory effects on GnRH neurons. Copyright © 2018 Endocrine Society.

Ethinyl Estradiol and Norelgestromin Transdermal Patch

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... time.Ask your pharmacist or doctor for a copy of the manufacturer's information for the patient. ... the uterus, cervix, or vagina; vaginal bleeding between menstrual periods; hepatitis (swelling of the liver); yellowing of ...

[{sup 11}C]diclofenac sodium: synthesis and PET assessment of transdermal penetration

Energy Technology Data Exchange (ETDEWEB)

Petroni, Debora, E-mail: debora.petroni@ifc.cnr.i [CNR Institute of Clinical Physiology, Via Moruzzi 1, 56124 Pisa (Italy); Menichetti, Luca; Sorace, Oreste; Poli, Michela [CNR Institute of Clinical Physiology, Via Moruzzi 1, 56124 Pisa (Italy); Vanasia, Massimo [Gienne Pharma, Via Lorenteggio 270/A, 20152 Milan (Italy); Salvadori, Piero A. [CNR Institute of Clinical Physiology, Via Moruzzi 1, 56124 Pisa (Italy)

2011-02-15

The aim of this work was to study the feasibility of using Positron Emission Tomography (PET) imaging as a new tool to detect transdermal penetration of topical drugs in human subjects. The compound used in the study is sodium 2-[(2,6-dichlorophenyl)amino]phenyl]acetate, better known as diclofenac sodium. This molecule belongs to the family of non-steroidal anti-inflammatory drugs and is considered one of the first choices among non-steroidal anti-inflammatory drugs for the treatment of inflammatory diseases; it is widely used and commercially present in a large number of pharmaceutical forms and formulations. {sup 11}C-labeled diclofenac has been synthesized and coformulated, as an internal indicator, with a proprietary preparation based on the use of a sprayer. The radiolabeled preparation was topically administered to healthy volunteers, and PET imaging was used to evaluate transdermal penetration. Results obtained have demonstrated the efficacy of PET and radiolabeled tracers for the evaluation of transdermal penetration of active pharmaceutical ingredients as topical formulations.

Evaluation of mesotherapy as a transdermal drug delivery tool.

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Kim, S; Kye, J; Lee, M; Park, B

2016-05-01

There has been no research about the exact mechanism of transdermal drug delivery during mesotherapy. We aimed to evaluate whether the commercial mesogun can be an appropriate technique for a transdermal drug delivery. We injected blue ink into the polyurethane foam or pig skin with three types of mesotherapy using a commercial mesogun, or local made intradermal injector, or a manual injection of syringe. To assess the internal pressure of the cylinder and drug delivery time, we designed the evaluation setup using a needle tip pressure transducer. All types of injectors induced adequate penetration of blue ink into the polyurethane foam without backflow. In the pig skin, blue ink leaked out rapidly with the backward movement of the needle in the commercial mesogun in contrast to the local made injector or the manual injection of syringe. When the time for backward movement of the syringe approaches 1000 ms, the cylinder pressure of the syringe is saturated at around 25 mmHg which can be translated into the dermal pressure of the pig skin. There should be sufficient time between the insertion and withdrawal of the needle of injector for the adequate transdermal drug delivery and it must be considered for mesotherapy. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Microneedles for Transdermal Biosensing: Current Picture and Future Direction.

Science.gov (United States)

Ventrelli, Letizia; Marsilio Strambini, Lucanos; Barillaro, Giuseppe

2015-12-09

A novel trend is rapidly emerging in the use of microneedles, which are a miniaturized replica of hypodermic needles with length-scales of hundreds of micrometers, aimed at the transdermal biosensing of analytes of clinical interest, e.g., glucose, biomarkers, and others. Transdermal biosensing via microneedles offers remarkable opportunities for moving biosensing technologies and biochips from research laboratories to real-field applications, and envisages easy-to-use point-of-care microdevices with pain-free, minimally invasive, and minimal-training features that are very attractive for both developed and emerging countries. In addition to this, microneedles for transdermal biosensing offer a unique possibility for the development of biochips provided with end-effectors for their interaction with the biological system under investigation. Direct and efficient collection of the biological sample to be analyzed will then become feasible in situ at the same length-scale of the other biochip components by minimally trained personnel and in a minimally invasive fashion. This would eliminate the need for blood extraction using hypodermic needles and reduce, in turn, related problems, such as patient infections, sample contaminations, analysis artifacts, etc. The aim here is to provide a thorough and critical analysis of state-of-the-art developments in this novel research trend, and to bridge the gap between microneedles and biosensors. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Inhibition of Estradiol Synthesis Impairs Fear Extinction in Male Rats

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Graham, Bronwyn M.; Milad, Mohammed R.

2014-01-01

Emerging research has demonstrated that the sex hormone estradiol regulates fear extinction in female rodents and women. Estradiol may also regulate fear extinction in males, given its role in synaptic plasticity in both sexes. Here we report that inhibition of estradiol synthesis during extinction training, via the aromatase inhibitor fadrozole,…

Estradiol blood test

Science.gov (United States)

... page: //medlineplus.gov/ency/article/003711.htm Estradiol blood test To use the sharing features on this page, ... of estrogens. How the Test is Performed A blood sample is needed . How to Prepare for the Test Your health care provider may tell you to ...

Development of Tat-Conjugated Dendrimer for Transdermal DNA Vaccine Delivery.

Science.gov (United States)

Bahadoran, Azadeh; Moeini, Hassan; Bejo, Mohd Hair; Hussein, Mohd Zobir; Omar, Abdul Rahman

In order to enhance cellular uptake and to facilitate transdermal delivery of DNA vaccine, polyamidoamine (PAMAM) dendrimers conjugated with HIV transactivator of transcription (TAT) was developed. First, the plasmid DNA (pIRES-H5/GFP) nanoparticle was formulated using PAMAM dendrimer and TAT peptide and then characterized for surface charge, particle size, DNA encapsulation and protection of the pIRES-H5/GFP DNA plasmid to enzymatic digestion. Subsequently, the potency of the TAT-conjugated dendrimer for gene delivery was evaluated through in vitro transfection into Vero cells followed by gene expression analysis including western blotting, fluorescent microscopy and PCR. The effect of the TAT peptide on cellular uptake of DNA vaccine was studied by qRT-PCR and flow cytometry. Finally, the ability of TAT-conjugated PAMAM dendrimer for transdermal delivery of the DNA plasmid was assessed through artificial membranes followed by qRT-PCR and flow cytometry. TAT-conjugated PAMAM dendrimer showed the ability to form a compact and nanometre-sized polyplexes with the plasmid DNA, having the size range of 105 to 115 nm and a positive charge of +42 to +45 mV over the N/P ratio of 6:1(+/-).  In vitro transfection analysis into Vero cells confirms the high potency of TAT-conjugated PAMAM dendrimer to enhance the cellular uptake of DNA vaccine.  The permeability value assay through artificial membranes reveals that TAT-conjugated PAMAM has more capacity for transdermal delivery of the DNA compared to unmodified PAMAM dendrimer (Pdendrimer is a promising non-viral vector for transdermal use.This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

Transdermal delivery and cutaneous targeting of antivirals using a penetration enhancer and lysolipid prodrugs.

Science.gov (United States)

Diblíková, Denisa; Kopečná, Monika; Školová, Barbora; Krečmerová, Marcela; Roh, Jaroslav; Hrabálek, Alexandr; Vávrová, Kateřina

2014-04-01

In this work, we investigate prodrug and enhancer approaches for transdermal and topical delivery of antiviral drugs belonging to the 2,6-diaminopurine acyclic nucleoside phosphonate (ANP) group. Our question was whether we can differentiate between transdermal and topical delivery, i.e., to control the delivery of a given drug towards either systemic absorption or retention in the skin. The in vitro transdermal delivery and skin concentrations of seven antivirals, including (R)- and (S)-9-[2-(phosphonomethoxy)propyl]-2,6-diaminopurine (PMPDAP), (S)-9-[3-hydroxy-2-(phosphonomethoxy)propyl]-2,6-diaminopurine ((S)-HPMPDAP), its 8-aza analog, and their cyclic and hexadecyloxypropyl (HDP) prodrugs, was investigated with and without the penetration enhancer dodecyl-6-(dimethylamino)hexanoate (DDAK) using human skin. The ability of ANPs to cross the human skin barrier was very low (0.5-1.4 nmol/cm(2)/h), and the majority of the compounds were found in the stratum corneum, the uppermost skin layer. The combination of antivirals and the penetration enhancer DDAK proved to be a viable approach for transdermal delivery, especially in case of (R)-PMPDAP, an anti-HIV effective drug (30.2 ± 2.3 nmol/cm(2)/h). On the other hand, lysophospholipid-like HDP prodrugs, e.g., HDP-(S)-HPMPDAP, reached high concentrations in viable epidermis without significant systemic absorption. By using penetration enhancers or lysolipid prodrugs, it is possible to effectively target systemic diseases by the transdermal route or to target cutaneous pathologies by topical delivery.

Contingency management for alcohol use reduction: a pilot study using a transdermal alcohol sensor.

Science.gov (United States)

Barnett, Nancy P; Tidey, Jennifer; Murphy, James G; Swift, Robert; Colby, Suzanne M

2011-11-01

Contingency management (CM) has not been thoroughly evaluated as a treatment for alcohol abuse or dependence, in part because verification of alcohol use reduction requires frequent in-person breath tests. Transdermal alcohol sensors detect alcohol regularly throughout the day, providing remote monitoring and allowing for rapid reinforcement of reductions in use. The purpose of this study was to evaluate the efficacy of CM for reduction in alcohol use, using a transdermal alcohol sensor to provide a continuous measure of alcohol use. Participants were 13 heavy drinking adults who wore the Secure Continuous Remote Alcohol Monitoring (SCRAM) bracelet for three weeks and provided reports of alcohol and drug use using daily web-based surveys. In Week 1, participants were asked to drink as usual; in Weeks 2 and 3, they were reinforced on an escalating schedule with values ranging from $5 to $17 per day on days when alcohol use was not reported or detected by the SCRAM. Self-reports of percent days abstinent and drinks per week, and transdermal measures of average and peak transdermal alcohol concentration and area under the curve declined significantly in Weeks 2-3. A nonsignificant but large effect size for reduction in days of tobacco use also was found. An adjustment to the SCRAM criteria for detecting alcohol use provided an accurate but less conservative method for use with non-mandated clients. Results support the efficacy of CM for alcohol use reductions and the feasibility of using transdermal monitoring of alcohol use for clinical purposes. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Contingency Management for Alcohol Use Reduction: A Pilot Study using a Transdermal Alcohol Sensor*

Science.gov (United States)

Barnett, Nancy P.; Tidey, Jennifer; Murphy, James G.; Swift, Robert; Colby, Suzanne M.

2011-01-01

Background Contingency management (CM) has not been thoroughly evaluated as a treatment for alcohol abuse or dependence, in part because verification of alcohol use reduction requires frequent in-person breath tests. Transdermal alcohol sensors detect alcohol regularly throughout the day, providing remote monitoring and allowing for rapid reinforcement of reductions in use. Methods The purpose of this study was to evaluate the efficacy of CM for reduction in alcohol use, using a transdermal alcohol sensor to provide a continuous measure of alcohol use. Participants were 13 heavy drinking adults who wore the Secure Continuous Remote Alcohol Monitoring (SCRAM) bracelet for three weeks and provided reports of alcohol and drug use using daily web-based surveys. In Week 1, participants were asked to drink as usual; in Weeks 2 and 3, they were reinforced on an escalating schedule with values ranging from $5-$17 per day on days when alcohol use was not reported or detected by the SCRAM. Results Self-reports of percent days abstinent and drinks per week, and transdermal measures of average and peak transdermal alcohol concentration and area under the curve declined significantly in Weeks 2-3. A nonsignificant but large effect size for reduction in days of tobacco use also was found. An adjustment to the SCRAM criteria for detecting alcohol use provided an accurate but less conservative method for use with non-mandated clients. Conclusion Results support the efficacy of CM for alcohol use reductions and the feasibility of using transdermal monitoring of alcohol use for clinical purposes. PMID:21665385

Current and emerging lipid-based systems for transdermal drug delivery.

Science.gov (United States)

Singla, Sumeet K; Sachdeva, Vishal

2015-01-01

Developing a transdermal drug delivery system is a challenging task considering the selective permeability of the skin and the physicochemical properties the drug must possess to permeate through the skin. Lipid-based drug delivery systems have contributed a great deal in this direction in the last few decades, and thereby have helped to expand the range of therapeutic molecules that can be delivered through the skin in a safe and effective manner. Additionally, vesicular delivery systems such as nanoparticles and emulsions have also played important roles in providing alternative novel approaches for drug delivery. In this article, we will discuss some of the current and future lipid-based systems for transdermal drug delivery along with the associated challenges.

Origin of estradiol fatty acid esters in human ovarian follicular fluid.

Science.gov (United States)

Pahuja, S L; Kim, A H; Lee, G; Hochberg, R B

1995-03-01

The estradiol fatty acid esters are the most potent of the naturally occurring steroidal estrogens. These esters are present predominantly in fat, where they are sequestered until they are hydrolyzed by esterases. Thus they act as a preformed reservoir of estradiol. We have previously shown that ovarian follicular fluid from patients undergoing gonadotropin stimulation contains very high amounts of estradiol fatty acid esters (approximately 10(-7) M). The source of these esters is unknown. They can be formed by esterification of estradiol in the follicular fluid by lecithin:cholesterol acyltransferase (LCAT), or in the ovary by an acyl coenzyme A:acyltransferase. In order to determine which of these enzymatic processes is the source of the estradiol esters in the follicular fluid, we incubated [3H]estradiol with follicular fluid and cells isolated from human ovarian follicular fluid and characterized the fatty acid composition of the [3H]estradiol esters biosynthesized in each. In addition, we characterized the endogenous estradiol fatty acid esters in the follicular fluid and compared them to the biosynthetic esters. The fatty acid composition of the endogenous esters was different than those synthesized by the cellular acyl coenzyme A:acyltransferase, and the same as the esters synthesized by LCAT, demonstrating that the esters are produced in situ in the follicular fluid. Although the role of these estradiol esters in the ovary is not known, given their remarkable estrogenic potency it is highly probable that they have an important physiological role.

Dendrimer-coupled sonophoresis-mediated transdermal drug-delivery system for diclofenac.

Science.gov (United States)

Huang, Bin; Dong, Wei-Jiang; Yang, Gao-Yi; Wang, Wei; Ji, Cong-Hua; Zhou, Fei-Ni

2015-01-01

The purpose of the present study was to develop a novel transdermal drug-delivery system comprising a polyamidoamine dendrimer coupled with sonophoresis to enhance the permeation of diclofenac (DF) through the skin. The novel transdermal drug-delivery system was developed by using a statistical Plackett-Burman design. Hairless male Wistar rat skin was used for the DF-permeation study. Coupling media concentration, ultrasound-application time, duty cycle, distance from probe to skin, and a third-generation polyamidoamine-dendrimer concentration were selected as independent variables, while in vitro drug release was selected as a dependent variable. Independent variables were found to be statistically significant (Pdelivery, run 13) showed 56.69 µg/cm(2) cumulative drug permeated through the skin, while the DF-dendrimer gel without sonophoresis treatment (run 14) showed 257.3 µg/cm(2) cumulative drug permeated through the skin after 24 hours. However, when the same gel was applied to sonophoresis-treated skin, drastic permeation enhancement was observed. In the case of run 3, the cumulative drug that permeated through the skin was 935.21 µg/cm(2). It was concluded that dendrimer-coupled sonophoresis-mediated transdermal drug delivery system has the potential to enhance the permeation of DF through the skin.

Impact of cardio-synchronous brain pulsations on Monte Carlo calculated doses for synchrotron micro- and mini-beam radiation therapy.

Science.gov (United States)

Manchado de Sola, Francisco; Vilches, Manuel; Prezado, Yolanda; Lallena, Antonio M

2018-05-15

To assess the effects of brain movements induced by heartbeat on dose distributions in synchrotron micro- and mini-beam radiaton therapy and to develop a model to help guide decisions and planning for future clinical trials. The Monte Carlo code PENELOPE was used to simulate the irradiation of a human head phantom with a variety of micro- and mini-beam arrays, with beams narrower than 100 μm and above 500 μm, respectively, and with radiation fields of 1cm × 2cm and 2cm × 2cm. The dose in the phantom due to these beams was calculated by superposing the dose profiles obtained for a single beam of 1μm × 2cm. A parameter δ, accounting for the total displacement of the brain during the irradiation and due to the cardio-synchronous pulsation, was used to quantify the impact on peak-to-valley dose ratios and the full-width at half-maximum. The difference between the maximum (at the phantom entrance) and the minimum (at the phantom exit) values of the peak-to-valley dose ratio reduces when the parameter δ increases. The full-width at half-maximum remains almost constant with depth for any δ value. Sudden changes in the two quantities are observed at the interfaces between the various tissues (brain, skull and skin) present in the head phantom. The peak-to-valley dose ratio at the center of the head phantom reduces when δ increases, remaining above 70% of the static value only for mini-beams and δ smaller than ~ 200 μm. Optimal setups for brain treatments with synchrotron radiation micro- and mini-beam combs depend on the brain displacement due to cardio-synchronous pulsation. Peak-to-valley dose ratios larger than 90% of the maximum values obtained in the static case occur only for mini-beams and relatively large dose rates. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Basal and dynamic relationships between implicit power motivation and estradiol in women.

Science.gov (United States)

Stanton, Steven J; Schultheiss, Oliver C

2007-12-01

This study investigated basal and reciprocal relationships between implicit power motivation (n Power), a preference for having impact and dominance over others, and both salivary estradiol and testosterone in women. 49 participants completed the Picture Story Exercise, a measure of n Power. During a laboratory contest, participants competed in pairs on a cognitive task and contest outcome (win vs. loss) was experimentally varied. Estradiol and testosterone levels were determined in saliva samples collected at baseline and several times post-contest, including 1 day post-contest. n Power was positively associated with basal estradiol concentrations. The positive correlation between n Power and basal estradiol was stronger in single women, women not taking oral contraceptives, or in women with low-CV estradiol samples than in the overall sample of women. Women's estradiol responses to a dominance contest were influenced by the interaction of n Power and contest outcome: estradiol increased in power-motivated winners but decreased in power-motivated losers. For power-motivated winners, elevated levels of estradiol were still present the day after the contest. Lastly, n Power and estradiol did not correlate with self-reported dominance and correlated negatively with self-reported aggression. Self-reported dominance and aggression did not predict estradiol changes as a function of contest outcome. Overall, n Power did not predict basal testosterone levels or testosterone changes as a function of dominance contest outcome.

Ultrasound in Biomedical Engineering: Ultrasound Microbubble Contrast Agents Promote Transdermal Permeation of Drugs

OpenAIRE

Ai-Ho Liao

2016-01-01

This report discusses a new development in the use of ultrasound microbubble contrast agents on transdermal drug delivery. The medium surrounding the microbubbles at the optimum concentration from liquid to gel can be modified and it can still achieve the same enhancement for transdermal drug permeation as liquid medium. It was also found that under the same ultrasound power density, microbubbles of larger particle sizes can extend the penetration depths of dye at the phantom surface.

Poly(lactic-co-glycolic) acid drug delivery systems through transdermal pathway: an overview

OpenAIRE

Naves, Lucas; Dhand, Chetna; Almeida, Luis; Rajamani, Lakshminarayanan; Ramakrishna, Seeram; Soares, Gra?a

2017-01-01

In past few decades, scientists have made tremendous advancement in the field of drug delivery systems (DDS), through transdermal pathway, as the skin represents a ready and large surface area for delivering drugs. Efforts are in progress to design efficient transdermal DDS that support sustained drug release at the targeted area for longer duration in the recommended therapeutic window without producing side-effects. Poly(lactic-co-glycolic acid) (PLGA) is one of the most promising Food and ...

Plasma and faecal testosterone and estradiol in chicken

International Nuclear Information System (INIS)

Mekchay, S.; Apichartsrungkoon, T.; Pongpiachan, P.

1996-01-01

Identification of sex in some kind of fowls can not be done by using their external appearances. Sex steroid hormone levels may be used as an indicator of sexual dimorphism in birds. The objective of this investigation was to measure plasma and faecal testosterone and estradiol concentrations in 8 male and 15 female chickens by using radioimmunoassay (RIA) technique. The relationship between plasma and faecal testosterone, and plasma and faecal estradiol are positively correlated. The correlation coefficients (r 2 ) between plasma and faecal steroids concentration were 0.621 (p<0.05) for testosterone and 0.692 (p<0.05) for estradiol. The average plasma and faecal sex steroid concentrations in male and female chickens were 10.05 ± 1.97 ng/ml and 511.50 ± 95.89 ng/g (for male testosterone), 24.85 ± 1.60 pg/ml and 49.65 ± 6.01 ng/g (for male estradiol), 0.79 ± 0.05 ng/ml and 134.20 ± 14.70 ng/ml (for female testosterone), 129.91 ± 19.30 pg/ml and 334.80 ± 15.62 ng/g (for female estradiol), respectively. Plasma and faecal testosterone and estradiol levels in male and female chickens are significant difference (p<0.01, p<0.01, p<0.001 and p<0.001 respectively). The results of this investigation suggested that plasma or faecal sex steroid concentrations can be used to discriminate sex of chicken which is show the possibility to use the plasma or faecal sex steroids for identification of sex in other bird species

Radiation-induced decomposition of trace amounts of 17 β-estradiol in water

International Nuclear Information System (INIS)

Kimura, Atsushi; Taguchi, Mitsumasa; Arai, Hidehiko; Hiratsuka, Hiroshi; Namba, Hideki; Kojima, Takuji

2004-01-01

The radiation-induced decomposition of trace amounts of 17 β-estradiol (E2) in water was studied as a function of the dose of 60 Co γ-rays. The rate constant of the reaction of the OH radicals with E2 was estimated to be 1.6x10 10 mol dm -3 s -1 by a comparison with the known rate constant for the reaction with phenol. Both E2 and E2-equivalent concentrations were estimated by LC-MS and ELISA, and decreased with an increase in γ-rays dose. E2 (1.8 nmol dm -3 ) in water was degraded almost completely by irradiations up to 10 Gy. The estrogen activity of the same sample solution still remained at a dose of 10 Gy, but decreased at 30 Gy to the lower than the threshold level of contamination to induce some estrogenic effects on the environmental ecology

Hyaluronan-Based Nanohydrogels as Effective Carriers for Transdermal Delivery of Lipophilic Agents: Towards Transdermal Drug Administration in Neurological Disorders

Directory of Open Access Journals (Sweden)

Seong Uk Son

2017-12-01

Full Text Available We suggest a convenient nanoemulsion fabrication method to create hyaluronan (HA-based nanohydrogels for effective transdermal delivery. First, hyaluronan-conjugated dodecylamine (HA–Do HA-based polymers to load the lipophilic agents were synthesized with hyaluronan (HA and dodecylamine (Do by varying the substitution ratio of Do to HA. The synthetic yield of HA–Do was more than 80% (HA–Do (A: 82.7 ± 4.7%, HA–Do (B: 87.1 ± 3.9% and HA–Do (C: 81.4 ± 4.5%. Subsequently, nanohydrogels were fabricated using the nanoemulsion method. Indocyanine green (ICG simultaneously self-assembled with HA–Do, and the size depended on the substitution ratio of Do in HA–Do (nanohydrogel (A: 118.0 ± 2.2 nm, nanohydrogel (B: 121.9 ± 11.4 nm, and nanohydrogel (C: 142.2 ± 3.8 nm. The nanohydrogels were delivered into cells, and had excellent biocompatibility. Especially, nanohydrogel (A could deliver and permeate ICG into the deep skin layer, the dermis. This suggests that nanohydrogels can be potent transdermal delivery systems.

Inkjet printing of insulin microneedles for transdermal delivery.

Science.gov (United States)

Ross, Steven; Scoutaris, Nicolaos; Lamprou, Dimitrios; Mallinson, David; Douroumis, Dennis

2015-08-01

Inkjet printing technology was used to apply insulin polymeric layers on metal microneedles for transdermal delivery. A range of various polymers such as gelatin (GLN), polyvinyl caprolactame-polyvinyl acetate-polyethylene glycol (SOL), poly(2-ethyl-2-oxazoline) (POX) and trehalose (THL) were assessed for their capacity to form thin uniform and homogeneous layers that preserve insulin intact. Atomic force microscopy (AFM) showed homogeneous insulin-polymer layers without any phase separation while SOL demonstrated the best performance. Circular discroism (CD) analysis of rehydrated films showed that insulin's alpha helices and β-sheet were well preserved for THL and SOL. In contrast, GLN and POX insulin layers revealed small band shifts indicating possible conformational changes. Insulin release in Franz diffusion cells from MNs inserted into porcine skin showed rapid release rates for POX and GLN within the first 20 min. Inkjet printing was proved an effective approach for transdermal delivery of insulin in solid state.

Application of different 125I tracers in radioimmunoassays of estradiol-17β

International Nuclear Information System (INIS)

Bienert, R.; Flentje, H.; Herzmann, H.; Akademie der Wissenschaften der DDR, Leipzig. Zentralinstitut fuer Isotopen- und Strahlenforschung)

1984-01-01

Some different 125 I-labelled estradiol tracers were produced by direct radioiodizing of estradiol and also of the histamine and tyramine conjugates of estradiol-3-carboxymethylether (E 2 -3-CM) by means of the chloramine-T method. The linkage properties of these tracers were investigated in relation to the 3 H-labelled estradiol opposite to the antisera, which were produced against the cow serum albumin (RSA) conjugates of E 2 -3-CM and estradiol-6-carboxymethyloxime (E 2 -6-CMO). As suitable system for the radioimmunological estradiol determination could be revealed 4- 125 I-iodine estradiol in connection with one antiserum in each case of the radioligand antiserum combinations against E 2 -3-CM-RSA- and E 2 -6-CMO-RSA-conjugate. The double antibody method is used for separation in optimized RIA systems. The first and the second antibody reaction take place simultaneously. (author)

Fabrication, appraisal, and transdermal permeation of sildenafil citrate-loaded nanostructured lipid carriers versus solid lipid nanoparticles

Science.gov (United States)

Elnaggar, Yosra SR; El-Massik, Magda A; Abdallah, Ossama Y

2011-01-01

Although sildenafil citrate (SC) is used extensively for erectile dysfunction, oral delivery of SC encounters many obstacles. Furthermore, the physicochemical characteristics of this amphoteric drug are challenging for delivery system formulation and transdermal permeation. This article concerns the assessment of the potential of nanomedicine for improving SC delivery and transdermal permeation. SC-loaded nanostructured lipid carriers (NLCs) and solid lipid nanoparticles (SLNs) were fabricated using a modified high-shear homogenization technique. Nanoparticle optimization steps included particle size analysis, entrapment efficiency (EE) determination, freeze-drying and reconstitution, differential scanning calorimetry, in vitro release, stability study and high-performance liquid chromatography analysis. Transdermal permeation of the nanocarriers compared with SC suspension across human skin was assessed using a modified Franz diffusion cell assembly. Results revealed that SLNs and NLCs could be optimized in the nanometric range (180 and 100 nm, respectively) with excellent EE (96.7% and 97.5%, respectively). Nanoparticles have significantly enhanced in vitro release and transdermal permeation of SC compared with its suspensions. Furthermore, transdermal permeation of SC exhibited higher initial release from both SLN and NLC formulations followed by controlled release, with promising implications for faster onset and longer drug duration. Nanomedicines prepared exhibited excellent physical stability for the study period. Solid nanoparticles optimized in this study successfully improved SC characteristics, paving the way for an efficient topical Viagra® product. PMID:22238508

Dissolving and biodegradable microneedle technologies for transdermal sustained delivery of drug and vaccine

Science.gov (United States)

Hong, Xiaoyun; Wei, Liangming; Wu, Fei; Wu, Zaozhan; Chen, Lizhu; Liu, Zhenguo; Yuan, Weien

2013-01-01

Microneedles were first conceptualized for drug delivery many decades ago, overcoming the shortages and preserving the advantages of hypodermic needle and conventional transdermal drug-delivery systems to some extent. Dissolving and biodegradable microneedle technologies have been used for transdermal sustained deliveries of different drugs and vaccines. This review describes microneedle geometry and the representative dissolving and biodegradable microneedle delivery methods via the skin, followed by the fabricating methods. Finally, this review puts forward some perspectives that require further investigation. PMID:24039404

Enhancement of transdermal delivery of ibuprofen using microemulsion vehicle.

Science.gov (United States)

Hu, Liandong; Hu, Qiaofeng; Yang, Jianxue

2014-10-01

The objective of this study was to find a stable microemulsion vehicle for transdermal delivery of ibuprofen to improve the skin permeability. Microemulsion was prepared using different sorts of oils, surfactants and co-surfactants. Pseudo-ternary phase diagrams were used to evaluate the microemulsion domain. The effects of oleic acid and surfactant mixture on skin permeation of ibuprofen were evaluated with excised skins. The optimum formulation F3 consisting of 6% oleic acid, 30% Cremophor RH40/Transcutol P (2:1, w/w) and 59% water phase, showed a high permeation rate of 42.98 µg/cm(2)/hr. The mean droplet size of microemulsion was about 43 nm and no skin irritation signs were observed on the skin of rabbits. These results indicated that this novel microemulsion is a useful formulation for the transdermal delivery of ibuprofen.

Synchronization of skin ablation and microjet injection for an effective transdermal drug delivery

Science.gov (United States)

Jang, Hun-jae; Yeo, Seonggu; Yoh, Jack J.

2016-04-01

An Er:YAG laser with 2940-nm wavelength and 150-µs pulse duration was built for the purpose of combined ablation and microjet injection. A shorter pulse duration compared to common erbium lasers in dentistry is desirable for a synchronization of skin ablation and subsequent microjet injection into target skin for transdermal injection of liquid dose. A single laser beam is split into two for an optimal energy of pre-ablation of skin and the residual energy allocated to a microjet ejection. A newly designed injector consists of an L-shaped chamber and a parabolic mirror in a single unit, and the handheld laser is a part of an integrated system requiring no optical fiber. Through various injection tests using the porcine skin, the effectiveness of the new delivery system is herein evaluated.

Low doses of 17α-ethinyl estradiol alter the maternal brain and induce stereotypies in CD-1 mice exposed during pregnancy and lactation.

Science.gov (United States)

Catanese, Mary C; Vandenberg, Laura N

2017-10-01

Maternal care is critical for the survival, development and long-term success of offspring. Despite our current understanding of the role of endogenous estrogen in both maternal behavior and the maternal brain, the potential effects of exogenous estrogens on these endpoints remain poorly understood. Here, pregnant CD-1 mice were exposed to low doses of 17α-ethinyl estradiol (EE2), commonly used as a positive control in studies of other xenoestrogens, from day 9 of pregnancy until weaning. Using traditional maternal behavior assays, we document no significant changes in maternal behavior throughout the lactational period. However, EE2 induced increases in repetitive tail retrieval, which may indicate a stereotypy or obsessive compulsive (OCD)-like behavior. We also observed a significant reduction in tyrosine hydroxylase (TH) immunoreactivity in the ventral tegmental area (VTA), a region important for maternal motivation. These results suggest that pregnant adult females are not immune to the effects of this compound. Copyright © 2017 Elsevier Inc. All rights reserved.

Detection of sub micro Gray dose levels using OSL phosphor LiMgPO{sub 4}:Tb,B

Energy Technology Data Exchange (ETDEWEB)

Rawat, N.S., E-mail: naru@barc.gov.in [Radiological Physics and Advisory Division, Bhabha Atomic Research Centre, Trombay, Mumbai (India); Dhabekar, Bhushan [Radiological Physics and Advisory Division, Bhabha Atomic Research Centre, Trombay, Mumbai (India); Muthe, K.P. [Technical Physics Division, Bhabha Atomic Research Centre, Trombay, Mumbai (India); Koul, D.K.; Datta, D. [Radiological Physics and Advisory Division, Bhabha Atomic Research Centre, Trombay, Mumbai (India)

2017-04-15

Highlights: • LiMgPO4:Tb,B has been studied and shown to possesses minimum measurable dose (MMD) in sub micro Gray region. • MMD as low as 0.49 µGy in readout time of less than 1 s at stimulation intensity of 32 mW/cm{sup 2} has been achieved. • The OSL measurements for low doses has strengthened and validated this claim. • OSL spectrum shows several emission peaks and the prominent peak around 380 nm. - Abstract: Detection of sub micro Gray doses finds application in personnel and environmental monitoring, and nuclear forensics. Recently developed LiMgPO{sub 4}:Tb,B (LMP) is highly sensitive Optically Stimulated Luminescence (OSL) phosphor with excellent dosimetric properties. The OSL emission spectrum of LMP consists of several peaks attributed to characteristic Tb{sup 3+} emission. The OSL emission peak at 380 nm is favorable for bi-alkali PMT used in RISO reader system. It is demonstrated that significant improvement in dose detection threshold can be realized for LMP by optimization of continuous wave (CW–) OSL parameters like stimulation intensity and readout time. The minimum measurable dose (MMD) as low as 0.49 µGy in readout time of less than 1 s at stimulation intensity of 32 mW/cm{sup 2} has been achieved using this phosphor. The recommendations for choice of parameters for personnel and environmental monitoring are also discussed.

Local effect of bisphenol A on the estradiol synthesis of ovarian granulosa cells from PCOS.

Science.gov (United States)

Wang, Yuan; Zhu, Qinling; Dang, Xuan; He, Yaqiong; Li, Xiaoxue; Sun, Yun

2017-01-01

Close relationship between polycystic ovary syndrome (PCOS) and bisphenol A (BPA) has drawn much attention in recent years, while the underlying mechanisms are poorly understood. In our study, we aim to detect BPA concentration in the follicular fluid and investigate its effect on estradiol synthesis in human granulosa cells from PCOS and non-PCOS patients. Follicular fluid and granulosa cells were collected from women who underwent controlled ovarian stimulation for in vitro fertilization or intracytoplasmic sperm injection. BPA concentration in the follicular fluid from PCOS patients (440.50 ± 63.70 pg/ml) was significantly higher than that from non-PCOS patients (338.00 ± 57.88 pg/ml). Expression of aromatase and estradiol synthesis in cultured granulosa cells was examined after treatment with BPA from 0.01 to 1 μM for 24 h. Expression of aromatase and estradiol synthesis was downregulated by BPA in a dose-dependent manner in PCOS, but no effect was observed in granulosa cells from non-PCOS patients. These findings provide evidence that increased BPA concentration in the follicular fluid of PCOS patients may play an important role in its pathogenesis by attenuating the expression of aromatase in granulosa cells.

New developments in oral contraception: clinical utility of estradiol valerate/dienogest (Natazia® for contraception and for treatment of heavy menstrual bleeding: patient considerations

Directory of Open Access Journals (Sweden)

Nelson AL

2012-12-01

Full Text Available Anita L NelsonObstetrics and Gynecology, David Geffen School of Medicine at UCLA, Harbor UCLA Medical Center, Torrance, California, USAAbstract: Natazia® is a new oral contraceptive with estradiol valerate and dienogest in a unique multiphasic formulation that includes a shortened hormone-free interval. This new formulation has been approved for both contraception and also as a treatment for heavy menstrual bleeding in women who desire to use oral contraceptives as their method of birth control. It is marketed in the US as Natazia® and elsewhere as Qlaira®. This article will review the properties of each of the major new features of this pill: estradiol used in place of ethinyl estradiol, dienogest as the progestin, and the unique dosing pattern of this product. It will also summarize the results of the pivotal clinical trials of contraceptive effectiveness, bleeding patterns, safety and tolerability. The lessons learned from the clinical trials about the effectiveness of this formulation in the treatment of excessive menstrual bleeding will be summarized. Also, results of trials comparing this new pill to other popular formulations for "menstrually-related" symptoms and for potential female sexual dysfunction related to use of oral contraceptives will be presented. This review will suggest how all this information might be used to counsel women about how to use this pill most successfully.Keywords: oral contraceptives, estradiol valerate, dienogest, heavy menstrual bleeding, menorrhagia, dynamic dosing

Transdermal and intradermal delivery of therapeutic agents: application of physical technologies

National Research Council Canada - National Science Library

Banga, Ajay K

2011-01-01

.... Commercialization of transdermal drug delivery requires technology from many disciplines beyond pharmaceutical sciences, such as polymer chemistry, adhesion sciences, mass transport, web film coating...

Estradiol concentrations and working memory performance in women of reproductive age.

Science.gov (United States)

Hampson, Elizabeth; Morley, Erin E

2013-12-01

Estrogen has been proposed to exert a regulatory influence on the working memory system via actions in the female prefrontal cortex. Tests of this hypothesis have been limited almost exclusively to postmenopausal women and pharmacological interventions. We explored whether estradiol discernibly influences working memory within the natural range of variation in concentrations characteristic of the menstrual cycle. The performance of healthy women (n=39) not using hormonal contraceptives, and a control group of age- and education-matched men (n=31), was compared on a spatial working memory task. Cognitive testing was done blind to ovarian status. Women were retrospectively classified into low- or high-estradiol groups based on the results of radioimmunoassays of saliva collected immediately before and after the cognitive testing. Women with higher levels of circulating estradiol made significantly fewer errors on the working memory task than women tested under low estradiol. Pearson's correlations showed that the level of salivary estradiol but not progesterone was correlated inversely with the number of working memory errors produced. Women tested at high levels of circulating estradiol tended to be more accurate than men. Superior performance by the high estradiol group was seen on the working memory task but not on two control tasks, indicating selectivity of the effects. Consistent with previous studies of postmenopausal women, higher levels of circulating estradiol were associated with better working memory performance. These results add further support to the hypothesis that the working memory system is modulated by estradiol in women, and show that the effects can be observed under non-pharmacological conditions. Copyright © 2013 Elsevier Ltd. All rights reserved.

Efficacy and transdermal absorption of permethrin in scabies patients

NARCIS (Netherlands)

van der Rhee, H.J.; Farquhar, J A; Vermeulen, N P

1989-01-01

The clinical efficacy and transdermal absorption of permethrin, a new synthetic insecticide was investigated in ten scabies patients. All patients were successfully treated with one application of a cream, containing 5% permethrin. Apart from mild postscabies dermatitis no side-effects were

[Effects of Frankincense and Myrrh essential oil on transdermal absorption in vitro of Chuanxiong and penetration mechanism of skin blood flow].

Science.gov (United States)

Zhu, Xiao-Fang; Luo, Jing; Guan, Yong-Mei; Yu, Ya-Ting; Jin, Chen; Zhu, Wei-Feng; Liu, Hong-Ning

2017-02-01

The aim of this paper was to explore the effects of Frankincense and Myrrh essential oil on transdermal absorption in vitro of Chuanxiong, and to investigate the possible penetration mechanism of their essential oil from the perspective of skin blood perfusion changes. Transdermal tests were performed in vitro with excised mice skin by improved Franz diffusion cells. The cumulative penetration amounts of ferulic acid in Chuanxiong were determined by HPLC to investigate the effects of Frankincense and Myrrh essential oil on transdermal permeation properties of Chuanxiong. Simultaneously, the skin blood flows were determined by laser flow doppler. The results showed that the cumulative penetration amount of ferulic acid in Chuanxiong was (8.13±0.76) μg•cm⁻² in 24 h, and was (48.91±4.87), (57.80±2.86), (63.34±4.56), (54.17±4.40), (62.52±7.79) μg•cm⁻² respectively in Azone group, Frankincense essential oil group, Myrrh essential oil, frankincense and myrrh singly extracted essential oil mixture group, and frankincense and myrrh mixed extraction essential oil group. The enhancement ratios of each essential oil groups were 7.68, 8.26, 7.26, 8.28, which were slightly greater than 6.55 in Azone group. In addition, as compared with the conditions before treatment, there were significant differences and obvious increasing trend in blood flow of rats in Frankincense essential oil group, Myrrh essential oil group, frankincense and myrrh singly extracted essential oil mixture group, and frankincense and myrrh mixed extraction essential oil group when were dosed at 10, 20, 30, 10 min respectively, indicating that the skin blood flows were increased under the effects of Frankincense and Myrrh essential oil to a certain extent. Thus, Frankincense and Myrrh essential oil had certain effect on promoting permeability of Chuanxiong both before and after drug combination, and may promote the elimination of drugs from epidermis to dermal capillaries through increase of

The role of histamine in estradiol-induced conditioned consumption reductions.

Science.gov (United States)

Hintiryan, Houri; Hayes, Unja L; Chambers, Kathleen C

2005-01-31

Conditioned consumption reductions (CCRs) develop toward novel taste stimuli as a consequence of associating those tastes with certain physiological changes. Few studies have focused on the neurochemical basis of this learned behavior. The purpose of these experiments was to reexamine the role of histamine in CCRs elicited by estradiol. Previous studies have suggested that histamine mediates CCRs induced by radiation, centrifugal rotation, and estradiol. However, because the animals were trained in a drug state, but tested in a nondrug state, it is possible that state-dependent learning confounded the results of these studies. The following series of experiments was performed to test this possibility for estradiol-induced CCRs. Implementing our own methodologies in Experiment 1, we demonstrated that an estradiol-induced CCR was blocked by treatment with the histamine 1 receptor blocker, chlorpheniramine maleate, before sucrose consumption during acquisition. In Experiment 2, identical states were maintained during acquisition and extinction by administering chlorpheniramine prior to sucrose exposure during both phases. The results indicated that chlorpheniramine blocked the estradiol-induced CCR. However, circumventing state-dependency in Experiment 3 by administering chlorpheniramine following exposure to sucrose during acquisition augmented the estradiol CCR. Taken together, the results of these experiments suggest that the ability of chlorpheniramine to abolish estradiol-induced CCRs is not due to state-dependency or to the antihistaminergic properties of chlorpheniramine. It is proposed that the results of all of the experiments can be accounted for by the aversive properties of chlorpheniramine.

Design and Development of a Proniosomal Transdermal Drug ...

African Journals Online (AJOL)

Purpose: The aim of the study was to develop a proniosomal carrier system for captopril for the treatment of hypertension that is capable of efficiently delivering entrapped drug over an extended period of time. Method: The potential of proniosomes as a transdermal drug delivery system for captopril was investigated by ...

In vivo real-time monitoring system of electroporation mediated control of transdermal and topical drug delivery.

Science.gov (United States)

Blagus, Tanja; Markelc, Bostjan; Cemazar, Maja; Kosjek, Tina; Preat, Veronique; Miklavcic, Damijan; Sersa, Gregor

2013-12-28

Electroporation (EP) is a physical method for the delivery of molecules into cells and tissues, including the skin. In this study, in order to control the degree of transdermal and topical drug delivery, EP at different amplitudes of electric pulses was evaluated. A new in vivo real-time monitoring system based on fluorescently labeled molecules was developed, for the quantification of transdermal and topical drug delivery. EP of the mouse skin was performed with new non-invasive multi-array electrodes, delivering different amplitudes of electric pulses ranging from 70 to 570 V, between the electrode pin pairs. Patches, soaked with 4 kDa fluorescein-isothiocyanate labeled dextran (FD), doxorubicin (DOX) or fentanyl (FEN), were applied to the skin before and after EP. The new monitoring system was developed based on the delivery of FD to and through the skin. FD relative quantity was determined with fluorescence microscopy imaging, in the treated region of the skin for topical delivery and in a segment of the mouse tail for transdermal delivery. The application of electric pulses for FD delivery resulted in enhanced transdermal delivery. Depending on the amplitude of electric pulses, it increased up to the amplitude of 360 V, and decreased at higher amplitudes (460 and 570 V). Topical delivery steadily enhanced with increasing the amplitude of the delivered electric pulses, being even higher than after tape stripping used as a positive control. The non-invasive monitoring of the delivery of DOX, a fluorescent chemotherapeutic drug, qualitatively and quantitatively confirmed the effects of EP at 360 and 570 V pulse amplitudes on topical and transdermal drug delivery. Delivery of FEN at 360 and 570 V pulse amplitudes verified the observed effects as obtained with FD and DOX, by the measured physiological responses of the mice as well as FEN plasma concentration. This study demonstrates that with the newly developed non-invasive multi-array electrodes and with the

Relationship between Estradiol and Antioxidant Enzymes Activity of Ischemic Stroke

Directory of Open Access Journals (Sweden)

Nasrin Sheikh

2009-01-01

Full Text Available Some evidence suggests the neuroprotection of estrogen provided by the antioxidant activity of this compound. The main objective of this study was to determine the level of estradiol and its correlation with the activity of antioxidant enzymes, total antioxidant status and ferritin from ischemic stroke subjects. The study population consisted of 30 patients with acute ischemic stroke and 30 controls. There was no significant difference between estradiol in stroke and control group. The activity of superoxide dismutase and level of ferritin was higher in stroke compared with control group (<.05, <.001, resp.. There was no significant correlation between estradiol and glutathione peroxidase, glutathione reductase, catalase, total antioxidant status, and ferritin in stroke and control groups. We observed inverse correlation between estradiol with superoxide dismutase in males of stroke patients (=−0.54, =.029. Our results supported that endogenous estradiol of elderly men and women of stroke or control group has no antioxidant activity.

Synthesis of conjugated chitosan and its effect on drug permeation from transdermal patches.

Science.gov (United States)

Satheeshababu, B K; Shivakumar, K L

2013-03-01

The aim of this study was to synthesis the conjugated chitosan by covalent attachment of thiol moieties to the cationic polymer, mediated by a carbodiimide to improve permeation properties of chitosan. Thioglycolic acid was covalently attached to chitosan by the formation of amide bonds between the primary amino groups of the polymer and the carboxylic acid groups of thioglycolic acid. Hence, these polymers are called as thiomers or thiolated polymers. Conjugation of chitosan was confirmed by Fourier transform-infrared and differential scanning calorimetric analysis. Matrix type transdermal patches of carvedilol were prepared using the different proportions of chitosan and chitosan-thioglycolic acid conjugates (2:0, 1.7:0.3, 1.4:0.6, 1:1, 0.6:1.4 and 0.3:1.7) by solvent casting technique. Prepared matrix type patches were evaluated for their physicochemical characterization followed by in vitro evaluation. Selected formulations were subjected for their ex vivo studies on Wistar albino rat skin and human cadaver skin using the modified Franz diffusion cell. As the proportion of conjugated chitosan increased, the transdermal patches showed increased drug permeation. The mechanism of drug release was found to be nonFickian profiles. The present study concludes that the transdermal patches of carvedilol using conjugated chitosan with different proportions of chitosan were successfully developed to provide improved drug permeation. The transdermal patches can be a good approach to improve drug bioavailability by bypassing the extensive hepatic first-pass metabolism of the drug.

The action of fast neutrons on Walker tumor chromatin in rats treated with thiotepa and lomustine cytostatics and with estradiol hormone

International Nuclear Information System (INIS)

Radu, L.; Constantinescu, B.; Gostian, O.

1994-01-01

Wistar rats bearing Walker carcinosarcoma were treated with thiotepa (1 mg) and lomustine (3 mg) cytostatics and with each of these cytostatics associated with estradiol hormone (0.15 mg). The extracted chromatins were subjected to fast neutrons (d(13 MeV)+Be thick target) at 30-100 Gy doses. The parameters estimated at chromatin samples were: the tyrosine and tryptophan intrinsic fluorescence, the fluorescence of chromatin - ethidium bromide complexes and thermal transition. A different and specific susceptibility to fast neutrons was observed in treated chromatin samples, when compared with controls. The chromatin acidic proteins destruction was greater in the case of estradiol - thiotepa association. (Author)

Dispersal of estradiol-17 beta from the site of injection in the pectoral muscles of Japanese quail

Energy Technology Data Exchange (ETDEWEB)

Robinson, G.A.

1985-09-01

Exogenous estrogens, if given in sufficient quantity, stimulate vitellogenesis in the males of vitellogenic species. In the present study, ethanolic solutions of estradiol-17 beta (E2), labeled with 16-alpha-( SVI)iodoestradiol (( SVI)E2) or sodium iodide (Na SVI), were injected into the pectoral muscles of male Japanese quail. The rate of dispersal of the estradiol from the site of injection was measured in vivo during 4 days. The curves of radioactivity appeared to be diphasic. The dose percentages forming the second phase of these curves and the half-time for the second phase were: for 16 mumol E2 (( SVI)E2 label)/100 g body weight, 84.6% and 27.6 hr; for 6 pmol ( SVI)E2/100 g, 20.0% and 17.2 hr; for 16 mumol E2 (Na SVI label)/100 g, 6.7% and 99.0 hr, and for Na SVI, 6.1% and 83.1 hr. Thus, in male quail the estradiol-induced stimulation of vitellogenesis apparently resulted from a continuing hormonal pressure on the liver during the period of study and not from a rapid flow of E2 to the liver shortly after injection.

Comparison of follicular dynamics, superovulatory response, and embryo recovery between estradiol based and conventional superstimulation protocol in buffaloes (Bubalus bubalis

Directory of Open Access Journals (Sweden)

Narinder Singh

2015-08-01

Full Text Available Aim: To evaluate the follicular dynamics, superovulatory response, and embryo recovery following superstimulatory treatment initiated at estradiol-17β induced follicular wave emergence and its comparison with conventional superstimulatory protocol in buffaloes. Materials and Methods: Six normal cycling pluriparous buffaloes, lactating, 90-180 days post-partum, and weighing between 500 and 660 kg were superstimulated twice with a withdrawal period of 35 days in between two treatments. In superstimulation protocol-1 (estradiol group buffaloes were administered estradiol-17β (2 mg, i.m. and eazibreed controlled internal drug release (CIDR was inserted intravaginally (day=0 at the random stage of the estrous cycle. On the day 4, buffaloes were superstimulated using follicle stimulating hormone (FSH 400 mg, divided into 10 tapering doses given at 12 hourly intervals. Prostaglandin F2α analogs (PGF2α was administered at day 7.5 and day 8, and CIDR was removed with the second PGF2α injection. In superstimulation protocol - 2 (conventional group buffaloes were superstimulated on the 10th day of the estrous cycle with same FSH dose regimen and similar timings for PGF2α injections. In both groups, half of the buffaloes were treated with luteinizing hormone (LH 25 mg and other half with 100 ug buserelin; gonadotrophin releasing hormone (GnRH analog at 12 h after the end of FSH treatment. All buffaloes in both protocols were inseminated twice at 12 and 24 h of LH/GnRH treatment. Daily ultrasonography was performed to record the size and number of follicles and superovulatory response. Results: Significantly higher number of small follicles (8 mm, corpora lutea, and transferable embryos was higher in buffaloes superstimulated at estradiol-induced follicular wave compared to the conventional protocol: Further the percentage of transferable embryos was significantly higher in buffaloes administered with LH compared to GnRH.

Novel engineered systems for oral, mucosal and transdermal drug delivery.

Science.gov (United States)

Li, Hairui; Yu, Yuan; Faraji Dana, Sara; Li, Bo; Lee, Chi-Ying; Kang, Lifeng

2013-08-01

Technological advances in drug discovery have resulted in increasing number of molecules including proteins and peptides as drug candidates. However, how to deliver drugs with satisfactory therapeutic effect, minimal side effects and increased patient compliance is a question posted before researchers, especially for those drugs with poor solubility, large molecular weight or instability. Microfabrication technology, polymer science and bioconjugate chemistry combine to address these problems and generate a number of novel engineered drug delivery systems. Injection routes usually have poor patient compliance due to their invasive nature and potential safety concerns over needle reuse. The alternative non-invasive routes, such as oral, mucosal (pulmonary, nasal, ocular, buccal, rectal, vaginal), and transdermal drug delivery have thus attracted many attentions. Here, we review the applications of the novel engineered systems for oral, mucosal and transdermal drug delivery.

Current advances in transdermal delivery of drugs for Alzheimer's disease

Science.gov (United States)

Nguyen, Thuy Trang; Giau, Vo Van; Vo, Tuong Kha

2017-01-01

Alzheimer's disease (AD) is a common, progressive, fatal neurodegenerative disorder, which will play an increasingly important role both socially and financially in the aging populations. Treatments for AD show modest improvements in cognition and global functioning among patients. Furthermore, the oral administration of treating AD has had some drawbacks that decrease the medication adherence and efficacy of the therapy. Transdermal drugs are proposed as an alternative remedy to overcome the disadvantages of current pharmaceutical dosage options for this chronic disorder. They could have different strengths, such as offering a stable diffusion of active substance, avoiding the first pass metabolism, and reducing system adverse reactions. This article reviews the technical principles, novel techniques of transdermal delivery drug, and prospects for future development for the management of cognitive and behavioral dysfunctions in AD patients. PMID:28706327

Current advances in transdermal delivery of drugs for Alzheimer's disease.

Science.gov (United States)

Nguyen, Thuy Trang; Giau, Vo Van; Vo, Tuong Kha

2017-01-01

Alzheimer's disease (AD) is a common, progressive, fatal neurodegenerative disorder, which will play an increasingly important role both socially and financially in the aging populations. Treatments for AD show modest improvements in cognition and global functioning among patients. Furthermore, the oral administration of treating AD has had some drawbacks that decrease the medication adherence and efficacy of the therapy. Transdermal drugs are proposed as an alternative remedy to overcome the disadvantages of current pharmaceutical dosage options for this chronic disorder. They could have different strengths, such as offering a stable diffusion of active substance, avoiding the first pass metabolism, and reducing system adverse reactions. This article reviews the technical principles, novel techniques of transdermal delivery drug, and prospects for future development for the management of cognitive and behavioral dysfunctions in AD patients.

Estradiol increases choice of cocaine over food in male rats.

Science.gov (United States)

Bagley, Jared R; Adams, Julia; Bozadjian, Rachel V; Bubalo, Lana; Ploense, Kyle L; Kippin, Tod E

2017-10-19

Estradiol modulates the rewarding and reinforcing properties of cocaine in females, including an increase in selection of cocaine over alternative reinforcers. However, the effects of estradiol on male cocaine self-administration behavior are less studied despite equivalent levels of estradiol in the brains of adult males and females, estradiol effects on motivated behaviors in males that share underlying neural substrates with cocaine reinforcement as well as expression of estrogen receptors in the male brain. Therefore, we sought to characterize the effects of estradiol in males on choice between concurrently-available cocaine and food reinforcement as well as responding for cocaine or food in isolation. Male castrated rats (n=46) were treated daily with estradiol benzoate (EB) (5μg/0.1, S.C.) or vehicle (peanut oil) throughout operant acquisition of cocaine (1mg/kg, IV; FI20 sec) and food (3×45mg; FI20 sec) responding, choice during concurrent access and cocaine and food reinforcement under progressive ratio (PR) schedules. EB increased cocaine choice, both in terms of percent of trials on which cocaine was selected and the proportion of rats exhibiting a cocaine preference as well as increased cocaine, but not food, intake under PR. Additionally, within the EB treated group, cocaine-preferring rats exhibited enhanced acquisition of cocaine, but not food, reinforcement whereas no acquisition differences were observed across preferences in the vehicle treated group. These findings demonstrate that estradiol increases cocaine choice in males similarly to what is observed in females. Copyright © 2017 Elsevier Inc. All rights reserved.

Custom-made micro applicators for high-dose-rate brachytherapy treatment of chronic psoriasis

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Ivan M. Buzurovic

2017-06-01

Full Text Available Purpose: In this study, we present the treatment of the psoriatic nail beds of patients refractory to standard therapies using high-dose-rate (HDR brachytherapy. The custom-made micro applicators (CMMA were designed and constructed for radiation dose delivery to small curvy targets with complicated topology. The role of the HDR brachytherapy treatment was to stimulate the T cells for an increased immune response. Material and methods: The patient diagnosed with psoriatic nail beds refractory to standard therapies received monthly subunguinal injections that caused significant pain and discomfort in both hands. The clinical target was defined as the length from the fingertip to the distal interphalangeal joint. For the accurate and reproducible setup in the multi-fractional treatment delivery, the CMMAs were designed. Five needles were embedded into the dense plastic mesh and covered with 5 mm bolus material for each micro applicator. Five CMMAs were designed, resulting in the usage of 25 catheters in total. Results: The prescription dose was planned to the depth of the anterior surface of the distal phalanx, allowing for the sparing of the surrounding tissue. The total number of the active dwell positions was 145 with step size of 5 mm. The total treatment time was 115 seconds with a 7.36 Ci activity of the 192Ir source. The treatment resulted in good pain control. The patient did not require further injections to the nail bed. After this initial treatment, additional two patients with similar symptoms received HDR brachytherapy. The treatment outcome was favorable in all cases. Conclusions : The first HDR brachytherapy treatment of psoriasis of the nail bed is presented. The initial experience revealed that brachytherapy treatment was well-tolerated and resulted in adequate control of the disease. A larger cohort of patients will be required for additional conclusions related to the long-term clinical benefits.

Transdermal thiol-acrylate polyethylene glycol hydrogel synthesis using near infrared light

Science.gov (United States)

Chung, Solchan; Lee, Hwangjae; Kim, Hyung-Seok; Kim, Min-Gon; Lee, Luke P.; Lee, Jae Young

2016-07-01

Light-induced polymerization has been widely applied for hydrogel synthesis, which conventionally involves the use of ultraviolet or visible light to activate a photoinitiator for polymerization. However, with these light sources, transdermal gelation is not efficient and feasible due to their substantial interactions with biological systems, and thus a high power is required. In this study, we used biocompatible and tissue-penetrating near infrared (NIR) light to remotely trigger a thiol-acrylate reaction for efficient in vivo gelation with good controllability. Our gelation system includes gold nanorods as a photothermal agent, a thermal initiator, diacrylate polyethylene glycol (PEG), and thiolated PEG. Irradiation with a low-power NIR laser (0.3 W cm-2) could induce gelation via a mixed-mode reaction with a small increase in temperature (~5 °C) under the optimized conditions. We also achieved successful transdermal gelation via the NIR-assisted photothermal thiol-acryl reactions. This new type of NIR-assisted thiol-acrylate polymerization provides new opportunities for in situ hydrogel formation for injectable hydrogels and delivery of drugs/cells for various biomedical applications.Light-induced polymerization has been widely applied for hydrogel synthesis, which conventionally involves the use of ultraviolet or visible light to activate a photoinitiator for polymerization. However, with these light sources, transdermal gelation is not efficient and feasible due to their substantial interactions with biological systems, and thus a high power is required. In this study, we used biocompatible and tissue-penetrating near infrared (NIR) light to remotely trigger a thiol-acrylate reaction for efficient in vivo gelation with good controllability. Our gelation system includes gold nanorods as a photothermal agent, a thermal initiator, diacrylate polyethylene glycol (PEG), and thiolated PEG. Irradiation with a low-power NIR laser (0.3 W cm-2) could induce gelation

Experimental design and optimization of raloxifene hydrochloride loaded nanotransfersomes for transdermal application

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Mahmood S

2014-09-01

Full Text Available Syed Mahmood, Muhammad Taher, Uttam Kumar Mandal Department of Pharmaceutical Technology, Kulliyyah of Pharmacy, International Islamic University Malaysia (IIUM, Pahang Darul Makmur, Malaysia Abstract: Raloxifene hydrochloride, a highly effective drug for the treatment of invasive breast cancer and osteoporosis in post-menopausal women, shows poor oral bioavailability of 2%. The aim of this study was to develop, statistically optimize, and characterize raloxifene hydrochloride-loaded transfersomes for transdermal delivery, in order to overcome the poor bioavailability issue with the drug. A response surface methodology experimental design was applied for the optimization of transfersomes, using Box-Behnken experimental design. Phospholipon® 90G, sodium deoxycholate, and sonication time, each at three levels, were selected as independent variables, while entrapment efficiency, vesicle size, and transdermal flux were identified as dependent variables. The formulation was characterized by surface morphology and shape, particle size, and zeta potential. Ex vivo transdermal flux was determined using a Hanson diffusion cell assembly, with rat skin as a barrier medium. Transfersomes from the optimized formulation were found to have spherical, unilamellar structures, with a ­homogeneous distribution and low polydispersity index (0.08. They had a particle size of 134±9 nM, with an entrapment efficiency of 91.00%±4.90%, and transdermal flux of 6.5±1.1 µg/cm2/hour. Raloxifene hydrochloride-loaded transfersomes proved significantly superior in terms of amount of drug permeated and deposited in the skin, with enhancement ratios of 6.25±1.50 and 9.25±2.40, respectively, when compared with drug-loaded conventional liposomes, and an ethanolic phosphate buffer saline. Differential scanning calorimetry study revealed a greater change in skin structure, compared with a control sample, during the ex vivo drug diffusion study. Further, confocal laser

Galactosyl Pentadecene Reversibly Enhances Transdermal and Topical Drug Delivery

Czech Academy of Sciences Publication Activity Database

Kopečná, M.; Macháček, M.; Prchalová, Eva; Štěpánek, P.; Drašar, P.; Kotora, Martin; Vávrová, K.

2017-01-01

Roč. 34, č. 10 (2017), s. 2097-2108 ISSN 0724-8741 Institutional support: RVO:61388963 Keywords : galactoside * penetration enhancers * sugar * topical drug delivery * transdermal drug delivery Subject RIV: FR - Pharmacology ; Medidal Chemistry OBOR OECD: Pharmacology and pharmacy Impact factor: 3.002, year: 2016

Estradiol influences the mechanical properties of human fetal osteoblasts through cytoskeletal changes

Energy Technology Data Exchange (ETDEWEB)

Muthukumaran, Padmalosini [Department of Bioengineering, National University of Singapore (Singapore); Lim, Chwee Teck [Department of Bioengineering, National University of Singapore (Singapore); Department of Mechanical Engineering, National University of Singapore (Singapore); Mechanobiology Institute, National University of Singapore (Singapore); Singapore-MIT Alliance for Research and Technology (SMART), National University of Singapore (Singapore); Lee, Taeyong, E-mail: bielt@nus.edu.sg [Department of Bioengineering, National University of Singapore (Singapore)

2012-07-06

Highlights: Black-Right-Pointing-Pointer Estradiol induced stiffness changes of osteoblasts were quantified using AFM. Black-Right-Pointing-Pointer Estradiol causes significant decrease in the stiffness of osteoblasts. Black-Right-Pointing-Pointer Decreased stiffness was caused by decreased density of f-actin network. Black-Right-Pointing-Pointer Stiffness changes were not associated with mineralized matrix of osteoblasts. Black-Right-Pointing-Pointer Estradiol increases inherent alkaline phosphatase activity of osteoblasts. -- Abstract: Estrogen is known to have a direct effect on bone forming osteoblasts and bone resorbing osteoclasts. The cellular and molecular effects of estrogen on osteoblasts and osteoblasts-like cells have been extensively studied. However, the effect of estrogen on the mechanical property of osteoblasts has not been studied yet. It is important since mechanical property of the mechanosensory osteoblasts could be pivotal to its functionality in bone remodeling. This is the first study aimed to assess the direct effect of estradiol on the apparent elastic modulus (E{sup Asterisk-Operator }) and corresponding cytoskeletal changes of human fetal osteoblasts (hFOB 1.19). The cells were cultured in either medium alone or medium supplemented with {beta}-estradiol and then subjected to Atomic Force Microscopy indentation (AFM) to determine E{sup Asterisk-Operator }. The underlying changes in cytoskeleton were studied by staining the cells with TRITC-Phalloidin. Following estradiol treatment, the cells were also tested for proliferation, alkaline phosphatase activity and mineralization. With estradiol treatment, E{sup Asterisk-Operator} of osteoblasts significantly decreased by 43-46%. The confocal images showed that the changes in f-actin network observed in estradiol treated cells can give rise to the changes in the stiffness of the cells. Estradiol also increases the inherent alkaline phosphatase activity of the cells. Estradiol induced stiffness

Estradiol influences the mechanical properties of human fetal osteoblasts through cytoskeletal changes

International Nuclear Information System (INIS)

Muthukumaran, Padmalosini; Lim, Chwee Teck; Lee, Taeyong

2012-01-01

Highlights: ► Estradiol induced stiffness changes of osteoblasts were quantified using AFM. ► Estradiol causes significant decrease in the stiffness of osteoblasts. ► Decreased stiffness was caused by decreased density of f-actin network. ► Stiffness changes were not associated with mineralized matrix of osteoblasts. ► Estradiol increases inherent alkaline phosphatase activity of osteoblasts. -- Abstract: Estrogen is known to have a direct effect on bone forming osteoblasts and bone resorbing osteoclasts. The cellular and molecular effects of estrogen on osteoblasts and osteoblasts-like cells have been extensively studied. However, the effect of estrogen on the mechanical property of osteoblasts has not been studied yet. It is important since mechanical property of the mechanosensory osteoblasts could be pivotal to its functionality in bone remodeling. This is the first study aimed to assess the direct effect of estradiol on the apparent elastic modulus (E ∗ ) and corresponding cytoskeletal changes of human fetal osteoblasts (hFOB 1.19). The cells were cultured in either medium alone or medium supplemented with β-estradiol and then subjected to Atomic Force Microscopy indentation (AFM) to determine E ∗ . The underlying changes in cytoskeleton were studied by staining the cells with TRITC-Phalloidin. Following estradiol treatment, the cells were also tested for proliferation, alkaline phosphatase activity and mineralization. With estradiol treatment, E ∗ of osteoblasts significantly decreased by 43–46%. The confocal images showed that the changes in f-actin network observed in estradiol treated cells can give rise to the changes in the stiffness of the cells. Estradiol also increases the inherent alkaline phosphatase activity of the cells. Estradiol induced stiffness changes of osteoblasts were not associated with changes in the synthesized mineralized matrix of the cells. Thus, a decrease in osteoblast stiffness with estrogen treatment was

In vitro evaluation of transdermal nicotine delivery systems commercially available in Brazil

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André Luís Morais Ruela

2013-09-01

Full Text Available The aim of this study was to develop and validate a method for evaluating the release and skin permeation from transdermal nicotine patches using the vertical diffusion cell (VDC. The VDC is an experimental apparatus employed in research, development, and the pharmaceutical field because it can simulate conditions closest to those established in clinical trials. Two transdermal nicotine delivery systems marketed in Brazil to release 14 mg over 24 hours were evaluated. Release studies were carried out using a regenerated cellulose dialysis membrane and permeation studies were carried out using excised porcine ear skin. The results indicated that nicotine release from both evaluated patches follows Higuchi's release kinetics, while skin permeation studies indicated zero-order release kinetics. Nicotine release rates were different between both evaluated patches, but drug permeation rates were not significantly different. According to validation studies, the method was appropriate for evaluating in vitro performance of nicotine patches. The proposed method can be applied to in vitro comparative studies between different commercial nicotine patches and may be used as an auxiliary tool in the design of new transdermal nicotine delivery systems.

Dydrogesterone does not reverse the cardiovascular benefits of percutaneous estradiol.

Science.gov (United States)

Kuba, V M; Teixeira, M A M; Meirelles, R M R; Assumpção, C R L; Costa, O S

2013-02-01

To evaluate the influence of dydrogesterone on estimated cardiovascular risk of users of hormone replacement therapy (HRT) (with percutaneous 17β-estradiol in monotherapy and in combination with dydrogesterone) and HRT non-users through the Framingham score tool for a period of 2 years. Framingham scores were calculated from the medical records of patients treated for at least 2 years with 17β-estradiol alone or in combination with dydrogesterone, along with HRT non-users, through the analysis of patient medical records, followed for at least 2 years at Instituto Estadual de Diabetes e Endocrinologia Luiz Capriglione. Improvements in lipid profile, glucose and blood pressure levels, which reduced the estimated cardiovascular risk, were observed in the 17β-estradiol group. Similar changes were observed in the users of 17β-estradiol + dydrogesterone, suggesting that this progestogen does not attenuate the effects caused by 17β-estradiol. Both HRT groups showed a reduction in their Framingham score. In contrast to data from other HRT investigations on cardiovascular risk, these formulations proved to be safe, even in the first year of use.

Microneedle-mediated transdermal delivery of nanostructured lipid carriers for alkaloids from Aconitum sinomontanum.

Science.gov (United States)

Guo, Teng; Zhang, Yongtai; Li, Zhe; Zhao, Jihui; Feng, Nianping

2017-09-12

A combination method using microneedle (MN) pretreatment and nanostructured lipid carriers (NLCs) was developed to improve the transdermal delivery of therapeutics. The MN treatment of the skin and co-administration of NLCs loaded with total alkaloids isolated from Aconitum sinomontanum (AAS-NLCs) significantly increased the skin permeation of the drugs. Fluorescence imaging confirmed that MNs could provide microchannels penetrating the stratum corneum, and delivery of NLCs through the channels led to their deeper permeation. In vivo studies showed that combination of AAS-NLCs with MNs (AAS-NLCs-MN) in transdermal delivery could improve the bioavailability and maintain stable drug concentrations in the blood. Moreover, AAS-NLCs-MN showed benefits in eliminating paw swelling, decreasing inflammation and pain, and regulating immune function in adjuvant arthritis rats. After administration of AAS-NLCs-MN, no skin irritation was observed in rabbits, and electrocardiograms of rats showed improved arrhythmia. These results indicated that the dual approach combining MN insertion and NLCs has the potential to provide safe transdermal delivery and to improve the therapeutic efficacy through sustained release of AAS.

Stimulation of estradiol biosynthesis by tributyltin in rat hippocampal slices.

Science.gov (United States)

Munetsuna, Eiji; Hattori, Minoru; Yamazaki, Takeshi

2014-01-01

Hippocampal functions are influenced by steroid hormones, such as testosterone and estradiol. It has been demonstrated that hippocampus-derived steroid hormones play important roles in neuronal protection and synapse formation. Our research groups have demonstrated that estradiol is de novo synthesized in the rat hippocampus. However, the mechanism(s) regulating this synthesis remains unclear. It has been reported that tributyltin, an environmental pollutant, binds to the retinoid X receptor (RXR) and modifies estrogen synthesis in human granulosa-like tumor cells. This compound can penetrate the blood brain barrier, and tends to accumulate in the brain. Based on these facts, we hypothesized that tributyltin could influence the hippocampal estradiol synthesis. A concentration of 0.1 μM tributyltin induced an increase in the mRNA content of P450(17α) and P450arom in hippocampal slices, as determined using real-time PCR. The transcript levels of other steroidogenic enzymes and a steroidogenic acute regulatory protein were not affected. The estradiol level in rat hippocampal slices was subsequently determined using a radioimmunoassay. We found that the estradiol synthesis was stimulated by ∼2-fold following a 48-h treatment with 0.1 μM tributyltin, and this was accompanied by transcriptional activation of P450(17α) and P450arom. Tributyltin stimulated de novo hippocampal estradiol synthesis by modifying the transcription of specific steroidogenic enzymes.

Serum level modifications of female sex hormones after radiocastration with different total doses

International Nuclear Information System (INIS)

Naujokat, B.; Rohloff, R.; Willich, N.; Eiermann, W.

1988-01-01

We determined serum level of estradiol, FSH and LH over a period of six to eight weeks after ovarian irradiation for castration with different doses (2x2.5 Gy/3x2.5 Gy/4x2.5 Gy) in 15 patients with metastatic breast cancer as compared to changes after ovarectomy in five patients. The time course of the changing estradiol-, FSH and LH-serum levels sigificantly depends on the ovarian dose. After radiological castration with a dose of 4x2.5 Gy = 10 Gy in four days the estrogen levels decrease within two to three weeks, and the FSH- and LH-levels increase after three to four weeks into the postmenopausal range. Therefore, the time course is not very different from changes after ovarectomy. (orig.) [de

Estradiol decreases iodide uptake by rat thyroid follicular FRTL-5 cells

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Furlanetto T.W.

2001-01-01

Full Text Available Estradiol has well-known indirect effects on the thyroid. A direct effect of estradiol on thyroid follicular cells, increasing cell growth and reducing the expression of the sodium-iodide symporter gene, has been recently reported. The aim of the present investigation was to study the effect of estradiol on iodide uptake by thyroid follicular cells, using FRTL-5 cells as a model. Estradiol decreased basal iodide uptake by FRTL-5 cells from control levels of 2.490 ± 0.370 to 2.085 ± 0.364 pmol I-/µg DNA at 1 ng/ml (P<0.02, to 1.970 ± 0.302 pmol I-/µg DNA at 10 ng/ml (P<0.003, and to 2.038 ± 0.389 pmol I-/µg DNA at 100 ng/ml (P<0.02. In addition, 4 ng/ml estradiol decreased iodide uptake induced by 0.02 mIU/ml thyrotropin from 8.678 ± 0.408 to 7.312 ± 0.506 pmol I-/µg DNA (P<0.02. A decrease in iodide uptake by thyroid cells caused by estradiol has not been described previously and may have a role in goiter pathogenesis.

Dose fractionation in synchrotron radiation x-ray phase micro-tomography

International Nuclear Information System (INIS)

Frachon, Thibaut; Weber, Loriane; Hesse, Bernhard; Rit, Simon; Dong, Pei; Olivier, Cecile; Peyrin, Françoise; Langer, Max

2015-01-01

Phase sensitive x-ray imaging expands the applicability of standard attenuation based techniques by offering several orders of magnitude of increase in sensitivity. Due to the short wavelength, x-ray phase is not directly measurable, but has to be put in evidence by the use of phase contrast techniques. The phase can then be reconstructed from one or several phase contrast images. In this study, we consider synchrotron x-ray phase micro-computed tomography (μCT) based on free space propagation for heterogeneous and strongly absorbing objects. This technique generally relies on acquiring several scans of the sample at different detector distances. It is also generally believed that multi-distance phase μCT needs a higher dose input than single distance phase μCT. The purpose of this work is to study the impact of different means of dose fractionation on the reconstructed image quality. We define different acquistion schemes in multi-distance in-line phase μCT. Previously, the exposure time at each sample-to-detector distance was usually kept the same. Here, we let not only the number of distances vary but also the fraction of exposure time at each distance, the total exposure time being kept constant. Phase retrieval is performed with the mixed approach algorithm. The reconstructed μCT images are compared in terms of accuracy, precision and resolution. In addition, we also compare the result of dose fractionated multi distance phase μCT to single distance phase μCT using the same total radiation dose. In the multi-distance approach, we find that using different exposure times on each distance improves the image quality in the reconstructed image. Further, we show that, despite having the same total dose delivery, the multi distance imaging method gives better image quality than the single distance method, at the cost of an additional overhead from camera displacements and reference images. We show that by optimizing the acquistion parameters in terms of

Acute Intoxication by Transdermal Opium Application in Infants: Two Case Reports

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Iraj Sedighi

2012-05-01

Full Text Available Background: Acute opium intoxication is one of the most common causes of poisoning in children in Iran. Although most cases are accidental, traditional misuse of opium for symptomatic therapy of various childhood diseases also contributes to high rate of opium intoxication in Iran. Cases: Here, we report two cases of opium intoxication in infants resulted from transdermal application of opium on burned skin. To our knowledge this is the first case report of intoxication from transdermal misuse of opium. Conclusion: Health care providers should be aware about signs and symptoms of opium intoxication in children. Opium intoxication should be suspected in each child with history of a recent burn injury that presented with decreased level of consciousness.

The Influence of Solid Microneedles on the Transdermal Delivery of Selected Antiepileptic Drugs

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Julia Nguyen

2016-11-01

Full Text Available The aim of this project was to examine the effect of microneedle rollers on the percutaneous penetration of tiagabine hydrochloride and carbamazepine across porcine skin in vitro. Liquid chromatography-mass spectrometric analysis was carried out using an Agilent 1200 Series HPLC system coupled to an Agilent G1969A TOF-MS system. Transdermal flux values of the drugs were determined from the steady-state portion of the cumulative amount versus time curves. Following twelve hours of microneedle roller application, there was a 6.74-fold increase in the percutaneous penetration of tiagabine hydrochloride (86.42 ± 25.66 µg/cm2/h compared to passive delivery (12.83 ± 6.30 µg/cm2/h. For carbamazepine in 20% ethanol, passive transdermal flux of 7.85 ± 0.60 µg/cm2/h was observed compared to 10.85 ± 0.11 µg/cm2/h after microneedle treatment. Carbamazepine reconstituted in 30% ethanol resulted in only a 1.19-fold increase in drug permeation across porcine skin (36.73 ± 1.83 µg/cm2/h versus 30.74 ± 1.32 µg/cm2/h. Differences in flux values of untreated and microneedle-treated porcine skin using solid microneedles for the transdermal delivery of tiagabine were statistically significant. Although there were 1.38- and 1.19-fold increases in transdermal flux values of carbamazepine when applied as 20% and 30% ethanol solutions across microneedle-treated porcine skin, respectively, the increases were not statistically significant.

Gold nanorods in an oil-base formulation for transdermal treatment of type 1 diabetes in mice

Science.gov (United States)

Nose, Keisuke; Pissuwan, Dakrong; Goto, Masahiro; Katayama, Yoshiki; Niidome, Takuro

2012-05-01

Efficient transdermal insulin delivery to the systemic circulation would bring major benefit to diabetic patients. We investigated the possibility of using gold nanorods (GNRs) that formed a complex with an edible surfactant and insulin (INS) in an oil phase to form a solid-in-oil (SO) formulation (SO-INS-GNR) for transdermal treatment of diabetes. Diabetic mice comprised the model for our study. In vitro, there was high penetration of insulin through the stratum corneum (SC) and the dermis in mouse skin treated with an SO-INS-GNR complex plus near-infrared (NIR) light irradiation. Blood glucose levels in the diabetic mice were significantly decreased after treatment with SO-INS-GNR plus irradiation. To our knowledge, this is the first study to use gold nanorods for systemic insulin delivery through the skin. The use of an SO-INS-GNR complex combined with NIR irradiation may provide the possibility of transdermal insulin delivery to diabetic patients.Efficient transdermal insulin delivery to the systemic circulation would bring major benefit to diabetic patients. We investigated the possibility of using gold nanorods (GNRs) that formed a complex with an edible surfactant and insulin (INS) in an oil phase to form a solid-in-oil (SO) formulation (SO-INS-GNR) for transdermal treatment of diabetes. Diabetic mice comprised the model for our study. In vitro, there was high penetration of insulin through the stratum corneum (SC) and the dermis in mouse skin treated with an SO-INS-GNR complex plus near-infrared (NIR) light irradiation. Blood glucose levels in the diabetic mice were significantly decreased after treatment with SO-INS-GNR plus irradiation. To our knowledge, this is the first study to use gold nanorods for systemic insulin delivery through the skin. The use of an SO-INS-GNR complex combined with NIR irradiation may provide the possibility of transdermal insulin delivery to diabetic patients. Electronic supplementary information (ESI) available. See DOI: 10

In vitro regulation of LH biosynthesis and release by GnRH and estradiol

International Nuclear Information System (INIS)

Ramey, J.W.

1986-01-01

Anterior pituitaries were taken from female rats at random stages of the estrous cycle, enzymatically dispersed, and cultured for 48h in steroid-free α-modified Eagles medium followed by 24h in fresh medium +/- estradiol (E 2 ). The pituitary cells were then incubated in fresh medium containing radiolabeled precursors +/- gonadotropin releasing hormone (GnRH). Radioactive precursor incorporation into LH was determined by immuno-precipitation. The dose-dependent effects of E 2 (10 -11 to 10 -8 M) on 3 H-glucosamine ( 3 H-Gln) and 35 S-methionine ( 35 S-Met) incorporation into LH +/- 1 nM GnRH (4h) were investigated. GnRH (10 -9 M) and E 2 (all doses) significantly increased total 3 H-Gln LH. Moreover, E 2 at 10 -9 M and 10 -8 M significantly enhanced GnRH stimulated LH glycosylation. In contrast, addition of GnRH and/or E 2 did not significantly increase 35 S-Met incorporation into LH over a 4h period. The effects of various GnRH concentrations (10 -11 to 10 -9 M; 8h) +/- E 2 (0.05 nM) on 3 H-Gln LH and 35 S-Met LH production were also investigated. In the absence of E 2 , only 10 -9 M GnRH was effective in increasing total 3 H-Gln LH and 35 S-Met LH synthesis. However, in the presence of E 2 , all concentrations of GnRH stimulated LH synthesis with 3 H-Gln LH production responding in a dose related manner whereas 35 S-Met LH production was maximally stimulated at all doses of GnRH. In the final series of experiments, pituitary cells previously exposed to estradiol were incubated for 4 h in normal calcium or low calcium medium containing 3 H-Gln or 35 S-Met +/- GnRH. Removal of extracellular calcium completely inhibited GnRH stimulated 3 H-Gln LH and 35 S-Met LH production

Low-dose rhBMP2/7 heterodimer to reconstruct peri-implant bone defects: a micro-CT evaluation

NARCIS (Netherlands)

Wang, J.; Zheng, Y.; Zhao, J.; Liu, T.; Gao, L.; Gu, Z.; Wu, G.

2012-01-01

Objectives To delineate the dynamic micro-architectures of bone induced by low-dose bone morphogenetic protein (BMP)-2/7 heterodimer in peri-implant bone defects compared to BMP2 and BMP7 homodimer. Material and Methods Peri-implant bone defects (8 mm in diameter, 4 mm in depth) were created

NMR characterisation and transdermal drug delivery potential of microemulsion systems

DEFF Research Database (Denmark)

Kreilgaard, Mads; Pedersen, E J; Jaroszewski, J W

2000-01-01

The purpose of this study was to investigate the influence of structure and composition of microemulsions (Labrasol/Plurol Isostearique/isostearylic isostearate/water) on their transdermal delivery potential of a lipophilic (lidocaine) and a hydrophilic model drug (prilocaine hydrochloride), and ...

Insulin priming effect on estradiol-induced breast cancer metabolism and growth.

Science.gov (United States)

Wairagu, Peninah M; Phan, Ai N H; Kim, Min-Kyu; Han, Jeongwoo; Kim, Hyun-Won; Choi, Jong-Whan; Kim, Ki Woo; Cha, Seung-Kuy; Park, Kwang Hwa; Jeong, Yangsik

2015-01-01

Diabetes is a risk factor for breast cancer development and is associated with poor prognosis for breast cancer patients. However, the molecular and biochemical mechanisms underlying the association between diabetes and breast cancer have not been fully elucidated. Here, we investigated estradiol response in MCF-7 breast cancer cells with or without chronic exposure to insulin. We found that insulin priming is necessary and specific for estradiol-induced cancer cell growth, and induces anaplerotic shunting of glucose into macromolecule biosynthesis in the estradiol treated cells. Treatment with ERK or Akt specific inhibitors, U0126 or LY294002, respectively, suppressed estradiol-induced growth. Interestingly, molecular analysis revealed that estradiol treatment markedly increases expression of cyclin A and B, and decreases p21 and p27 in the insulin-primed cells. In addition, estradiol treatment activated metabolic genes in pentose phosphate (PPP) and serine biosynthesis pathways in the insulin-primed cells while insulin priming decreased metabolic gene expression associated with glucose catabolism in the breast cancer cells. Finally, we found that anti-diabetic drug metformin and AMPK ligand AICAR, but not thiazolidinediones (TZDs), specifically suppress the estradiol-induced cellular growth in the insulin-primed cells. These findings suggest that estrogen receptor (ER) activation under chronic hyperinsulinemic condition increases breast cancer growth through the modulation of cell cycle and apoptotic factors and nutrient metabolism, and further provide a mechanistic evidence for the clinical benefit of metformin use for ER-positive breast cancer patients with diabetes.

Enhancing effect of negative polypropylene electret on in vitro transdermal delivery of cyclosporine A solution and its synergistic effect with ethyl oleate

International Nuclear Information System (INIS)

Cui, L L; Liu, H Y; Ma, L; Liang, Y Y; Guo, X; Jiang, J

2013-01-01

In this study, the corona charged electrets at voltages of −500 V, −1000 V and −2000 V were made from polypropylene (PP) film. The cyclosporine A (CsA) and 10% ethyl oleate were chosen as the model drug and chemical enhancer, respectively. The charge storage stability of the electrets and the in vitro transdermal behaviour of the model drug in solution under different conditions were studied. The results indicate that the external electrostatic field of the negative PP electrets could penetrate through the rat skin and enhance the transdermal delivery of cyclosporine A. A synergistic effect on enhancing the transdermal delivery of cyclosporine A was observed by combining different surface potential negative PP electrets with 10% ethyl oleate, and the amount of transdermal delivery of CsA was greatly increased comparing with only application of electrets. Therefore, the combination application of electret and chemical enhancer could be a feasible strategy in enhancing transdermal delivery of small peptide drugs or some large molecular drugs.

Patient-controlled analgesia: therapeutic interventions using transdermal electro-activated and electro-modulated drug delivery.

Science.gov (United States)

Indermun, Sunaina; Choonara, Yahya E; Kumar, Pradeep; Du Toit, Lisa C; Modi, Girish; Luttge, Regina; Pillay, Viness

2014-02-01

Chronic pain poses a major concern to modern medicine and is frequently undertreated, causing suffering and disability. Patient-controlled analgesia, although successful, does have limitations. Transdermal delivery is the pivot to which analgesic research in drug delivery has centralized, especially with the confines of needle phobias and associated pain related to traditional injections, and the existing limitations associated with oral drug delivery. Highlighted within is the possibility of further developing transdermal drug delivery for chronic pain treatment using iontophoresis-based microneedle array patches. A concerted effort was made to review critically all available therapies designed for the treatment of chronic pain. The drug delivery systems developed for this purpose and nondrug routes are elaborated on, in a systematic manner. Recent developments and future goals in transdermal delivery as a means to overcome the individual limitations of the aforementioned delivery routes are represented as well. The approval of patch-like devices that contain both the microelectronic-processing mechanism and the active medicament in a small portable device is still awaited by the pharmaceutical industry. This anticipated platform may provide transdermal electro-activated and electro-modulated drug delivery systems a feasible attempt in chronic pain treatment. Iontophoresis has been proven an effective mode used to administer ionized drugs in physiotherapeutic, diagnostic, and dermatological applications and may be an encouraging probability for the development of devices and aids in the treatment of chronic pain. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association.

Effects of estradiol on radiation-induced apoptosis in immunocytes of mouse

International Nuclear Information System (INIS)

Wu Wei; Yang Rujun; Kong Xiantao; Zhang Lingzhen; Li Bolong; Cai Jianming

2000-01-01

Objective: To assess the effects of estradiol on 60 Co γ-radiation induced apoptosis of splenic lymphocytes and thymocytes, and surface molecule expression of splenic lymphocytes. Methods: Mice were whole body irradiated with 4.0 Gy γ-rays. By flow cytometry and electrophoretic analysis of DNA, the changes in apoptosis of mouse immunocytes were determined. The splenic lymphocytes were analyzed by flow cytometry with fluorescent monoclonal antibodies. Results: 10 days after administration of estradiol, the characteristic DNA ladder in mice 8h after irradiation was minor than in mice without estradiol administration,indicating that the apoptotic rate reduced on flow cytometry. CD4+ T cells, CD8+ T cells and IgM+ B cells up regulated Fas, CD25 and CD69 expression, but did not so in the estradiol treated mice. Conclusion: Estradiol can block CD25, CD69 and Fas overexpression, thereby inhibiting Fas mediated apoptosis induced by γ-irradiation

Exposures to estradiol, ethinylestradiol and octylphenol affect survival and growth of Rana pipiens and Rana sylvatica tadpoles.

Science.gov (United States)

Hogan, Natacha S; Lean, David R S; Trudeau, Vance L

2006-08-01

Endocrine disrupting compounds (EDCs) are often detected in the aquatic environment and can negatively affect the health of wildlife populations. However, little is known about the sensitivity of native amphibians to EDCs. Wood frogs (Rana sylvatica) and Northern leopard frogs (Rana pipiens) were exposed to three estrogenic EDCs: estradiol (E2), ethinylestradiol (EE2), and 4-tert-octylphenol (OP). In addition, R. pipiens were exposed during two developmental stages (Gosner stages 26 and 36) to examine life-stage differences in sensitivity. Tadpoles were exposed for 2 wk to 8 nominal concentrations (0.25 microM-10 microM) of each compound. Individual mortality was recorded during the exposure period, while body weight was measured at the end of 2 wk. LC50 values were calculated, and differences in body weight between vehicle control and exposed groups were assessed. Rank order toxicity of the compounds for both R. pipiens stages and both species was OP > EE2 > E2. Gosner stage 26 tadpoles were more sensitive (LC50: E2 [5.57 microM], EE2 [3.01 microM], OP [1.36 microM]) to all three compounds when compared to stage 36 tadpoles (LC50: E2 [>10 microM], EE2 [4.17 microM], OP [2.80 microM]). Interspecies comparisons revealed R. sylvatica tadpoles (LC50: E2 [2.50 microM], EE2 [1.89 microM], OP [0.74 microM]) as being more sensitive to the three compounds than R. pipiens (LC50: E2 [4.56 microM], EE2 [2.75 microM], OP [1.42 microM]). Xenoestrogen exposure also affected tadpole body weight which may have long-term adverse effects on the rate of metamorphosis. These results provide toxicological data needed for assessing sublethal effects of estrogenic compounds on amphibian development and suggest that environmental levels of OP may pose a serious risk to the health of amphibian populations.

Sex, estradiol, and spatial memory in a food-caching corvid.

Science.gov (United States)

Rensel, Michelle A; Ellis, Jesse M S; Harvey, Brigit; Schlinger, Barney A

2015-09-01

Estrogens significantly impact spatial memory function in mammalian species. Songbirds express the estrogen synthetic enzyme aromatase at relatively high levels in the hippocampus and there is evidence from zebra finches that estrogens facilitate performance on spatial learning and/or memory tasks. It is unknown, however, whether estrogens influence hippocampal function in songbirds that naturally exhibit memory-intensive behaviors, such as cache recovery observed in many corvid species. To address this question, we examined the impact of estradiol on spatial memory in non-breeding Western scrub-jays, a species that routinely participates in food caching and retrieval in nature and in captivity. We also asked if there were sex differences in performance or responses to estradiol. Utilizing a combination of an aromatase inhibitor, fadrozole, with estradiol implants, we found that while overall cache recovery rates were unaffected by estradiol, several other indices of spatial memory, including searching efficiency and efficiency to retrieve the first item, were impaired in the presence of estradiol. In addition, males and females differed in some performance measures, although these differences appeared to be a consequence of the nature of the task as neither sex consistently out-performed the other. Overall, our data suggest that a sustained estradiol elevation in a food-caching bird impairs some, but not all, aspects of spatial memory on an innate behavioral task, at times in a sex-specific manner. Copyright © 2015 Elsevier Inc. All rights reserved.

Transdermal and intradermal delivery of therapeutic agents: application of physical technologies

National Research Council Canada - National Science Library

Banga, Ajay K

2011-01-01

.... Advancements in science combined with the need for diverse drug delivery modalities have introduced a variety of transdermal and intradermal products for existing drugs at a fraction of the cost of new drug development...

Superiority of liquid crystalline cubic nanocarriers as hormonal transdermal vehicle: comparative human skin permeation-supported evidence.

Science.gov (United States)

Mohyeldin, Salma M; Mehanna, Mohammed M; Elgindy, Nazik A

2016-08-01

The aim of this investigation was to explore the feasibility of various nanocarriers to enhance progesterone penetration via the human abdominal skin. Four progesterone-loaded nanocarriers; cubosomes, nanoliposomes, nanoemulsions and nanomicelles were formulated and characterized regarding particle size, zeta potential, % drug encapsulation and in vitro release. Structural elucidation of each nanoplatform was performed using transmission electron microscopy. Ex vivo skin permeation, deposition ability and histopathological examination were evaluated using Franz diffusion cells. Each nanocarrier was fabricated with a negative surface, nanometric size (≤ 270 nm), narrow size distribution and reasonable encapsulation efficiency. In vitro progesterone release showed a sustained release pattern for 24 h following a non-Fickian transport diffusion mechanism. All nanocarriers exhibited higher transdermal flux relative to free progesterone. Cubosomes revealed a higher skin penetration with transdermal steady flux of 48.57.10(-2) ± 0.7 µg/cm(2) h. Nanoliposomes offered a higher percentage of skin progesterone deposition compared to other nanocarriers. Based on the histopathological examination, cubosomes and nanoliposomes were found to be biocompatible for transdermal application. Confocal laser scanning microscopy confirmed the ability of fluoro-labeled cubosomes to penetrate through the whole skin layers. The elaborated cubosomes proved to be a promising non-invasive nanocarrier for transdermal hormonal delivery.

Dissipation of 17β-estradiol in composted poultry litter.

Science.gov (United States)

Hakk, Heldur; Sikora, Lawrence

2011-01-01

The excreted estrogen rate of all livestock in the United States is estimated at 134 kg d. The influence of manure treatment on the fate of estrogens is critical in deciding the recycling of over 300 million dry tons of livestock produced annually. The effects of two common manure management practices, heated composting and ambient temperature decomposition, on the fate of 17β-estradiol in poultry litter were determined. A mixture of poultry litter, wood chips, and straw was amended with [C]17β-estradiol and allowed to undergo decomposition with a laboratory-scale heated composter (HC) or room temperature incubation (RTI) for 24 d. Radiolabel in the finished products was fractionated into water-extractable, acetone-extractable, nonextractable, and mineralized fractions. Total 17β-estradiol radioactive residues in the HC and RTI ( = 2) treatments were not different ( > 0.05), except that statistically less 17β-estradiol was mineralized to CO during HC than RTI (1.1 vs. 10.0% for HC and RTI, respectively). Estrone was the major degradation product in extracts of HC and RTI treatments as determined by liquid chromatography/mass spectrometry analyses. The nonextractable residues indicated no quantitative differences among the humins between the treatments. An estimated 3% of the fortified estrogenicity remained after HC treatment, and 15% of the fortified estrogenicity remained after RTI treatment. If reduction of water-removable, biologically active 17β-estradiol is the treatment goal, then HC treatment would be slightly preferred over ambient temperature degradation. However, unmanaged, ambient temperature litter piles are less costly and time consuming for food animal producers and result in greater mineralization and similar immobilization of estradiol. by the American Society of Agronomy, Crop Science Society of America, and Soil Science Society of America, Inc.

Ultradeformable Liposomes: a Novel Vesicular Carrier For Enhanced Transdermal Delivery of Procyanidins: Effect of Surfactants on the Formation, Stability, and Transdermal Delivery.

Science.gov (United States)

Chen, Rencai; Li, Rongli; Liu, Qian; Bai, Chao; Qin, Benlin; Ma, Yue; Han, Jing

2017-07-01

The aims of this work were to develop a novel vesicular carrier, procyanidins, ultradeformable liposomes (PUDLs), to expand the applications for procyanidins, and increase their stability and transdermal delivery. In this study, we prepared procyanidins ultradeformable liposomes using thin film hydration method and evaluated their encapsulation efficiency, vesicle deformability, storage stability, and skin permeation in vitro. The influence of different surfactants on the properties of PUDLs was also investigated. The results obtained showed that the PUDLs containing Tween 80 had a high entrapment efficiency (80.27 ± 0.99%), a small particle size (140.6 ± 19 nm), high elasticity, and prolonged drug release. Compared with procyanidins solution, the stability of procyanidins in PUDLs improved significantly when stored at 4, 25, and 30°C. The penetration rate of PUDLs was 6.25-fold greater than that of procyanidins solution. Finally, the results of our study suggested that PUDLs could increase the transdermal flux, prolong the release and improve the stability of procyanidins, and could serve as an effective dermal delivery system for procyanidins.

Studies on estradiol-2/4-hydroxylase activity in rat brain and liver

International Nuclear Information System (INIS)

Theron, C.N.

1985-03-01

A sensitive and specific radio-enzymatic assay was used to study estradiol-2/4-hydroxylase activity in rat liver microsomes and in microsomes obtained from 6 discrete brain areas of the rat. Kinetic parameters were determined for these enzyme activities. The effects of different P-450 inhibitors on estradiol-2/4-hydroxylase activity in brain and liver microsomes were also studied. In both organs these enzyme activities were found to be located mainly in the microsomal fraction and were inhibited by the 3 P-450 inhibitors tested. The hepatic estradiol-2/4-hydroxylase activity in adult male rats was significantly higher than that of females, but the enzyme activity in the brain did not exhibit a similar sex difference. Furthermore, estradiol-2/4-hydroxylase activity in rat liver was strongly induced by phenobarbitone treatment, but not in the brain. The phenobarbitone-induced activity in male and female rats exhibited significant kinetic differences. In female rats sexual maturation was associated with significant changes in the apparent Km of estradiol-2/4-hydroxylases in the liver and hypothalamus. Evidence was found that the in vitro estradiol-2/4-hydroxylase activity in rat brain and liver is due to more than one form of microsomal P-450. Kinetic studies showed important differences between the estradiol-2/4-hydroxylase activities in the hippocampus and hypothalamus. Significant differences in estradiol-2/4-hydroxylase activities were observed in the 6 brain areas studied, with the hippocampus showing the highest, and the hypothalamus the lowest activity at all developmental stages in both male and female rats

Low-dose rhBMP2/7 heterodimer to reconstruct peri-implant bone defects: a micro-CT evaluation.

Science.gov (United States)

Wang, Jingxiao; Zheng, Yuanna; Zhao, Juan; Liu, Tie; Gao, Lixia; Gu, Zhiyuan; Wu, Gang

2012-01-01

To delineate the dynamic micro-architectures of bone induced by low-dose bone morphogenetic protein (BMP)-2/7 heterodimer in peri-implant bone defects compared to BMP2 and BMP7 homodimer. Peri-implant bone defects (8 mm in diameter, 4 mm in depth) were created surrounding SLA-treated titanium implants (3.1 mm in diameter, 10 mm in length) in minipig's calvaria. We administrated collagen sponges with adsorbed low-dose (30 ng/mm(3) ) BMP2/7 to treat the defects using BMP2, BMP7 or no BMP as controls.2, 3 and 6 weeks after implantation, we adopted micro-computer tomography to evaluate the micro-architectures of new bone using the following parameters: relative bone volume (BV/TV), trabecular number (Tb.N), trabecular thickness (Tb.Th), trabecular separation (Tb.Sp), connectivity density, and structure mode index (SMI). Bone implant contact (BIC) was also revealed histologically. Consistent with 2 and 3 weeks, after 6 weeks post-operation, BMP2/7 resulted in significantly higher BV/TV (63.033 ± 2.055%) and significantly lower SMI (-4.405 ± 0.500) than BMP2 (BV/TV: 43.133 ± 2.001%; SMI: -0.086 ± 0.041) and BMP7 (BV/TV: 41.467 ± 1.850%; SMI: -0.044 ± 0.016) respectively. Significant differences were also found in Tb.N, Tb.Th and Tb.Sp at all time points. At 2 weeks, BMP2/7 resulted in significantly higher BIC than the controls. Low-dose BMP2/7 heterodimer facilitated more rapid bone regeneration in better quality in peri-implant bone defects than BMP2 and BMP7 homodimers. © 2011 John Wiley & Sons A/S.

Transdermal delivery of scopolamine by natural submicron injectors: in-vivo study in pig.

Directory of Open Access Journals (Sweden)

Esther Shaoul

Full Text Available Transdermal drug delivery has made a notable contribution to medical practice, but has yet to fully achieve its potential as an alternative to oral delivery and hypodermic injections. While transdermal delivery systems would appear to provide an attractive solution for local and systemic drug delivery, only a limited number of drugs can be delivered through the outer layer of the skin. The most difficult to deliver in this way are hydrophilic drugs. The aquatic phylum Cnidaria, which includes sea anemones, corals, jellyfish and hydra, is one of the most ancient multicellular phyla that possess stinging cells containing organelles (cnidocysts, comprising a sophisticated injection system. The apparatus is folded within collagenous microcapsules and upon activation injects a thin tubule that immediately penetrates the prey and delivers its contents. Here we show that this natural microscopic injection system can be adapted for systemic transdermal drug delivery once it is isolated from the cells and uploaded with the drug. Using a topically applied gel containing isolated natural sea anemone injectors and the muscarinic receptor antagonist scopolamine, we found that the formulated injectors could penetrate porcine skin and immediately deliver this hydrophilic drug. An in-vivo study in pigs demonstrated, for the first time, rapid systemic delivery of scopolamine, with T(max of 30 minutes and C(max 5 times higher than in controls treated topically with a scopolamine-containing gel without cnidocysts. The ability of the formulated natural injection system to penetrate a barrier as thick as the skin and systemically deliver an exogenous compound presents an intriguing and attractive alternative for hydrophilic transdermal drug delivery.

Effect of Electron-Beam Irradiation on Bacterial Cellulose Membranes Used as Transdermal Drug Delivery Systems

International Nuclear Information System (INIS)

Stoica-Guzun, A.

2006-01-01

Multiple methods are used to modify material surfaces. Radiation is an effective tool for polymer surfaces modification in order to obtain transdermal systems with different controlled release properties. Bacterial cellulose is a promising biomaterial synthesized by Acetobacter xylinum. It has a distinctive ultrafine reticulated structure that may become a perfect matrix as an optimal wound healing environment. In this work, high energy irradiation (γ rays from 137 C s) was applied to modify bacterial cellulose membranes. The effect of varying irradiation doses on membranes permeability was studied. Tetracycline was involved in the study of diffusivity as model drug. Release and permeation of drug from irradiated and non-irradiated membranes were done using a diffusion cell. The membrane permeability was determined using a psudo-steady state analysis based on Fick's law

Transdermal glimepiride delivery system based on optimized ethosomal nano-vesicles: Preparation, characterization, in vitro, ex vivo and clinical evaluation.

Science.gov (United States)

Ahmed, Tarek A; El-Say, Khalid M; Aljaeid, Bader M; Fahmy, Usama A; Abd-Allah, Fathy I

2016-03-16

This work aimed to develop an optimized ethosomal formulation of glimepiride then loading into transdermal films to offer lower drug side effect, extended release behavior and avoid first pass effect. Four formulation factors were optimized for their effects on vesicle size (Y1), entrapment efficiency (Y2) and vesicle flexibility (Y3). Optimum desirability was identified and, an optimized formulation was prepared, characterized and loaded into transdermal films. Ex-vivo permeation study for the prepared films was conducted and, the permeation parameters and drug permeation mechanism were identified. Penetration through rat skin was studied using confocal laser microscope. In-vivo study was performed following transdermal application on human volunteers. The percent of alcohol was significantly affecting all the studied responses while the other factors and their interaction effects were varied on their effects on each response. The optimized ethosomal formulation showed observed values for Y1, Y2 and Y3 of 61 nm, 97.12% and 54.03, respectively. Ex-vivo permeation of films loaded with optimized ethosomal formulation was superior to that of the corresponding pure drug transdermal films and this finding was also confirmed after confocal laser microscope study. Permeation of glimepiride from the prepared films was in favor of Higushi-diffusion model and exhibited non-Fickian or anomalous release mechanism. In-vivo study revealed extended drug release behavior and lower maximum drug plasma level from transdermal films loaded with drug ethosomal formulation. So, the ethosomal formulation could be considered a suitable drug delivery system especially when loaded into transdermal vehicle with possible reduction in side effects and controlling the drug release. Copyright © 2016 Elsevier B.V. All rights reserved.

Evaluation of diclofenac prodrugs for enhancing transdermal delivery.

Science.gov (United States)

Lobo, Shabbir; Li, Henan; Farhan, Nashid; Yan, Guang

2014-03-01

Abstract Objective: The purpose of this study was to evaluate the approach of using diclofenac acid (DA) prodrugs for enhancing transdermal delivery. Methanol diclofenac ester (MD), ethylene glycol diclofenac ester (ED), glycerol diclofenac ester (GD) and 1,3-propylene glycol diclofenac ester (PD) were synthesized and evaluated for their physicochemical properties such as solubilities, octanol/water partition coefficients, stratum corneum/water partition coefficients, hydrolysis rates and bioconversion rates. In vitro fluxes across human epidermal membrane (HEM) in the Franz diffusion cell were determined on DA-, MD-, ED-, GD- and PD-saturated aqueous solutions. The formation of GD and ED led to the prodrugs with higher aqueous solubilities and lower partition coefficients than those of the parent drug. Prodrugs with improved aqueous solubility showed better fluxes across HEM in aqueous solution than that of the parent drug, with GD showing the highest aqueous solubility and also the highest flux. There is a linear relationship between the aqueous solubility and flux for DA, ED and PD, but GD and MD deviated from the linear line. Diclofenac prodrugs with improved hydrophilicity than the parent drug could be utilized for enhancing transdermal diclofenac delivery.

Evaluation of Diclofenac Prodrugs for Enhancing Transdermal Delivery

Science.gov (United States)

Lobo, Shabbir; Li, Henan; Farhan, Nashid; Yan, Guang

2016-01-01

The purpose of this study was to evaluate the approach of using diclofenac acid (DA) prodrugs for enhancing transdermal delivery. Methanol diclofenac ester (MD), ethylene glycol diclofenac ester (ED), glycerol diclofenac ester (GD), and 1,3-propylene glycol diclofenac ester (PD) were synthesized and evaluated for their physicochemical properties such as solubilities, octanol/water partition coefficients, stratum corneum/water partition coefficients, hydrolysis rates, and bioconversion rates. In vitro fluxes across human epidermal membrane (HEM) in Franz diffusion cell were determined on DA, MD, ED, GD, and PD saturated aqueous solutions. The formation of GD and ED led to the prodrugs with higher aqueous solubilities and lower partition coefficients than those of the parent drug. Prodrugs with improved aqueous solubility showed better fluxes across HEM in aqueous solution than that of the parent drug, with GD showing the highest aqueous solubility and also the highest flux. There is a linear relationship between the aqueous solubility and flux for DA, ED and PD, but GD and MD deviated from the linear line. Overall, diclofenac prodrugs with improved hydrophilicity than the parent drug could be utilized for enhancing transdermal diclofenac delivery. PMID:24517636

An open label, dose response study to determine the effect of a dietary supplement on dihydrotestosterone, testosterone and estradiol levels in healthy males

Directory of Open Access Journals (Sweden)

Anderson Mark L

2008-08-01

Full Text Available Abstract Background Maintaining endogenous testosterone (T levels as men age may slow the symptoms of sarcopenia, andropause and decline in physical performance. Drugs inhibiting the enzyme 5α-reductase (5AR produce increased blood levels of T and decreased levels of dihydrotestosterone (DHT. However, symptoms of gynecomastia have been reported due to the aromatase (AER enzyme converting excess T to estradiol (ES. The carotenoid astaxanthin (AX from Haematococcus pluvialis, Saw Palmetto berry lipid extract (SPLE from Serenoa repens and the precise combination of these dietary supplements, Alphastat® (Mytosterone(™, have been reported to have inhibitory effects on both 5AR and AER in-vitro. Concomitant regulation of both enzymes in-vivo would cause DHT and ES blood levels to decrease and T levels to increase. The purpose of this clinical study was to determine if patented Alphastat® (Mytosterone(™ could produce these effects in a dose dependent manner. Methods To investigate this clinically, 42 healthy males ages 37 to 70 years were divided into two groups of twenty-one and dosed with either 800 mg/day or 2000 mg/day of Alphastat® (Mytosterone(™ for fourteen days. Blood samples were collected on days 0, 3, 7 and 14 and assayed for T, DHT and ES. Body weight and blood pressure data were collected prior to blood collection. One-way, repeated measures analysis of variance (ANOVA-RM was performed at a significance level of alpha = 0.05 to determine differences from baseline within each group. Two-way analysis of variance (ANOVA-2 was performed after baseline subtraction, at a significance level of alpha = 0.05 to determine differences between dose groups. Results are expressed as means ± SEM. Results ANOVA-RM showed significant within group increases in serum total T and significant decreases in serum DHT from baseline in both dose groups at a significance level of alpha = 0.05. Significant decreases in serum ES are reported for the 2000

Design, development, physicochemical, and in vitro and in vivo evaluation of transdermal patches containing diclofenac diethylammonium salt.

Science.gov (United States)

Arora, Priyanka; Mukherjee, Biswajit

2002-09-01

In this study, matrix-type transdermal patches containing diclofenac diethylamine were prepared using different ratios of polyvinylpyrrolidone (PVP) and ethylcellulose (EC) by solvent evaporation technique. The drug matrix film of PVP and EC was casted on a polyvinylalcohol backing membrane. All the prepared formulations were subjected to physical studies (moisture content, moisture uptake, and flatness), in vitro release studies and in vitro skin permeation studies. In vitro permeation studies were performed across cadaver skin using a modified diffusion cell. Variations in drug release profiles among the formulations studied were observed. Based on a physicochemical and in vitro skin permeation study, formulation PA4 (PVP/EC, 1:2) and PA5 (PVP/EC, 1:5) were chosen for further in vivo experiments. The antiinflammatory effect and a sustaining action of diclofenac diethylamine from the two transdermal patches selected were studied by inducing paw edema in rats with 1% w/v carrageenan solution. When the patches were applied half an hour before the subplantar injection of carrageenan in the hind paw of male Wistar rats, it was observed that formulation PA4 produced 100% inhibition of paw edema in rats 12 h after carrageenan insult, whereas in the case of formulation PA5, 4% mean paw edema was obtained half an hour after the carrageenan injection and the value became 19.23% 12 h after the carrageenan insult. The efficacy of transdermal patches was also compared with the marketed Voveran gel and it was found that PA4 transdermal patches produced a better result as compared with the Voveran gel. Hence, it can be reasonably concluded that diclofenac diethylamine can be formulated into the transdermal matrix type patches to sustain its release characteristics and the polymeric composition (PVP/EC, 1:2) was found to be the best choice for manufacturing transdermal patches of diclofenac diethylamine among the formulations studied. Copyright 2002 Wiley-Liss, Inc.

Hormone-dependent nuclear export of estradiol receptor and DNA synthesis in breast cancer cells

Science.gov (United States)

Lombardi, Maria; Castoria, Gabriella; Migliaccio, Antimo; Barone, Maria Vittoria; Di Stasio, Rosina; Ciociola, Alessandra; Bottero, Daniela; Yamaguchi, Hiroshi; Appella, Ettore; Auricchio, Ferdinando

2008-01-01

In breast cancer cells, cytoplasmic localization of the estradiol receptor α (ERα) regulates estradiol-dependent S phase entry. We identified a nuclear export sequence (NES) in ERα and show that its export is dependent on both estradiol-mediated phosphatidylinositol-3-kinase (PI3K)/AKT activation and chromosome region maintenance 1 (CRM1). A Tat peptide containing the ERα NES disrupts ERα–CRM1 interaction and prevents nuclear export of ERα- and estradiol-induced DNA synthesis. NES-ERα mutants do not exit the nucleus and inhibit estradiol-induced S phase entry; ERα-dependent transcription is normal. ERα is associated with Forkhead proteins in the nucleus, and estradiol stimulates nuclear exit of both proteins. ERα knockdown or ERα NES mutations prevent ERα and Forkhead nuclear export. A mutant of forkhead in rhabdomyosarcoma (FKHR), which cannot be phosphorylated by estradiol-activated AKT, does not associate with ERα and is trapped in the nucleus, blocking S phase entry. In conclusion, estradiol-induced AKT-dependent phosphorylation of FKHR drives its association with ERα, thereby triggering complex export from the nucleus necessary for initiation of DNA synthesis and S phase entry. PMID:18644889

Plasma Concentrations of Fentanyl Achieved With Transdermal Application in Chickens

NARCIS (Netherlands)

Delaski, Kristina M; Gehring, Ronette; Heffron, Brendan T; Negrusz, Adam; Gamble, Kathryn C

2017-01-01

Providing appropriate analgesia is an important concern in any species. Fentanyl, a μ-receptor specific opioid, use is common in mammalian species but has been incompletely evaluated for this purpose in avian species. Transdermal fentanyl patches were applied to domestic chickens (n = 10) of varying

Preconception folic acid use modulates estradiol and follicular responses to ovarian stimulation.

Science.gov (United States)

Twigt, John M; Hammiche, Fatima; Sinclair, Kevin D; Beckers, Nicole G; Visser, Jenny A; Lindemans, Jan; de Jong, Frank H; Laven, Joop S E; Steegers-Theunissen, Régine P

2011-02-01

Folate is a methyl donor. Availability of folate affects DNA methylation profiles and thereby gene expression profiles. We investigated the effects of low-dose folic acid use (0.4 mg/d) on the ovarian response to mild and conventional ovarian stimulation in women. In a randomized trial among subfertile women, 24 and 26 subjects received conventional and mild ovarian stimulation, respectively. Blood samples were taken during the early follicular phase of the cycle prior to treatment and on the day of human chorionic gonadotropin administration for determination of serum total homocysteine, anti-Müllerian hormone (AMH), estradiol, and folate. Folic acid use was validated by questionnaire and serum folate levels. Preovulatory follicles were visualized, counted, and diameters recorded using transvaginal ultrasound. The relation between folic acid use and ovarian response was assessed using linear regression analysis. Folic acid use modified the ovarian response to ovarian stimulation treatment. The estradiol response was higher in nonfolic acid users receiving conventional treatment [β(interaction) = 0.52 (0.07-0.97); P = 0.03], and this effect was independent of serum AMH levels and the preovulatory follicle count. In the conventional treatment, the mean follicle number was also greater in nonusers compared with the users group (14.1 vs. 8.9, P = 0.03). Low-dose folic acid use attenuates follicular and endocrine responses to conventional stimulation, independent of AMH and follicle count. The nature of this observation suggests that the effect of folic acid is most prominent during early follicle development, affecting immature follicles. Deleterious effects of folate deficiency, like DNA hypomethylation and oxidative stress, can help to explain our observations.

Estradiol Synthesis in Gut-Associated Lymphoid Tissue: Leukocyte Regulation by a Sexually Monomorphic System.

Science.gov (United States)

Oakley, Oliver R; Kim, Kee Jun; Lin, Po-Ching; Barakat, Radwa; Cacioppo, Joseph A; Li, Zhong; Whitaker, Alexandra; Chung, Kwang Chul; Mei, Wenyan; Ko, CheMyong

2016-12-01

17β-estradiol is a potent sex hormone synthesized primarily by gonads in females and males that regulates development and function of the reproductive system. Recent studies show that 17β-estradiol is locally synthesized in nonreproductive tissues and regulates a myriad of events, including local inflammatory responses. In this study, we report that mesenteric lymph nodes (mLNs) and Peyer's patches (Pps) are novel sites of de novo synthesis of 17β-estradiol. These secondary lymphoid organs are located within or close to the gastrointestinal tract, contain leukocytes, and function at the forefront of immune surveillance. 17β-estradiol synthesis was initially identified using a transgenic mouse with red fluorescent protein coexpressed in cells that express aromatase, the enzyme responsible for 17β-estradiol synthesis. Subsequent immunohistochemistry and tissue culture experiments revealed that aromatase expression was localized to high endothelial venules of these lymphoid organs, and these high endothelial venule cells synthesized 17β-estradiol when isolated and cultured in vitro. Both mLNs and Pps contained 17β-estradiol with concentrations that were significantly higher than those of peripheral blood. Furthermore, the total amount of 17β-estradiol in these organs exceeded that of the gonads. Mice lacking either aromatase or estrogen receptor-β had hypertrophic Pps and mLNs with more leukocytes than their wild-type littermates, demonstrating a role for 17β-estradiol in leukocyte regulation. Importantly, we did not observe any sex-dependent differences in aromatase expression, 17β-estradiol content, or steroidogenic capacity in these lymphoid organs.

Evaluation of Diclofenac Prodrugs for Enhancing Transdermal Delivery

OpenAIRE

Lobo, Shabbir; Li, Henan; Farhan, Nashid; Yan, Guang

2013-01-01

The purpose of this study was to evaluate the approach of using diclofenac acid (DA) prodrugs for enhancing transdermal delivery. Methanol diclofenac ester (MD), ethylene glycol diclofenac ester (ED), glycerol diclofenac ester (GD), and 1,3-propylene glycol diclofenac ester (PD) were synthesized and evaluated for their physicochemical properties such as solubilities, octanol/water partition coefficients, stratum corneum/water partition coefficients, hydrolysis rates, and bioconversion rates. ...

Evaluation of paeonol-loaded transethosomes as transdermal delivery carriers.

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Chen, Z X; Li, B; Liu, T; Wang, X; Zhu, Y; Wang, L; Wang, X H; Niu, X; Xiao, Y; Sun, Q

2017-03-01

Paeonol shows effective anti-allergic, anti-inflammatory and analgesic activities. However, because of its poor solubility in water and high volatility at room temperature, the application of this drug is restricted in the clinic. The objective of this research was to develop a biocompatible paeonol formulation with improved stability, skin delivery and pharmacokinetic efficiency. In this paper, paeonol-loaded vesicles were prepared using an ethanol injection method. Nano-vesicles were characterized for their physical properties and encapsulation efficiency (EE). Drug permeation behavior in vitro and deposition quantity in porcine ear skin were measured with a Valia-Chien (V-C) diffusion device. Additionally, a validated and sensitive high performance liquid chromatography (HPLC) method was developed to analyze paeonol concentrations in rat plasma after transdermal administration. The results showed that the particle-size order of the nano-vesicles was the following: transethosomes (122.5±7.5nm)transethosomes had a higher EE (85.5±5.2%), and they showed a spherical morphology with a smooth surface when viewed under a transmission electron microscope (TEM). In an in vitro permeation study, the paeonol transethosomes showed an enhanced transdermal flux of 95.7±8.8μg/cm 2 /h and a higher deposition quantity in porcine ear skin compared to the transfersomes. A one-compartment first-order absorption model could be used to describe the pharmacokinetics of paeonol in rats after transdermal administration. The AUC of the paeonol transethosomes was approximately 1.57- and 3.52-fold higher than those of the transfersomes and a saturated solution of paeonol in 35% ethanol, respectively. The results demonstrated that the paeonol transethosomes had a narrow size distribution, high encapsulation efficiency, and long residence in the plasma. This formulation remarkably enhanced the bioavailability of paeonol. Copyright © 2016 Elsevier B.V. All rights reserved.

Synthesis and evaluation of 7α-(3-[18F]fluoropropyl) estradiol

International Nuclear Information System (INIS)

Okamoto, Mayumi; Naka, Kyosuke; Kitagawa, Yuya; Ishiwata, Kiichi; Yoshimoto, Mitsuyoshi; Shimizu, Isao; Toyohara, Jun

2015-01-01

estradiol dose-dependently inhibited C3-7α-[ 18 F]FES uptake in the uterus and ovary. The in vivo IC 50 values of estradiol in the uterus and ovary were 34.4 and 38.5 nmol/kg, respectively. Furthermore, in vivo tumor uptake of C3-7α-[ 18 F]FES was significantly higher (unpaired t test with Welch’s correction; p = 0.015) in ER-positive T-47D tumors (2.3%ID/g ± 0.4%ID/g) than ER-negative MDA-MB-231 tumors (0.9%ID/g ± 0.1%ID/g). Conclusions: Although extensive metabolism was observed in rodents, C3-7α-[ 18 F]FES showed promising results for quantitative analysis of ER density in vivo. However, the selective uptake of C3-7α-[ 18 F]FES was lower than that of 16α-[ 18 F]FES. Further optimizations and structure–activity relationship studies of the C-7α-substituted estradiol are needed

Hybrid electrospun chitosan-phospholipids nanofibers for transdermal drug delivery.

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Mendes, Ana C; Gorzelanny, Christian; Halter, Natalia; Schneider, Stefan W; Chronakis, Ioannis S

2016-08-20

Chitosan (Ch) polysaccharide was mixed with phospholipids (P) to generate electrospun hybrid nanofibers intended to be used as platforms for transdermal drug delivery. Ch/P nanofibers exibithed average diameters ranging from 248±94nm to 600±201nm, depending on the amount of phospholipids used. Fourier Transformed Infra-Red (FTIR) spectroscopy and Dynamic Light Scattering (DLS) data suggested the occurrence of electrostatic interactions between amine groups of chitosan with the phospholipid counterparts. The nanofibers were shown to be stable for at least 7days in Phosphate Buffer Saline (PBS) solution. Cytotoxicity studies (WST-1 and LDH assays) demonstrated that the hybrid nanofibers have suitable biocompatibility. Fluorescence microscopy, also suggested that L929 cells seeded on top of the CH/P hybrid have similar metabolic activity comparatively to the cells seeded on tissue culture plate (control). The release of curcumin, diclofenac and vitamin B12, as model drugs, from Ch/P hybrid nanofibers was investigated, demonstrating their potential utilization as a transdermal drug delivery system. Copyright © 2016 Elsevier B.V. All rights reserved.

In vivo studies of transdermal nanoparticle delivery with microneedles using photoacoustic microscopy

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Moothanchery, Mohesh; Seeni, Razina Z.; Xu, Chenjie; Pramanik, Manojit

2017-01-01

Microneedle technology allows micron-sized conduits to be formed within the outermost skin layers for both localized and systemic delivery of therapeutics including nanoparticles. Histological methods are often employed for characterization, and unfortunately do not allow for the in vivo visualization of the delivery process. This study presents the utilization of optical resolution-photoacoustic microscopy to characterize the transdermal delivery of nanoparticles using microneedles. Specifically, we observe the in vivo transdermal delivery of gold nanoparticles using microneedles in mice ear and study the penetration, diffusion, and spatial distribution of the nanoparticles in the tissue. The promising results reveal that photoacoustic microscopy can be used as a potential imaging modality for the in vivo characterization of microneedles based drug delivery. PMID:29296482

High Total Ionizing Dose and Temperature Effects on Micro- and Nano-electronic Devices

International Nuclear Information System (INIS)

Gaillardin, M.; Martinez, M.; Paillet, P.; Leray, J.L.; Marcandella, C.; Duhamel, O.; Raine, M.; Richard, N.; Girard, S.; Ouerdane, Y.; Boukenter, A.; Goiffon, V.; Magnan, P.; Andrieu, F.; Barraud, S.; Faynot, O.

2013-06-01

This paper investigates the vulnerability of several micro- and nano-electronic technologies to a mixed harsh environment including high total ionizing dose at MGy levels and high temperature. Such operating conditions have been revealed recently for several applications like new security systems in existing or future nuclear power plants, fusion experiments, or deep space missions. In this work, the competing effects already reported in literature of ionizing radiations and temperature are characterized in elementary devices made of MOS transistors from several technologies. First, devices are irradiated using a radiation laboratory X-ray source up to MGy dose levels at room temperature. Devices are grounded during irradiation to simulate a circuit which waits for a wake up signal, representing most of the lifetime of an integrated circuit operating in a harsh environment. Devices are then annealed at several temperatures to discuss the post-irradiation behavior and to determine whether an elevated temperature is an issue or not for circuit function in mixed harsh environments. (authors)

Estradiol stimulation of inositolphospholipid metabolism in human endometrial fibroblasts

International Nuclear Information System (INIS)

Iida, K.; Imai, A.; Tamaya, T.

1989-01-01

Stimulated inositolphospholipid turnover has been proposed to constitute a signal-transducing mechanism in many cell types. To determine the inositolphospholipid turnover during stimulation by 17 beta-estradiol, the turnover kinetics of phospholipids was investigated in human endometrial fibroblasts. In cells incubated with [ 32 P] phosphate for 1 h, estradiol rapidly and persisitently (for at least 30 min) enhanced the rate of 32 P-labeling of phosphatidic acid (PA). On the other hand, after a lag time of 5 min, 32 P-labeling of phosphatidylinositol (PI) was also increased also. These sequential 32 P-labeling of PA and PI demonstrated that inositolphospholipid turnover was stimulated in fibroblasts exposed to estradiol. The rapid estrogen-stimulated inositolphospholipid turnover may not be through the mechanism associated with classical action of estrogen

3D model of amphioxus steroid receptor complexed with estradiol

Energy Technology Data Exchange (ETDEWEB)

Baker, Michael E., E-mail: mbaker@ucsd.edu [Department of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0693 (United States); Chang, David J. [Department of Biology, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0693 (United States)

2009-08-28

The origins of signaling by vertebrate steroids are not fully understood. An important advance was the report that an estrogen-binding steroid receptor [SR] is present in amphioxus, a basal chordate with a similar body plan as vertebrates. To investigate the evolution of estrogen-binding to steroid receptors, we constructed a 3D model of amphioxus SR complexed with estradiol. This 3D model indicates that although the SR is activated by estradiol, some interactions between estradiol and human ER{alpha} are not conserved in the SR, which can explain the low affinity of estradiol for the SR. These differences between the SR and ER{alpha} in the steroid-binding domain are sufficient to suggest that another steroid is the physiological regulator of the SR. The 3D model predicts that mutation of Glu-346 to Gln will increase the affinity of testosterone for amphioxus SR and elucidate the evolution of steroid-binding to nuclear receptors.

Effect of Gamma Irradiation Doses and Micro Elements on Some Physical, Chemical and Crop Parameters of Vigna sinensis

International Nuclear Information System (INIS)

Hussein, L.O.S.; Saleh, O.I.; Abdullah, M.I.

2011-01-01

The present work aim to expose Vigna sinensis L. (cowpea) seeds to gamma rays at dose levels 40, 80 and 120 Gy and to spray the growing plants with micro elements; boron (B) and zinc (Zn) after one month of planting; until harvest date, for increasing crop quality and quantity. Some physical parameters, some chemical analysis, the yield and net percentage of the produced crop were evaluated. The result obtained refer that, the 40 Gy dose enhanced most of physical, chemical and yield parameters of cowpea crop. Moreover, the harvested crop was increased and improved in case of those produced from plants sprayed with different concentrations of B or Zn plus 40 Gy dose as compared with the other treatments used followed by the dose of 80 Gy. Meanwhile, the dose of 120 Gy gave the least enhancement on the quality and quantity of the aforementioned treatments in cowpea crop

Role of Mas receptor in renal blood flow response to angiotensin-(1-7) in ovariectomized estradiol treated rats.

Science.gov (United States)

Saberi, Shadan; Dehghani, Aghdas; Nematbakhsh, Mehdi

2016-01-01

The angiotensin 1-7 (Ang 1-7), is abundantly produced in kidneys and antagonizes the function of angiotensin II through Mas receptor (MasR) or other unknown mechanisms. In the current study, the role of MasR and steroid hormone estrogen on renal blood flow response to Ang 1-7 administration was investigated in ovariectomized (OV) female rats. OV female Wistar-rats received estradiol (500 μg/kg/week) or vehicle for two weeks. In the day of the experiment, the animals were anesthetized, cannulated, and the responses including mean arterial pressure, renal blood flow (RBF), and renal vascular resistance at the constant level of renal perfusion pressure to graded infusion of Ang 1-7 at 0, 100 and 300 ng/kg/min were determined in OV and OV estradiol-treated (OVE) rats, treated with vehicle or MasR antagonist; A779. RBF response to Ang 1-7 infusion increased dose-dependently in vehicle (Pdose <0.001) and A779-treated (Pdose <0.01) animals. However, when MasR was blocked, the RBF response to Ang 1-7 significantly increased in OV animals compared with OVE rats (P<0.05). When estradiol was limited by ovariectomy, A779 increased RBF response to Ang 1-7 administration, while this response was attenuated in OVE animals.

Transdermal Physostigmine—Absence of Effect on Topographic Brain Mapping

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M. Y. Neufeld

1993-01-01

Full Text Available Nine patients with primary degenerative dementia (PDD participated in an open trial of transdermal physostigmine (TPh. In order to evaluate the neurophysiologic effects of TPh, EEG data were recorded and compared at baseline and following 2 months of continuous treatment. There was no significant effect of TPh on EEG spectra in patients with PDD.

Effects of estradiol and FSH on leptin levels in women with suppressed pituitary.

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Geber, Selmo; Brandão, Augusto H F; Sampaio, Marcos

2012-06-15

Female fertility depends on adequate nutrition and energy reserves, suggesting a correlation between the metabolic reserve and reproductive capacity. Leptin regulates body weight and energy homeostasis. The aim of this study was to investigate whether estradiol or FSH alone has a direct effect on the production of leptin. A total of 64 patients submitted to controlled ovarian hyperstimulation with recombinant FSH for assisted reproduction and 20 patients using estradiol valerate for endometrial preparation for oocyte donation treatment were included in the study. All patients used GnRH analogues before starting treatment to achieve pituitary suppression. Blood samples for hormonal measurements were collected before starting and after completing the respective treatments. Data were analyzed statistically by the chi-square test, Student's t-test and Pearson's correlation test. We observed an elevation of serum leptin levels secondary to the increase in estradiol, in the absence of influence of any other ovarian or pituitary hormone. The rising rate of leptin levels was higher in women treated with recombinant FSH, which also had higher levels of estradiol, than in those treated with estradiol valerate. This study demonstrates a correlation between serum levels of estradiol and leptin, suggesting that estradiol is an important regulator of leptin production and that its effects can be amplified by its association with FSH.

The Effect of Transdermal Scopolamine for the Prevention of Postoperative Nausea and Vomiting

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Maria A. Antor

2014-04-01

Full Text Available Postoperative nausea and vomiting is one of the most common and undesirable complaints recorded in as many as 70%-80% of high-risk surgical patients. The current prophylactic therapy recommendations for PONV management stated in the Society of Ambulatory Anesthesia guidelines should start with monotherapy and patients at moderate to high risk, a combination of antiemetic medication should be considered. Consequently, if rescue medication is required, the antiemetic drug chosen should be from a different therapeutic class and administration mode than the drug used for prophylaxis. The guidelines restrict the use of dexamethasone, transdermal scopolamine, aprepitant, and palonosetron as rescue medication 6 hours after surgery. In an effort to find a safer and reliable therapy for postoperative nausea and vomiting, new drugs with antiemetic properties and minimal side effects are needed, and scopolamine may be considered an effective alternative. Scopolamine is a belladonna alkaloid, α-(hydroxymethyl benzene acetic acid 9-methyl-3-oxa-9-azatricyclo non-7-yl ester, acting as a nonselective muscarinic antagonist and producing both peripheral antimuscarinic and central sedative, antiemetic, and amnestic effects. The empirical formula is C17H21NO4 and its structural formula is a tertiary amine L-(2-scopolamine (tropic acid ester with scopine; MW = 303.4. Scopolamine became the first drug commercially available as a transdermal therapeutic system used for extended continuous drug delivery during 72 hours. Clinical trials with transdermal scopolamine have consistently demonstrated its safety and efficacy in postoperative nausea and vomiting. Thus, scopolamine is a promising candidate for the management of postoperative nausea and vomiting in adults as a first line monotherapy or in combination with other drugs. In addition, transdermal scopolamine might be helpful in preventing postoperative discharge nausea and vomiting owing to its long

Nanoethosomes for transdermal delivery of tropisetron HCl: multi-factorial predictive modeling, characterization, and ex vivo skin permeation.

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Abdel Messih, Hanaa A; Ishak, Rania A H; Geneidi, Ahmed S; Mansour, Samar

2017-06-01

The aim of the present work is to exclusively optimize and model the effect of phospholipid type either egg phosphatidylcholine (EPC) or soybean phosphatidylcholine (SPC), together with other formulation variables, on the development of nano-ethosomal systems for transdermal delivery of a water-soluble antiemetic drug. Tropisetron HCl (TRO) is available as hard gelatin capsules and IV injections. The transdermal delivery of TRO is considered as a novel alternative route supposing to improve BAV as well as patient convenience. TRO-loaded ethanolic vesicular systems were prepared by hot technique. The effect of formulation variables were optimized through a response surface methodology using 3 × 2 2 -level full factorial design. The concentrations of both PC (A) and ethanol (B) and PC type (C) were the factors, while entrapment efficiency (Y 1 ), vesicle size (Y 2 ), polydispersity index (Y 3 ), and zeta potential (Y 4 ) were the responses. The drug permeation across rat skin from selected formulae was studied. Particle morphology, drug-excipient interactions, and vesicle stability were also investigated. The results proved the critical role of all formulation variables on ethosomal characteristics. The suggested models for all responses showed good predictability. Only the concentration of phospholipid, irrespective to PC type, had a significant effect on the transdermal flux (p transdermal TRO delivery.

A metabolomics study of the inhibitory effect of 17-beta-estradiol on osteoclast proliferation and differentiation.

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Liu, Xiaoyan; Liu, Yanqiu; Cheng, Mengchun; Zhang, Xiaozhe; Xiao, Hongbin

2015-02-01

Estradiol is a major drug used clinically to alleviate osteoporosis, partly through inhibition of the activity of osteoclasts, which play a crucial role in bone resorption. So far, little is known about the effects of estradiol on osteoclast metabolism. In this study, ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC/MS)-based metabolomics strategy was used to investigate the metabolite response to 17β-estradiol in mouse osteoclast RAW264.7, a commonly used cell model for studying osteoporosis. Our results showed that the application of estradiol altered the levels of 27 intracellular metabolites, including lysophosphatidylcholines (LysoPCs), other lipids and amino acid derivants. The changes of all the 27 metabolites were observed in the study of estradiol induced osteoclast proliferation inhibition (1 μM estradiol applied), while the changes of only 18 metabolites were observed in the study of differentiation inhibition (0.1 μM estradiol applied). Further pathway impact analysis determined glycerophospholipid metabolism as the main potential target pathway of estradiol, which was further confirmed by LCAT (phosphatidylcholine-sterol acyltransferase) activity changes and lipid peroxidative product (MDA, methane dicarboxylic aldehyde) changes caused by estradiol. Additionally, we found that estradiol significantly decreased intracellular oxidative stress during cell proliferation but not during cell differentiation. Our study suggested that estradiol generated a highly condition-dependent influence on osteoclast metabolism.

Estradiol or fluoxetine alters depressive behavior and tryptophan hydroxylase in rat raphe.

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Yang, Fu-Zhong; Wu, Yan; Zhang, Wei-Guo; Cai, Yi-Yun; Shi, Shen-Xun

2010-03-10

The effects of 17beta-estradiol and fluoxetine on behavior of ovariectomized rats subjected to the forced swimming test and the expression of tryptophan hydroxylase (TPH) in dorsal and median raphe were investigated, respectively through time sampling technique of behavior scoring and immunohistochemistry. Both estradiol and fluoxetine increased swimming and decreased immobility in the forced swimming test. The forced swimming stress decreased integrated optical density of TPH-positive regions in dorsal and median raphe. Both estradiol and fluoxetine administration prevented integrated optical density of TPH-positive regions from being decreased by forced swimming stress. These observations suggest that both estradiol and fluoxetine have protective bearing on ovariectomized rats enduring forced swimming stress.

Brain-derived neurotrophic factor mediates estradiol-induced dendritic spine formation in hippocampal neurons

Science.gov (United States)

Murphy, Diane D.; Cole, Nelson B.; Segal, Menahem

1998-01-01

Dendritic spines are of major importance in information processing and memory formation in central neurons. Estradiol has been shown to induce an increase of dendritic spine density on hippocampal neurons in vivo and in vitro. The neurotrophin brain-derived neurotrophic factor (BDNF) recently has been implicated in neuronal maturation, plasticity, and regulation of GABAergic interneurons. We now demonstrate that estradiol down-regulates BDNF in cultured hippocampal neurons to 40% of control values within 24 hr of exposure. This, in turn, decreases inhibition and increases excitatory tone in pyramidal neurons, leading to a 2-fold increase in dendritic spine density. Exogenous BDNF blocks the effects of estradiol on spine formation, and BDNF depletion with a selective antisense oligonucleotide mimics the effects of estradiol. Addition of BDNF antibodies also increases spine density, and diazepam, which facilitates GABAergic neurotransmission, blocks estradiol-induced spine formation. These observations demonstrate a functional link between estradiol, BDNF as a potent regulator of GABAergic interneurons, and activity-dependent formation of dendritic spines in hippocampal neurons. PMID:9736750

Use of electroporation and reverse iontophoresis for extraction of transdermal multibiomarkers

Directory of Open Access Journals (Sweden)

Ching CTS

2012-02-01

Full Text Available Congo Tak-Shing Ching1,2, Lin-Shien Fu3-5, Tai-Ping Sun1, Tzu-Hsiang Hsu1, Kang-Ming Chang21Department of Electrical Engineering, National Chi Nan University, Puli, Nantou County, 2Department of Photonics and Communication Engineering, Asia University, Wufeng, Taichung, 3Department of Pediatrics, National Yang Ming University, Taipei, 4Institute of Technology, National Chi Nan University, Puli, 5Department of Pediatrics, Taichung Veterans General Hospital, Taichung City, TaiwanBackground: Monitoring of biomarkers, like urea, prostate-specific antigen (PSA, and osteopontin, is very important because they are related to kidney disease, prostate cancer, and ovarian cancer, respectively. It is well known that reverse iontophoresis can enhance transdermal extraction of small molecules, and even large molecules if reverse iontophoresis is used together with electroporation. Electroporation is the use of a high-voltage electrical pulse to create nanochannels within the stratum corneum, temporarily and reversibly. Reverse iontophoresis is the use of a small current to facilitate both charged and uncharged molecule transportation across the skin. The objectives of this in vitro study were to determine whether PSA and osteopontin are extractable transdermally and noninvasively and whether urea, PSA, and osteopontin can be extracted simultaneously by electroporation and reverse iontophoresis.Methods: All in vitro experiments were conducted using a diffusion cell assembled with the stratum corneum of porcine skin. Three different symmetrical biphasic direct currents (SBdc, five various electroporations, and a combination of the two techniques were applied to the diffusion cell via Ag/AgCl electrodes. The three different SBdc had the same current density of 0.3 mA/cm2, but different phase durations of 0 (ie, no current, control group, 30, and 180 seconds. The five different electroporations had the same pulse width of 1 msec and number of pulses per second

Pharmaceutical Product Development: Intranasal Scopolamine (INSCOP) Metered Dose Spray

Science.gov (United States)

Putcha, Lakshmi; Crady, Camille; Putcha, Lakshmi

2012-01-01

Motion sickness (MS) has been a problem associated with space flight, the modern military and commercial air and water transportation for many years. Clinical studies have shown that scopolamine is the most effective medication for the prevention of motion sickness (Dornhoffer et al, 2004); however, the two most common methods of administration (transdermal and oral) have performance limitations that compromise its utility. Intranasal administration offers a noninvasive treatment modality, and has been shown to counter many of the problems associated with oral and transdermal administration. With the elimination of the first pass effect by the liver, intranasal delivery achieves higher and more reliable bioavailability than an equivalent oral dose. This allows for the potential of enhanced efficacy at a reduced dose, thus minimizing the occurrence of untoward side effects. An Intranasal scopolamine (INSCOP) gel formulation was prepared and tested in four ground-based clinical trials under an active Investigational New Drug (IND) application with the Food and Drug Administration (FDA). Although there were early indicators that the intranasal gel formulation was effective, there were aspects of formulation viscosity and the delivery system that were less desirable. The INSCOP gel formulation has since been reformulated into an aqueous spray dosage form packaged in a precise, metered dose delivery system; thereby enhancing dose uniformity, increased user satisfaction and palatability, and a potentially more rapid onset of action. Recent reports of new therapeutic indications for scopolamine has prompted a wide spread interest in new scopolamine dosage forms. The novel dosage form and delivery system of INSCOP spray shows promise as an effective treatment for motion sickness targeted at the armed forces, spaceflight, and commercial sea, air, and space travel markets, as well as prospective psychotherapy for mental and emotional disorders.

Comparison of estrus synchronization by controlled internal drug release device (CIDR) and adhesive transdermal progestin patch in postpartum beef cows.

Science.gov (United States)

Kajaysri, Jatuporn; Chumchoung, Chaiwat; Wutthiwitthayaphong, Supphathat; Suthikrai, Wanvipa; Sangkamanee, Praphai

2017-09-15

Estrous synchronization with progesterone based protocols has been essentially used in cattle industry. Although intravaginal devices have been commonly used, this technique may induce vaginitis. This study aimed at examining the efficiency of novel transdermal progestin patch on follicle development and comparing the progestin patch versus CIDR device on estrous synchronization, complication at treated site and pregnancy in beef cattle. In experiment 1, seven beef cows were treated with an adhesive transdermal progestin patch on the ventral surface of the proximal part of the tail for 7 days. The cows were daily examined the follicular development using ultrasonography starting on Day 0 till 3 days after hormone removal. Experiment 2, forty beef cows were divided into two equal groups (20 cows per group). The cows randomly allocated to received either vaginal insertion of CIDR (n = 20) or treated with an adhesive transdermal progestin patch (n = 20). The levels of plasma progesterone during the experiment and the numbers of standing estrous cows were recorded. Timed artificial inseminated (TAI) was performed at 60 h after CIDR or patch termination. Pregnancy rates were determined at 60 days after TAI. Experiment 1 revealed that the novel transdermal progestin patch could efficiently control follicular growth. All the seven treated cows had dominant follicle upon dermal patch removal indicating the effectiveness of the progestin patch. In experiment 2, the percentages of cows exhibited standing estrus were similar between transdermal patch (72.22%) and CIDR (70.00%). The levels of plasma progesterone during CIDR treatment were significantly higher (4.06 ± 1.65 ng/mL on Day 1 and 3.62 ± 1.60 ng/mL on Day 7) compared with transdermal patch (2.60 ± 1.43 ng/mL on Day 1 and 1.81 ± 1.57 ng/mL on Day 7). Three cows treated with CIDR (15%) developed vaginitis while none of cows had physically dermal reaction at adhesive site. Cows synchronized with

Acute treatment with 17beta-estradiol attenuates astrocyte-astrocyte and astrocyte-neuron communication.

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Rao, Shilpa P; Sikdar, Sujit Kumar

2007-12-01

Astrocytes are now recognized as dynamic signaling elements in the brain. Bidirectional communication between neurons and astrocytes involves integration of neuronal inputs by astrocytes and release of gliotransmitters that modulate neuronal excitability and synaptic transmission. The ovarian steroid hormone, 17beta-estradiol, in addition to its rapid actions on neuronal electrical activity can rapidly alter astrocyte intracellular calcium concentration ([Ca2+]i) through a membrane-associated estrogen receptor. Using calcium imaging and electrophysiological techniques, we investigated the functional consequences of acute treatment with estradiol on astrocyte-astrocyte and astrocyte-neuron communication in mixed hippocampal cultures. Mechanical stimulation of an astrocyte evoked a [Ca2+]i rise in the stimulated astrocyte, which propagated to the surrounding astrocytes as a [Ca2+]i wave. Following acute treatment with estradiol, the amplitude of the [Ca2+]i elevation in astrocytes around the stimulated astrocyte was attenuated. Further, estradiol inhibited the [Ca2+]i rise in individual astrocytes in response to the metabotropic glutamate receptor agonist, trans-(+/-)-1-amino-1,3-cyclopentanedicarboxylic acid. Mechanical stimulation of astrocytes induced [Ca2+]i elevations and electrophysiological responses in adjacent neurons. Estradiol rapidly attenuated the astrocyte-evoked glutamate-mediated [Ca2+]i rise and slow inward current in neurons. Also, the incidence of astrocyte-induced increase in spontaneous postsynaptic current frequency was reduced in the presence of estradiol. The effects of estradiol were stereo-specific and reversible following washout. These findings may indicate that the regulation of neuronal excitability and synaptic transmission by astrocytes is sensitive to rapid estradiol-mediated hormonal control. (c) 2007 Wiley-Liss, Inc.

Modulation of SHBG binding to testosterone and estradiol by sex and morbid obesity.

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Grasa, María Del Mar; Gulfo, José; Camps, Núria; Alcalá, Rosa; Monserrat, Laura; Moreno-Navarrete, José María; Ortega, Francisco José; Esteve, Montserrat; Remesar, Xavier; Fernández-López, José Antonio; Fernández-Real, José Manuel; Alemany, Marià

2017-04-01

Sex hormone-binding globulin (SHBG) binds and transports testosterone and estradiol in plasma. The possibility that SHBG is a mixture of transporting proteins has been postulated. We analyzed in parallel the effects of obesity status on the levels and binding capacity of circulating SHBG and their relationship with testosterone and estradiol. Anthropometric measures and plasma were obtained from apparently healthy young (i.e. 35 ± 7 years) premenopausal women ( n =  32) and men ( n =  30), with normal weight and obesity (BMI >30 kg/m 2 ). SHBG protein (Western blot), as well as the plasma levels of testosterone, estradiol, cortisol and insulin (ELISA) were measured. Specific binding of estradiol and testosterone to plasma SHBG was analyzed using tritium-labeled hormones. Significant differences in SHBG were observed within the obesity status and gender, with discordant patterns of change in testosterone and estradiol. In men, testosterone occupied most of the binding sites. Estrogen binding was much lower in all subjects. Lower SHBG of morbidly obese (BMI >40 kg/m 2 ) subjects affected testosterone but not estradiol. The ratio of binding sites to SHBG protein levels was constant for testosterone, but not for estradiol. The influence of gender was maximal in morbid obesity, with men showing the highest binding / SHBG ratios. The results reported here are compatible with SHBG being a mixture of at least two functionally different hormone-binding globulins, being affected by obesity and gender and showing different structure, affinities for testosterone and estradiol and also different immunoreactivity. © 2017 European Society of Endocrinology.

Transdermal delivery of angiotensin II receptor blockers (ARBs), angiotensin-converting enzyme inhibitors (ACEIs) and others for management of hypertension.

Science.gov (United States)

Ahad, Abdul; Al-Mohizea, Abdullah Mohammed; Al-Jenoobi, Fahad Ibrahim; Aqil, Mohd

2016-01-01

Angiotensin II receptor blockers (ARBs), angiotensin-converting enzyme inhibitors (ACEIs) are some of the most commonly prescribed medications for hypertension. Most of all conventional dosage forms of ARBs and ACEIs undergo extensive first-pass metabolism, which significantly reduces bioavailability. Majority of ARBs and ACEIs are inherently short acting due to a rapid elimination half-life. In addition, oral dosage forms of ARBs and ACEIs have many high incidences of adverse effects due to variable absorption profiles, higher frequency of administration and poor patient compliance. Many attempts have been made globally at the laboratory level to investigate the skin permeation and to develop transdermal therapeutic systems of various ARBs, ACEIs and other anti-hypertensives, to circumvent the drawbacks associated with their conventional dosage form. This manuscript presents an outline of the transdermal research specifically in the area of ARBs, ACEIs and other anti-hypertensives reported in various pharmaceutical journals. The transdermal delivery has gained a significant importance for systemic treatment as it is able to avoid first-pass metabolism and major fluctuations of plasma levels typical of repeated oral administration. As we can experience from this review article that transdermal delivery of different ARBs and ACEIs improves bioavailability as well as patient compliance by many folds. In fact, the rationale development of some newer ARBs, ACEIs and other anti-hypertensives transdermal systems will provide new ways of treatment, circumventing current limitations for conventional dosage forms.

Pharmacodynamics of transdermal granisetron in women with nausea and vomiting of pregnancy.

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Caritis, Steve; Zhao, Yang; Chen, Hui-Jun; Venkataramanan, Raman

2016-07-01

Limited options exist for women with nausea and vomiting of pregnancy (NVP) who cannot tolerate oral intake. Transdermal delivery of granisetron, a 5-hydroxytryptamine-3 receptor antagonist, provides an effective alternative for such patients. The objective of this study was to evaluate the pharmacodynamics of granisetron administered intravenously (IV) and as a sustained release transdermal patch in women with NVP. We recruited 16 women with singleton gestation between 12 0/7-18 6/7 weeks who were receiving treatment for NVP and had a Pregnancy Unique Quantification of Emesis and Nausea (PUQE) score of ≥6. All consenting subjects received 1 mg of granisetron as an IV infusion over 5 minutes and blood was obtained prior to the infusion and at 10, 20, 30, and 60 minutes and at 2, 4, 6, 8, 12, and 24 hours after the start of the infusion. After a minimum washout of 48 hours after initiation of IV granisetron, a 52-cm(2) granisetron patch (34.3 mg) was placed on the upper arm of all subjects for 7 days. Blood was drawn prior to patch placement and daily thereafter for 9 days. The subjects were evaluated daily. The PUQE score was obtained from these subjects prior to the IV infusion and daily for 2 days after and again prior to and daily for 9 days after patch placement. Complete data were available in 15 women after IV administration and 13 women after patch placement. One woman stopped participation during the IV infusion while data were not available in 2 additional women after patch placement due to noncompliance. Peak plasma granisetron concentrations after IV and transdermal administration were similar (∼10 ng/mL). Prior to IV administration of granisetron, the PUQE score was 8.6 ± 1.8 (mean ± SD). The PUQE scores were significantly reduced for the ensuing 2 days (P Granisetron significantly improved symptoms of nausea and vomiting as gauged by the PUQE score. After IV infusion the reduction in PUQE score was observed within 1 day. When granisetron was

Effectiveness of a recombinant human follicle stimulating hormone on the ovarian follicles, peripheral progesterone, estradiol-17β, and pregnancy rate of dairy cows

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Mohamed Ali

2016-07-01

Full Text Available Aims: This study aimed at elucidating the effects of recombinant human follicle stimulating hormone (r-hFSH on the ovarian follicular dynamics, progesterone, estradiol-17β profiles, and pregnancy of dairy cows. Materials and Methods: Three groups (G, n=5 cows of multiparous dairy cows were used. G1 (C control cows were given controlled internal drug release (CIDR and prostaglandin F2α; G2 (L cows were given low dose (525 IU and G3 (H cows were given high dose (1800 IU of r-hFSH on twice daily basis at the last 3 days before CIDR removal. All cows were ultrasonically scanned for follicular growth and dynamics, and blood samples were collected every other day for two consecutive estrus cycles for the determination of estradiol-17β and progesterone. Results: Estrus was observed in all C and L but not in H cows. Dominant follicle was bigger in L compared to C and H cows. Dominant follicle in C (16.00±2.5 mm and L cows (17.40±2.3 mm disappeared at 72 h after CIDR removal. However, in H cows, no ovulation has occurred during 7 days post-CIDR removal. Progesterone was not different (p>0.10 among groups, whereas estradiol-17β revealed significant (p<0.01 reduction in H (15.96±2.5 pg/ml cows compared to C (112.26±26.1 pg/ml and L (97.49±15.9 pg/ml cows. Pregnancy rate was higher in L cows (60% compared with C cows (20%. However, H cows were not artificially inseminated due to non-ovulation. Only a cow of C group has calved one calf, however, 2 of the L cows gave birth of twins and a cow gave single calf. Conclusion: Administration of a low dose (525 IU of r-hFSH resulted in an optimal size of dominant follicle, normal values of progesterone and estradiol-17β, and 40% twinning rate, howeverusing 1800 IU of r-hFSH, have adverse effects on ovarian follicular dynamics and hormonal profiles with non-pregnancy of dairy cows raised under hot climate.

Role of the Na(+)/K(+)-ATPase beta-subunit in peptide-mediated transdermal drug delivery.

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Wang, Changli; Ruan, Renquan; Zhang, Li; Zhang, Yunjiao; Zhou, Wei; Lin, Jun; Ding, Weiping; Wen, Longping

2015-04-06

In this work, we discovered that the Na(+)/K(+)-ATPase beta-subunit (ATP1B1) on epidermal cells plays a key role in the peptide-mediated transdermal delivery of macromolecular drugs. First, using a yeast two-hybrid assay, we screened candidate proteins that have specific affinity for the short peptide TD1 (ACSSSPSKHCG) identified in our previous work. Then, we verified the specific binding of TD1 to ATP1B1 in yeast and mammalian cells by a pull-down ELISA and an immunoprecipitation assay. Finally, we confirmed that TD1 mainly interacted with the C-terminus of ATP1B1. Our results showed that the interaction between TD1 and ATP1B1 affected not only the expression and localization of ATP1B1, but also the epidermal structure. In addition, this interaction could be antagonized by the exogenous competitor ATP1B1 or be inhibited by ouabain, which results in the decreased delivery of macromolecular drugs across the skin. The discovery of a critical role of ATP1B1 in the peptide-mediated transdermal drug delivery is of great significance for the future development of new transdermal peptide enhancers.

Transdermal delivery of naltrexol and skin permeability lifetime after microneedle treatment in hairless guinea pigs.

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Banks, Stan L; Pinninti, Raghotham R; Gill, Harvinder S; Paudel, Kalpana S; Crooks, Peter A; Brogden, Nicole K; Prausnitz, Mark R; Stinchcomb, Audra L

2010-07-01

Controlled-release delivery of 6-beta-naltrexol (NTXOL), the major active metabolite of naltrexone, via a transdermal patch is desirable for treatment of alcoholism. Unfortunately, NTXOL does not diffuse across skin at a therapeutic rate. Therefore, the focus of this study was to evaluate microneedle (MN) skin permeation enhancement of NTXOL's hydrochloride salt in hairless guinea pigs. Specifically, these studies were designed to determine the lifetime of MN-created aqueous pore pathways. MN pore lifetime was estimated by pharmacokinetic evaluation, transepidermal water loss (TEWL) and visualization of MN-treated skin pore diameters using light microscopy. A 3.6-fold enhancement in steady-state plasma concentration was observed in vivo with MN treated skin with NTXOL.HCl, as compared to NTXOL base. TEWL measurements and microscopic evaluation of stained MN-treated guinea pig skin indicated the presence of pores, suggesting a feasible nonlipid bilayer pathway for enhanced transdermal delivery. Overall, MN-assisted transdermal delivery appears viable for at least 48 h after MN-application. (c) 2010 Wiley-Liss, Inc. and the American Pharmacists Association

L-Type Calcium Channels Modulation by Estradiol.

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Vega-Vela, Nelson E; Osorio, Daniel; Avila-Rodriguez, Marco; Gonzalez, Janneth; García-Segura, Luis Miguel; Echeverria, Valentina; Barreto, George E

2017-09-01

Voltage-gated calcium channels are key regulators of brain function, and their dysfunction has been associated with multiple conditions and neurodegenerative diseases because they couple membrane depolarization to the influx of calcium-and other processes such as gene expression-in excitable cells. L-type calcium channels, one of the three major classes and probably the best characterized of the voltage-gated calcium channels, act as an essential calcium binding proteins with a significant biological relevance. It is well known that estradiol can activate rapidly brain signaling pathways and modulatory/regulatory proteins through non-genomic (or non-transcriptional) mechanisms, which lead to an increase of intracellular calcium that activate multiple kinases and signaling cascades, in the same way as L-type calcium channels responses. In this context, estrogens-L-type calcium channels signaling raises intracellular calcium levels and activates the same signaling cascades in the brain probably through estrogen receptor-independent modulatory mechanisms. In this review, we discuss the available literature on this area, which seems to suggest that estradiol exerts dual effects/modulation on these channels in a concentration-dependent manner (as a potentiator of these channels in pM concentrations and as an inhibitor in nM concentrations). Indeed, estradiol may orchestrate multiple neurotrophic responses, which open a new avenue for the development of novel estrogen-based therapies to alleviate different neuropathologies. We also highlight that it is essential to determine through computational and/or experimental approaches the interaction between estradiol and L-type calcium channels to assist these developments, which is an interesting area of research that deserves a closer look in future biomedical research.

Effects of estradiol and FSH on leptin levels in women with suppressed pituitary

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Geber Selmo

2012-06-01

Full Text Available Abstract Background Female fertility depends on adequate nutrition and energy reserves, suggesting a correlation between the metabolic reserve and reproductive capacity. Leptin regulates body weight and energy homeostasis. The aim of this study was to investigate whether estradiol or FSH alone has a direct effect on the production of leptin. Methods A total of 64 patients submitted to controlled ovarian hyperstimulation with recombinant FSH for assisted reproduction and 20 patients using estradiol valerate for endometrial preparation for oocyte donation treatment were included in the study. All patients used GnRH analogues before starting treatment to achieve pituitary suppression. Blood samples for hormonal measurements were collected before starting and after completing the respective treatments. Data were analyzed statistically by the chi-square test, Student’s t-test and Pearson’s correlation test. Results We observed an elevation of serum leptin levels secondary to the increase in estradiol, in the absence of influence of any other ovarian or pituitary hormone. The rising rate of leptin levels was higher in women treated with recombinant FSH, which also had higher levels of estradiol, than in those treated with estradiol valerate. Conclusions This study demonstrates a correlation between serum levels of estradiol and leptin, suggesting that estradiol is an important regulator of leptin production and that its effects can be amplified by its association with FSH.

Evaluation of Potential Drug-Drug Interaction Between Delayed-Release Dimethyl Fumarate and a Commonly Used Oral Contraceptive (Norgestimate/Ethinyl Estradiol) in Healthy Women.

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Zhu, Bing; Nestorov, Ivan; Zhao, Guolin; Meka, Venkata; Leahy, Mark; Kam, Jeanelle; Sheikh, Sarah I

2017-11-01

Delayed-release dimethyl fumarate (DMF) is an oral therapy for relapsing multiple sclerosis with anti-inflammatory and neuroprotective properties. This 2-period crossover study was conducted to evaluate the potential for drug-drug interaction between DMF (240 mg twice daily) and a combined oral contraceptive (OC; norgestimate 250 μg, ethinyl estradiol 35 μg). Forty-six healthy women were enrolled; 32 completed the study. After the lead-in period (OC alone), 41 eligible participants were randomized 1:1 to sequence 1 (OC and DMF coadministration in period 1; OC alone in period 2) or sequence 2 (regimens reversed). Mean concentration profiles of plasma norelgestromin (primary metabolite of norgestimate) and ethinyl estradiol were superimposable following OC alone and OC coadministered with DMF, with 90% confidence intervals of geometric mean ratios for area under the plasma concentration-time curve over the dosing interval and peak plasma concentration contained within the 0.8-1.25 range. Low serum progesterone levels during combined treatment confirmed suppression of ovulation. The pharmacokinetics of DMF (measured via its primary active metabolite, monomethyl fumarate) were consistent with historical data when DMF was administered alone. No new safety concerns were identified. These results suggest that norgestimate/ethinyl estradiol-based OCs may be used with DMF without dose modification. © 2017, The Authors. Clinical Pharmacology in Drug Development Published by Wiley Periodicals, Inc. on behalf of The American College of Clinical Pharmacology.

Oleocanthal Modulates Estradiol-Induced Gene Expression Involving Estrogen Receptor α.

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Keiler, Annekathrin Martina; Djiogue, Sefirin; Ehrhardt, Tino; Zierau, Oliver; Skaltsounis, Leandros; Halabalaki, Maria; Vollmer, Günter

2015-09-01

Oleocanthal is a bioactive compound from olive oil. It has attracted considerable attention as it is anti-inflammatory, antiproliferative, and has been shown to possess neuroprotective properties in vitro and in vivo. Delineated from its polyphenolic structure, the aim of this study was to characterize oleocanthal towards estrogenic properties. This might contribute to partly explain the beneficial effects described for the Mediterranean diet. Estrogenic properties of oleocanthal were assessed by different methods: a) stimulation of reporter gene activity in MVLN or RNDA cells either expressing estrogen receptor α or β, b) stimulation of luciferase reporter gene activity in U2OS osteosarcoma cells expressing estrogen receptor α or β, and c) elucidation of the impact on estradiol-induced gene expression in U2OS cells transduced with both estrogen receptors. Depending on the cell line origin, oleocanthal inhibited luciferase activity (MVLN, U2OS-estrogen receptor β) or weakly induced reporter gene activity at 10 µM in U2OS-estrogen receptor α cells. However, oleocanthal inhibited stimulation of luciferase activity by estradiol from both estrogen receptors. Oleocanthal, if given alone, did not stimulate gene expression in U2OS cells, but it significantly modulated the response of estradiol. Oleocanthal enhanced the effect of estradiol on the regulation of those genes, which are believed to be regulated through heterodimeric estrogen receptors. As the estrogenic response pattern of oleocanthal is rather unique, we compared the results obtained with oleacein. Oleocanthal binds to both estrogen receptors inducing estradiol-agonistic or antiagonistic effects depending on the cell line. Regarding regulation of gene expression in U2OS-estrogen receptor α/β cells, oleocanthal and oleacein enhanced estradiol-mediated regulation of heterodimer-regulated genes. Georg Thieme Verlag KG Stuttgart · New York.

Mechanism of Estradiol-Induced Block of Voltage-Gated K+ Currents in Rat Medial Preoptic Neurons

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Druzin, Michael; Malinina, Evgenya; Grimsholm, Ola; Johansson, Staffan

2011-01-01

The present study was conducted to characterize possible rapid effects of 17-β-estradiol on voltage-gated K+ channels in preoptic neurons and, in particular, to identify the mechanisms by which 17-β-estradiol affects the K+ channels. Whole-cell currents from dissociated rat preoptic neurons were studied by perforated-patch recording. 17-β-estradiol rapidly (within seconds) and reversibly reduced the K+ currents, showing an EC50 value of 9.7 µM. The effect was slightly voltage dependent, but independent of external Ca2+, and not sensitive to an estrogen-receptor blocker. Although 17-α-estradiol also significantly reduced the K+ currents, membrane-impermeant forms of estradiol did not reduce the K+ currents and other estrogens, testosterone and cholesterol were considerably less effective. The reduction induced by estradiol was overlapping with that of the KV-2-channel blocker r-stromatoxin-1. The time course of K+ current in 17-β-estradiol, with a time-dependent inhibition and a slight dependence on external K+, suggested an open-channel block mechanism. The properties of block were predicted from a computational model where 17-β-estradiol binds to open K+ channels. It was concluded that 17-β-estradiol rapidly reduces voltage-gated K+ currents in a way consistent with an open-channel block mechanism. This suggests a new mechanism for steroid action on ion channels. PMID:21625454

Transdermal influenza immunization with vaccine-coated microneedle arrays.

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Dimitrios G Koutsonanos

Full Text Available Influenza is a contagious disease caused by a pathogenic virus, with outbreaks all over the world and thousands of hospitalizations and deaths every year. Due to virus antigenic drift and short-lived immune responses, annual vaccination is required. However, vaccine coverage is incomplete, and improvement in immunization is needed. The objective of this study is to investigate a novel method for transdermal delivery using metal microneedle arrays (MN coated with inactivated influenza virus to determine whether this route is a simpler and safer approach than the conventional immunization, capable to induce robust immune responses and confer protection against lethal virus challenge.Inactivated A/Aichi/2/68 (H3N2 influenza virus was coated on metal microneedle arrays and applied to mice as a vaccine in the caudal dorsal skin area. Substantial antibody titers with hemagglutination inhibition activity were detected in sera collected two and four weeks after a single vaccine dose. Challenge studies in mice with 5 x LD(50 of mouse adapted Aichi virus demonstrated complete protection. Microneedle vaccination induced a broad spectrum of immune responses including CD4+ and CD8+ responses in the spleen and draining lymph node, a high frequency of antigen-secreting cells in the lung and induction of virus-specific memory B-cells. In addition, the use of MN showed a dose-sparing effect and a strong Th2 bias when compared to an intramuscular (IM reference immunization.The present results show that delivery of inactivated influenza virus through the skin using metal microneedle arrays induced strong humoral and cellular immune responses capable of conferring protection against virus challenge as efficiently as intramuscular immunization, which is the standard vaccination route. In view of the convenience of delivery and the potential for self-administration, vaccine-coated metal microneedles may provide a novel and highly effective immunization method.

Diclofenac Potassium Transdermal Patches Using Natural Rubber Latex Biomembranes as Carrier

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Natan Roberto de Barros

2015-01-01

Full Text Available The aim of this study was to design a compound transdermal patch containing diclofenac potassium (Dic-K using natural rubber latex (NRL biomembrane. The NRL from Hevea brasiliensis is easily manipulated and low cost and presents high mechanical resistance. It is a biocompatible material which can stimulate natural angiogenesis and is capable of adhering cells on its surface. Recent researches have used the NRL for Transdermal Drug Delivery Systems (TDDSs. Dic-K is used for the treatment of rheumatoid arthritis and osteoarthritis and pain relief for postoperative and posttraumatic cases, as well as inflammation and edema. Results showed that the biomembrane can release Dic-K for up to 216 hours. The kinetics of the Dic-K release could be fitted with double exponential function. X-ray diffraction and Fourier Transform Infrared (FTIR spectroscopy show some interaction by hydrogen bound. The results indicated the potential of the compound patch.

Physical, chemical and biological studies of gelatin/chitosan based transdermal fims with embedded silver nanoparticles

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Sneha Paul

2015-12-01

Full Text Available Objective: To study the physical, chemical and biological properties of composite chitosangelatin transdermal film along with silver nanoparticles as binding agent and determine the compatibility of the prepared amalgamation towards wound management. Methods: Transdermal film preparations were done by solvent casting method containing different concentrations of biological synthesized silver nanoparticles. The films were characterized by using scanning electron microscope for their morphology and the determination of silver metal was done by using inductively coupled plasma atomic emission spectroscopy. Then a quantity of silver nanoparticles was further proceeded by physiochemical parameters (weight, thickness, temperature, solubility, absorption, tensile strength, in vitro drug release and skin permeation and biological parameters studies (anti-microbial, cytotoxicity and reactive oxygen species. Results: The film prepared by utilizing 2 g of gelatin and 0.5 g of chitosan exhibited better results. The physiochemical parameters studies revealed higher concentration of silver nanoparticles would give better results. In vitro drug release studies through dialysis and skin permeation showed the release of drug versus time (h. These films had shown excellent inhibition against Streptococcus and Escherichia coli species. Cytotoxicity study by MTT indicated the mild toxicity existed as the concentration of silver nanoparticles increased. Reactive oxygen species generation studies of transdermal film by using 2'7'-dichlorofluorescein diacetate assay demonstrated that the fluorescent cells were found in the higher concentration, which indicated cell damage (reactive oxygen species generated. Conclusions: Based on these observations, in vitro performances against various characteristics of transdermal film, would be utilized as a distinct dressing material and patches accessible in market.

Effects of 17 beta-estradiol on radiation transformation in vitro; inhibition of effects by protease inhibitors

International Nuclear Information System (INIS)

Kennedy, A.R.; Weichselbaum, R.R.

1981-01-01

We have investigated the effects of 17 beta-estradiol, given both alone and with X-irradiation, on the induction of malignant transformation in vitro. Treatment with 10(-6)M 17 beta-estradiol for 6 weeks, or 10(-5)M 17 beta-estradiol for only 5 days, induced malignant transformation in C3H 10T1/2 cells. Estradiol also acted as a cocarcinogen for X-ray induced transformation; the results indicate an additive effect when the cells were exposed to both agents together. The protease inhibitors antipain and leupeptin suppressed estradiol induced transformation as well as the additive effect observed for estradiol-radiation transformation

Effects of 17β-estradiol on radiation transformation in vitro; inhibition of effects by protease inhibitors

International Nuclear Information System (INIS)

Kennedy, A.R.; Weichselbaum, R.R.

1981-01-01

The effects of 17β-estradiol, given either alone or with X-radiation, on the induction of malignant transformation were investigated in vitro. Treatment with 10 -6 M 17β-estradiol for 6 weeks, or 10 -5 M 17β-estradiol for only 5 days, induced malignant transformation in C3H 10T1/2 cells. Estradiol also acted as a cocarcinogen for X-ray induced transformation; the results indicated an additive effect when the cells were exposed to both agents together. The protease inhibitors antipain and leupeptin suppressed estradiol induced transformation as well as the additive effect observed for estradiol-radiation transformation. (author)

Effects of 17 beta-estradiol on radiation transformation in vitro; inhibition of effects by protease inhibitors

Energy Technology Data Exchange (ETDEWEB)

Kennedy, A.R.; Weichselbaum, R.R.

1981-01-01

We have investigated the effects of 17 beta-estradiol, given both alone and with X-irradiation, on the induction of malignant transformation in vitro. Treatment with 10(-6)M 17 beta-estradiol for 6 weeks, or 10(-5)M 17 beta-estradiol for only 5 days, induced malignant transformation in C3H 10T1/2 cells. Estradiol also acted as a cocarcinogen for X-ray induced transformation; the results indicate an additive effect when the cells were exposed to both agents together. The protease inhibitors antipain and leupeptin suppressed estradiol induced transformation as well as the additive effect observed for estradiol-radiation transformation.

Modulation of vitellogenin synthesis through estrogen receptor beta-1 in goldfish (Carassius auratus) juveniles exposed to 17-β estradiol and nonylphenol

International Nuclear Information System (INIS)

Soverchia, L.; Ruggeri, B.; Palermo, F.; Mosconi, G.; Cardinaletti, G.; Scortichini, G.; Gatti, G.; Polzonetti-Magni, A.M.

2005-01-01

Many synthetic chemicals, termed xenoestrogens, have been shown to interact as agonists with the estrogen receptor (ER) to elicit biological responses similar to those of natural hormones. To date, the regulation of vitellogenesis in oviparous vertebrates has been widely used for evaluation of estrogenic effects. Therefore, Carassius auratus juveniles were chosen as a fish model for studying the effects of estradiol-17β and different concentrations (10 -6 and 10 -7 M) of 4-nonylphenol (4-NP) on the expression of liver ERβ-1 subtype; plasma vitellogenin and sex steroids (androgens and estradiol-17β) were also evaluated together with the bioaccumulation process, through mass-spectrometry. C. auratus is a species widespread in the aquatic environment and, on the toxicological point of view, can be considered a good 'sentinel' species. Juveniles of goldfish were maintained in tanks with only tap water or water with different concentrations (10 -6 and 10 -7 M) of 4-nonylphenol (4-NP), or 10 -7 M of estradiol-17β. After 3 weeks of treatment, animals were anesthetized within 5 min after capture, and blood was immediately collected into heparinized syringes by cardiac puncture and stored at -70 deg. C; the gonads were fixed, then frozen and stored at -70 deg. C; the whole fish, liver, and muscle tissues were harvested and immediately stored at -70 deg. C for molecular biology experiments and bioaccumulation measurements. The estrogenic effects of 4-NP were evidenced by the presence of plasma vitellogenin in juveniles exposed both to estradiol-17β and the two doses of 4-NP; moreover, exposure to 4-NP also increased aromatization of androgens, as suggested by decreasing androgens and increasing estradiol-17β plasma levels. The changes of these parameters were in agreement with the increasing transcriptional rate of ERβ-1 mRNA in the liver, demonstrating that both estradiol-17β and 4-NP modulate the vitellogenin rate through interaction with the ERβ-1 subtype. The

Enhancing the transdermal delivery of rigid nanoparticles using the simultaneous application of ultrasound and sodium lauryl sulfate.

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Lopez, Renata F V; Seto, Jennifer E; Blankschtein, Daniel; Langer, Robert

2011-01-01

The potential of rigid nanoparticles to serve as transdermal drug carriers can be greatly enhanced by improving their skin penetration. Therefore, the simultaneous application of ultrasound and sodium lauryl sulfate (referred to as US/SLS) was evaluated as a skin pre-treatment method for enhancing the passive transdermal delivery of nanoparticles. We utilized inductively coupled plasma mass spectrometry and an improved application of confocal microscopy to compare the delivery of 10- and 20-nm cationic, neutral, and anionic quantum dots (QDs) into US/SLS-treated and untreated pig split-thickness skin. Our findings include: (a) ∼0.01% of the QDs penetrate the dermis of untreated skin (which we quantify for the first time), (b) the QDs fully permeate US/SLS-treated skin, (c) the two cationic QDs studied exhibit different extents of skin penetration and dermal clearance, and (d) the QD skin penetration is heterogeneous. We discuss routes of nanoparticle skin penetration and the application of the methods described herein to address conflicting literature reports on nanoparticle skin penetration. We conclude that US/SLS treatment significantly enhances QD transdermal penetration by 500-1300%. Our findings suggest that an optimum surface charge exists for nanoparticle skin penetration, and motivate the application of nanoparticle carriers to US/SLS-treated skin for enhanced transdermal drug delivery. Copyright © 2010 Elsevier Ltd. All rights reserved.

Enhancement of the bioavailability of an antihypertensive drug by transdermal protransfersomal system: formulation and in vivo study.

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Morsi, Nadia M; Aboelwafa, Ahmed A; Dawoud, Marwa H S

2018-06-01

Timolol Maleate (TiM), a nonselective β-adrenergic blocker, is a potent highly effective agent for management of hypertension. The drug suffers from poor oral bioavailability (50%) due to its first pass effect and a short elimination half-life of 4 h; resulting in its frequent administration. Transdermal formulation may circumvent these problems in the form of protransfersomes. The aim of this study is to develop and optimize transdermal protransfersomal system of Timolol Maleate by film deposition on carrier method where protransfersomes were converted to transfersomes upon skin hydration following transdermal application under occlusive conditions. Two 2 3 full factorial designs were employed to investigate the influence of three formulation variables which were; phosphatidyl choline: surfactant molar ratio, carrier: mixture and the type of SAA each on particle size, drug entrapment efficiency and release rate. The optimized formulation was evaluated regarding permeation through hairless rat skin and compared with oral administration of aqueous solution on male Wistar rats. Optimized protransfersomal system had excellent permeation rate through shaved rat skin (780.69 μg/cm 2 /h) and showed six times increase in relative bioavailability with prolonged plasma profile up to 72 h. A potential protransfresomal transdermal system was successfully developed and factorial design was found to be a smart tool in its optimization.

Paradoxical action of fulvestrant in estradiol-induced regression of tamoxifen-stimulated breast cancer.

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Osipo, Clodia; Gajdos, Csaba; Liu, Hong; Chen, Bin; Jordan, V Craig

2003-11-05

Long-term tamoxifen treatment of breast cancer can result in tamoxifen-stimulated breast cancer, in which estrogen inhibits tumor growth after tamoxifen withdrawal. We investigated the molecular mechanism(s) of estradiol-induced tumor regression by using an in vivo model of tamoxifen-stimulated human breast cancer. Growth of parental estradiol-stimulated MCF-7E2 and long-term tamoxifen-stimulated MCF-7TAMLT xenografts in athymic mice was measured during treatment with vehicle, estradiol, estradiol plus tamoxifen, tamoxifen alone, estradiol plus fulvestrant, or fulvestrant alone. Apoptosis was detected by the terminal deoxynucleotidyltransferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) assay. Protein expression was assessed by western blot analysis. mRNA expression was assessed by real-time reverse transcription-polymerase chain reaction. All statistical tests were two-sided. MCF-7E2 tumor growth was stimulated by estradiol (cross-sectional area at week 13 = 1.06 cm2, 95% confidence interval [CI] = 0.82 to 1.30 cm2; Pestradiol-induced regression to 0.18 cm2 (95% CI = 0.15 to 0.21 cm2; P<.001), and tamoxifen or estradiol plus fulvestrant enhanced tumor growth to 1.00 cm2 (95% CI = 0.88 to 1.22 cm2). Estradiol increased the number of apoptotic cells in tumors by 23% (95% CI = 20% to 26%; P<.001) compared with all other treatments, decreased estrogen receptor alpha(ERalpha) protein expression, increased the expression of Fas mRNA and protein, decreased the expression of HER2/neu mRNA and protein and nuclear factor kappaB (NF-kappaB) protein but did not affect Fas ligand protein expression compared with control. Paradoxically, fulvestrant reversed this effect and stimulated MCF-7TAMLT tumor growth apparently through ERalpha-mediated regulation of Fas, HER2/neu, and NF-kappaB. Physiologic levels of estradiol induced regression of tamoxifen-stimulated breast cancer tumors, apparently by inducing the death receptor Fas and suppressing the antiapoptotic

High estradiol levels improve false memory rates and meta-memory in highly schizotypal women.

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Hodgetts, Sophie; Hausmann, Markus; Weis, Susanne

2015-10-30

Overconfidence in false memories is often found in patients with schizophrenia and healthy participants with high levels of schizotypy, indicating an impairment of meta-cognition within the memory domain. In general, cognitive control is suggested to be modulated by natural fluctuations in oestrogen. However, whether oestrogen exerts beneficial effects on meta-memory has not yet been investigated. The present study sought to provide evidence that high levels of schizotypy are associated with increased false memory rates and overconfidence in false memories, and that these processes may be modulated by natural differences in estradiol levels. Using the Deese-Roediger-McDermott paradigm, it was found that highly schizotypal participants with high estradiol produced significantly fewer false memories than those with low estradiol. No such difference was found within the low schizotypy participants. Highly schizotypal participants with high estradiol were also less confident in their false memories than those with low estradiol; low schizotypy participants with high estradiol were more confident. However, these differences only approached significance. These findings suggest that the beneficial effect of estradiol on memory and meta-memory observed in healthy participants is specific to highly schizotypal individuals and might be related to individual differences in baseline dopaminergic activity. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Membrane–initiated estradiol signaling regulating sexual receptivity

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Paul E Micevych

2011-09-01

Full Text Available Estradiol has profound actions on the structure and function of the nervous system. In addition to nuclear actions that directly modulate gene expression, the idea that estradiol can rapidly activate cell signaling by binding to membrane estrogen receptors (mERs has emerged. Even the regulation of sexual receptivity, an action previously thought to be completely regulated by nuclear ERs, has been shown to have a membrane-initiated estradiol signaling (MIES component. This highlighted the question of the nature of mERs. Several candidates have been proposed, ERα, ERβ, ER-X, GPR30 (G protein coupled estrogen receptor; GPER, and a receptor activated by a diphenylacrylamide compound, STX. Although each of these receptors has been shown to be active in specific assays, we present evidence for and against their participation in sexual receptivity by acting in the lordosis-regulating circuit. The initial MIES that activates the circuit is in the arcuate nucleus of the hypothalamus (ARH. Using both activation of μ-opioid receptors (MOR in the medial preoptic nucleus and lordosis behavior, we document that both ERα and the STX receptor participate in the required MIES. ERα and the STX receptor activation of cell signaling are dependent on the transactivation of type 1 metabotropic glutamate receptors (mGluR1a that augment progesterone synthesis in astrocytes and protein kinase C (PKC in ARH neurons. While estradiol-induced sexual receptivity does not depend on neuroprogesterone, proceptive behaviors do. Moreover, the ERα and the STX receptor activation of medial preoptic MORs and augmentation of lordosis were sensitive to mGluR1a blockade. These observations suggest a common mechanism through which mERs are coupled to intracellular signaling cascades, not just in regulating reproduction, but in actions throughout the neuraxis including the cortex, hippocampus, striatum and DRGs.

Membrane-Initiated Estradiol Signaling Regulating Sexual Receptivity

Science.gov (United States)

Micevych, Paul E.; Dewing, Phoebe

2011-01-01

Estradiol has profound actions on the structure and function of the nervous system. In addition to nuclear actions that directly modulate gene expression, the idea that estradiol can rapidly activate cell signaling by binding to membrane estrogen receptors (mERs) has emerged. Even the regulation of sexual receptivity, an action previously thought to be completely regulated by nuclear ERs, has been shown to have a membrane-initiated estradiol signaling (MIES) component. This highlighted the question of the nature of mERs. Several candidates have been proposed, ERα, ERβ, ER-X, GPR30 (G protein coupled estrogen receptor), and a receptor activated by a diphenylacrylamide compound, STX. Although each of these receptors has been shown to be active in specific assays, we present evidence for and against their participation in sexual receptivity by acting in the lordosis-regulating circuit. The initial MIES that activates the circuit is in the arcuate nucleus of the hypothalamus (ARH). Using both activation of μ-opioid receptors (MOR) in the medial preoptic nucleus and lordosis behavior, we document that both ERα and the STX-receptor participate in the required MIES. ERα and the STX-receptor activation of cell signaling are dependent on the transactivation of type 1 metabotropic glutamate receptors (mGluR1a) that augment progesterone synthesis in astrocytes and protein kinase C (PKC) in ARH neurons. While estradiol-induced sexual receptivity does not depend on neuroprogesterone, proceptive behaviors do. Moreover, the ERα and the STX-receptor activation of medial preoptic MORs and augmentation of lordosis were sensitive to mGluR1a blockade. These observations suggest a common mechanism through which mERs are coupled to intracellular signaling cascades, not just in regulating reproduction, but in actions throughout the neuraxis including the cortex, hippocampus, striatum, and dorsal root ganglias. PMID:22649369

The Effect and Mechanism of Transdermal Penetration Enhancement of Fu's Cupping Therapy: New Physical Penetration Technology for Transdermal Administration with Traditional Chinese Medicine (TCM) Characteristics.

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Xie, Wei-Jie; Zhang, Yong-Ping; Xu, Jian; Sun, Xiao-Bo; Yang, Fang-Fang

2017-03-27

In this paper, a new type of physical penetration technology for transdermal administration with traditional Chinese medicine (TCM) characteristics is presented. Fu's cupping therapy (FCT), was established and studied using in vitro and in vivo experiments and the penetration effect and mechanism of FCT physical penetration technology was preliminarily discussed. With 1-(4-chlorobenzoyl)-5-methoxy-2-methylindole-3-ylacetic acid (indomethacin, IM) as a model drug, the establishment of high, medium, and low references was completed for the chemical permeation system via in vitro transdermal tests. Furthermore, using chemical penetration enhancers (CPEs) and iontophoresis as references, the percutaneous penetration effect of FCT for IM patches was evaluated using seven species of in vitro diffusion kinetics models and in vitro drug distribution; the IM quantitative analysis method in vivo was established using ultra-performance liquid chromatography-tandem mass spectrometry technology (UPLC-MS/MS), and pharmacokinetic parameters: area under the zero and first moment curves from 0 to last time t (AUC 0-t , AUMC 0-t ), area under the zero and first moment curves from 0 to infinity (AUC 0-∞ , AUMC 0-∞ ), maximum plasma concentration (C max ) and mean residence time (MRT), were used as indicators to evaluate the percutaneous penetration effect of FCT in vivo. Additionally, we used the 3 K factorial design to study the joint synergistic penetration effect on FCT and chemical penetration enhancers. Through scanning electron microscopy (SEM) and transmission electron microscope (TEM) imaging, micro- and ultrastructural changes on the surface of the stratum corneum (SC) were observed to explore the FCT penetration mechanism. In vitro and in vivo skin permeation experiments revealed that both the total cumulative percutaneous amount and in vivo percutaneous absorption amount of IM using FCT were greater than the amount using CPEs and iontophoresis. Firstly, compared with

Applicability and safety of dual-frequency ultrasonic treatment for the transdermal delivery of drugs

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Schoellhammer, Carl M.; Srinivasan, Sharanya; Barman, Ross; Mo, Stacy H.; Polat, Baris E.; Langer, Robert; Blankschtein, Daniel

2016-01-01

Low-frequency ultrasound presents an attractive method for transdermal drug delivery. The controlled, yet nonspecific nature of enhancement broadens the range of therapeutics that can be delivered, while minimizing necessary reformulation efforts for differing compounds. Long and inconsistent treatment times, however, have partially limited the attractiveness of this method. Building on recent advances made in this area, the simultaneous use of low- and high-frequency ultrasound is explored in a physiologically relevant experimental setup to enable the translation of this treatment to testing in vivo. Dual-frequency ultrasound, utilizing 20 kHz and 1 MHz wavelengths simultaneously, was found to significantly enhance the size of localized transport regions (LTRs) in both in vitro and in vivo models while decreasing the necessary treatment time compared to 20 kHz alone. Additionally, LTRs generated by treatment with 20 kHz + 1 MHz were found to be more permeable than those generated with 20 kHz alone. This was further corroborated with pore-size estimates utilizing hindered-transport theory, in which the pores in skin treated with 20 kHz + 1 MHz were calculated to be significantly larger than the pores in skin treated with 20 kHz alone. This demonstrates for the first time that LTRs generated with 20 kHz + 1 MHz are also more permeable than those generated with 20 kHz alone, which could broaden the range of therapeutics and doses administered transdermally. With regard to safety, treatment with 20 kHz + 1 MHz both in vitro and in vivo appeared to result in no greater skin disruption than that observed in skin treated with 20 kHz alone, an FDA-approved modality. This study demonstrates that dual-frequency ultrasound is more efficient and effective than single-frequency ultrasound and is well-tolerated in vivo. PMID:25662228

The daidzein- and estradiol- induced anorectic action in CCK or leptin receptor deficiency rats.

Science.gov (United States)

Fujitani, Mina; Mizushige, Takafumi; Bhattarai, Keshab; Iwahara, Asami; Aida, Ryojiro; Kishida, Taro

2015-01-01

We investigated the effect of daidzein feeding and estradiol treatment on food intake in cholecystokinin-1 receptor (CCK1R) deficiency, leptin receptor (ObRb) deficiency rats and their wild-type rats. These rats underwent an ovariectomy or a sham operation. For the 5 week experiment, each rat was divided in three groups: control, daidzein (150 mg/kg diet), and estradiol (4.2 μg/rat/day) groups. In both CCK1R+ and CCK1R- rats, daidzein feeding and estradiol treatment significantly decreased food intake. Daidzein feeding significantly reduced food intake in ovariectomized ObRb- rats, although not in ObRb+ rats. Estradiol treatment significantly lowered food intake in ovariectomized ObRb+ and ObRb- rats. In the ovariectomized rats, estradiol treatment significantly increases uterine weight, while daidzein feeding did not change it, suggesting that daidzein might have no or weak estrogenic effect in our experiment. These results suggest that CCK1R and ObRb signalings were not essential for the daidzein- and estradiol-induced anorectic action.

A self-adherent, bullet-shaped microneedle patch for controlled transdermal delivery of insulin.

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Seong, Keum-Yong; Seo, Min-Soo; Hwang, Dae Youn; O'Cearbhaill, Eoin D; Sreenan, Seamus; Karp, Jeffrey M; Yang, Seung Yun

2017-11-10

Proteins are important biologic therapeutics used for the treatment of various diseases. However, owing to low bioavailability and poor skin permeability, transdermal delivery of protein therapeutics poses a significant challenge. Here, we present a new approach for transdermal protein delivery using bullet-shaped double-layered microneedle (MN) arrays with water-swellable tips. This design enabled the MNs to mechanically interlock with soft tissues by selective distal swelling after skin insertion. Additionally, prolonged release of loaded proteins by passive diffusion through the swollen tips was obtained. The bullet-shaped MNs provided an optimal geometry for mechanical interlocking, thereby achieving significant adhesion strength (~1.6Ncm -2 ) with rat skin. By harnessing the MN's reversible swelling/deswelling property, insulin, a model protein drug, was loaded in the swellable tips using a mild drop/dry procedure. The insulin-loaded MN patch released 60% of insulin when immersed in saline over the course of 12h and approximately 70% of the released insulin appeared to have preserved structural integrity. An in vivo pilot study showed a prolonged release of insulin from swellable MN patches, leading to a gradual decrease in blood glucose levels. This self-adherent transdermal MN platform can be applied to a variety of protein drugs requiring sustained release kinetics. Copyright © 2017 Elsevier B.V. All rights reserved.

Effect of estrogen-progestin hormonal replacement therapy on blood coagulation and fibrinolysis in postmenopausal women Efeitos da terapia de reposição hormonal estroprogestativa sobre o sistema de coagulação e de fibrinólise em mulheres na pós-menopausa

Directory of Open Access Journals (Sweden)

Claudio E Bonduki

2007-01-01

Full Text Available OBJECTIVE: To evaluate antithrombin III (AT, thrombin (Fragment 1+2 [F1+2] and thrombin-antithrombin [TAT] generation markers, as well as other coagulation parameters, such as prothrombin time, partial activated thromboplastin time, thrombin time, fibrinogen, euglobulin lysis time, and platelet count, in postmenopausal women after hormonal therapy. STUDY DESIGN: Forty-five patients who received either 0.625 mg/day unopposed oral conjugated equine estrogen (CEE, 0.625 mg/day oral CEE plus medroxyprogesterone acetate (MP, or 50 µg/day transdermal 17beta-estradiol plus MP, were included. Tests were performed before (T0 and after 3 (T3, 6 (T6 and 12 (T12 months of treatment. AT was determined by an amidolytic method, whereas F1+2 and TAT complex were measured by ELISA. RESULTS: There was a significant reduction in the AT level of patients who received oral CEE plus MP at T3. There was no AT reduction in patients taking either oral CEE alone or transdermal 17beta-estradiol plus MP. F1+2 increased in all patients, but it reached statistical significance only in patients receiving transdermal 17beta-estradiol MP at T3. CONCLUSIONS: The CEE associated with MP treatment may reduce AT levels, whereas unopposed CEE or transdermal 17beta-estradiol plus MP does not change AT. These changes might not be clinically relevant in the general population; however, hormonal replacement therapy may increase the risk of thrombosis in women with congenital or acquired thrombophilia.OBJETIVO: Avaliar os marcadores antitrombina III (AT, fragmento 1 + 2 da trombina (F1+2 e complexo trombina-antitrombina (TAT, bem como outros parâmetros da coagulação, como tempo de pró-trombina, tempo parcial de tromboplastina ativado, tempo de trombina, fibrinogênio e tempo de lise da euglobulina em mulheres na pós-menopausa após terapia hormonal. DESENHO DO ESTUDO: Foram incluídas 45 voluntárias que receberam estrogênios conjugados eqüinos (ECE 0,625 mg/dia, isoladamente ou

Estradiol inhibits hepatic stellate cell area and collagen synthesis in the chicken liver.

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Nishimura, Shotaro; Teshima, Akifumi; Kawabata, Fuminori; Tabata, Shoji

2017-11-01

Hepatic stellate cells (HSCs) are the main collagen-producing cells in the liver. The HSC area and amount of collagen fibers are different between male and female chickens. This study was performed to confirm the effect of estradiol on collagen synthesis in the growing chicken liver. Blood estradiol levels in chicks were compared at 4 and 8 weeks of age, and the collagen fibril network in liver tissue was observed at 8 weeks by scanning electron microscopy. Intraperitoneal administrations of estradiol and tamoxifen to male and female chicks, respectively, were performed daily from 5 to 8 weeks of age. The areas of HSCs and collagen contents were measured in the liver tissue. The blood estradiol level was higher in females than in males, and the collagen fibril network was denser in males than in females at 8 weeks of age. Estradiol administration in males induced decreases in the HSC area and collagen content of the liver. Conversely, tamoxifen administration in females induced an increase in the HSC area but did not facilitate collagen synthesis. Based on these results, estradiol inhibits the area and collagen synthesis of HSCs in the growing chicken liver under normal physiological conditions. © 2017 Japanese Society of Animal Science.

Faslodex inhibits estradiol-induced extracellular matrix dynamics and lung metastasis in a model of lymphangioleiomyomatosis.

Science.gov (United States)

Li, Chenggang; Zhou, Xiaobo; Sun, Yang; Zhang, Erik; Mancini, John D; Parkhitko, Andrey; Morrison, Tasha A; Silverman, Edwin K; Henske, Elizabeth P; Yu, Jane J

2013-07-01

Lymphangioleiomyomatosis (LAM) is a destructive lung disease primarily affecting women. Genetic studies indicate that LAM cells carry inactivating tuberous sclerosis complex (TSC)-2 mutations, and metastasize to the lung. We previously discovered that estradiol increases the metastasis of TSC2-deficient cells in mice carrying xenograft tumors. Here, we investigate the molecular basis underlying the estradiol-induced lung metastasis of TSC2-deficient cells, and test the efficacy of Faslodex (an estrogen receptor antagonist) in a preclinical model of LAM. We used a xenograft tumor model in which estradiol induces the lung metastasis of TSC2-deficient cells. We analyzed the impact of Faslodex on tumor size, the extracellular matrix organization, the expression of matrix metalloproteinase (MMP)-2, and lung metastasis. We also examined the effects of estradiol and Faslodex on MMP2 expression and activity in tuberin-deficient cells in vitro. Estradiol resulted in a marked reduction of Type IV collagen deposition in xenograft tumors, associated with 2-fold greater MMP2 concentrations compared with placebo-treated mice. Faslodex normalized the Type IV collagen changes in xenograft tumors, enhanced the survival of the mice, and completely blocked lung metastases. In vitro, estradiol enhanced MMP2 transcripts, protein accumulation, and activity. These estradiol-induced changes in MMP2 were blocked by Faslodex. In TSC2-deficient cells, estradiol increased MMP2 concentrations in vitro and in vivo, and induced extracellular matrix remodeling. Faslodex inhibits the estradiol-induced lung metastasis of TSC2-deficient cells. Targeting estrogen receptors with Faslodex may be of efficacy in the treatment of LAM.

Faslodex Inhibits Estradiol-Induced Extracellular Matrix Dynamics and Lung Metastasis in a Model of Lymphangioleiomyomatosis

Science.gov (United States)

Li, Chenggang; Zhou, Xiaobo; Sun, Yang; Zhang, Erik; Mancini, John D.; Parkhitko, Andrey; Morrison, Tasha A.; Silverman, Edwin K.; Henske, Elizabeth P.

2013-01-01

Lymphangioleiomyomatosis (LAM) is a destructive lung disease primarily affecting women. Genetic studies indicate that LAM cells carry inactivating tuberous sclerosis complex (TSC)–2 mutations, and metastasize to the lung. We previously discovered that estradiol increases the metastasis of TSC2-deficient cells in mice carrying xenograft tumors. Here, we investigate the molecular basis underlying the estradiol-induced lung metastasis of TSC2-deficient cells, and test the efficacy of Faslodex (an estrogen receptor antagonist) in a preclinical model of LAM. We used a xenograft tumor model in which estradiol induces the lung metastasis of TSC2-deficient cells. We analyzed the impact of Faslodex on tumor size, the extracellular matrix organization, the expression of matrix metalloproteinase (MMP)–2, and lung metastasis. We also examined the effects of estradiol and Faslodex on MMP2 expression and activity in tuberin-deficient cells in vitro. Estradiol resulted in a marked reduction of Type IV collagen deposition in xenograft tumors, associated with 2-fold greater MMP2 concentrations compared with placebo-treated mice. Faslodex normalized the Type IV collagen changes in xenograft tumors, enhanced the survival of the mice, and completely blocked lung metastases. In vitro, estradiol enhanced MMP2 transcripts, protein accumulation, and activity. These estradiol-induced changes in MMP2 were blocked by Faslodex. In TSC2-deficient cells, estradiol increased MMP2 concentrations in vitro and in vivo, and induced extracellular matrix remodeling. Faslodex inhibits the estradiol-induced lung metastasis of TSC2-deficient cells. Targeting estrogen receptors with Faslodex may be of efficacy in the treatment of LAM. PMID:23526212

New insights for identification of doping with recombinant human erythropoietin micro-doses after high hydration

DEFF Research Database (Denmark)

Martin, L.; Ashenden, M; Bejder, Jacob

2016-01-01

To minimize the chances of being caught after doping with recombinant human erythropoietins (rhEPO), athletes have turned to new practices using micro-doses and excess fluid ingestion to accelerate elimination and decrease the probability of detection. Our objective was to test the sensitivity...... subjects. After an injection in the evening, urine and plasma samples were collected the following morning. Half of the subjects then drank a bolus of water and new samples were collected 80 min later. Interestingly, rhEPO was detected in 100% of the samples even after water ingestion. A second similar...

Thermoresponsive Hydrogels and Their Biomedical Applications: Special Insight into Their Applications in Textile Based Transdermal Therapy

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Sudipta Chatterjee

2018-04-01

Full Text Available Various natural and synthetic polymers are capable of showing thermoresponsive properties and their hydrogels are finding a wide range of biomedical applications including drug delivery, tissue engineering and wound healing. Thermoresponsive hydrogels use temperature as external stimulus to show sol-gel transition and most of the thermoresponsive polymers can form hydrogels around body temperature. The availability of natural thermoresponsive polymers and multiple preparation methods of synthetic polymers, simple preparation method and high functionality of thermoresponsive hydrogels offer many advantages for developing drug delivery systems based on thermoresponsive hydrogels. In textile field applications of thermoresponsive hydrogels, textile based transdermal therapy is currently being applied using drug loaded thermoresponsive hydrogels. The current review focuses on the preparation, physico-chemical properties and various biomedical applications of thermoresponsive hydrogels based on natural and synthetic polymers and especially, their applications in developing functionalized textiles for transdermal therapies. Finally, future prospects of dual responsive (pH/temperature hydrogels made by these polymers for textile based transdermal treatments are mentioned in this review.

Formulation, characterization and clinical evaluation of propranolol hydrochloride gel for transdermal treatment of superficial infantile hemangioma.

Science.gov (United States)

Zhou, Wenhu; He, Shiying; Yang, Yijun; Jian, Dan; Chen, Xiang; Ding, Jinsong

2015-01-01

The objective of the present study is to formulate and characterize propranolol hydrochloride (PPL · HCl) gel, and to evaluate the efficacy of this formulation in transdermal treatment for superficial infantile hemangioma (IH). The transdermal PPL · HCl gel was prepared by a direct swelling method, which chose hydroxypropyl methylcellulose (HPMC) as the matrix and used terpenes plus alcohols as permeation enhancer. Permeation studies of PPL · HCl were carried out with modified Franz diffusion cells through piglet skin. Our results pointed to that among all studied permeation enhancers, farnesol plus isopropanol was the most effective combination (Q24, 6027.4 ± 563.1 μg/cm(2), ER, 6.8), which was significantly higher than that of control gel (p homemade PPL · HCl oral solution as a control. Clinical studies also confirmed the excellent therapeutic response and few side effects of the PPL · HCl gel. These results suggest that transdermal application of the PPL · HCl gel is an effective and safe formulation in treating superficial IH.

Assessment of dedicated low-dose cardiac micro-CT reconstruction algorithms using the left ventricular volume of small rodents as a performance measure

Energy Technology Data Exchange (ETDEWEB)

Maier, Joscha, E-mail: joscha.maier@dkfz.de [Medical Physics in Radiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg (Germany); Sawall, Stefan; Kachelrieß, Marc [Medical Physics in Radiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany and Institute of Medical Physics, University of Erlangen–Nürnberg, 91052 Erlangen (Germany)

2014-05-15

Purpose: Phase-correlated microcomputed tomography (micro-CT) imaging plays an important role in the assessment of mouse models of cardiovascular diseases and the determination of functional parameters as the left ventricular volume. As the current gold standard, the phase-correlated Feldkamp reconstruction (PCF), shows poor performance in case of low dose scans, more sophisticated reconstruction algorithms have been proposed to enable low-dose imaging. In this study, the authors focus on the McKinnon-Bates (MKB) algorithm, the low dose phase-correlated (LDPC) reconstruction, and the high-dimensional total variation minimization reconstruction (HDTV) and investigate their potential to accurately determine the left ventricular volume at different dose levels from 50 to 500 mGy. The results were verified in phantom studies of a five-dimensional (5D) mathematical mouse phantom. Methods: Micro-CT data of eight mice, each administered with an x-ray dose of 500 mGy, were acquired, retrospectively gated for cardiac and respiratory motion and reconstructed using PCF, MKB, LDPC, and HDTV. Dose levels down to 50 mGy were simulated by using only a fraction of the projections. Contrast-to-noise ratio (CNR) was evaluated as a measure of image quality. Left ventricular volume was determined using different segmentation algorithms (Otsu, level sets, region growing). Forward projections of the 5D mouse phantom were performed to simulate a micro-CT scan. The simulated data were processed the same way as the real mouse data sets. Results: Compared to the conventional PCF reconstruction, the MKB, LDPC, and HDTV algorithm yield images of increased quality in terms of CNR. While the MKB reconstruction only provides small improvements, a significant increase of the CNR is observed in LDPC and HDTV reconstructions. The phantom studies demonstrate that left ventricular volumes can be determined accurately at 500 mGy. For lower dose levels which were simulated for real mouse data sets, the

Assessment of dedicated low-dose cardiac micro-CT reconstruction algorithms using the left ventricular volume of small rodents as a performance measure

International Nuclear Information System (INIS)

Maier, Joscha; Sawall, Stefan; Kachelrieß, Marc

2014-01-01

Purpose: Phase-correlated microcomputed tomography (micro-CT) imaging plays an important role in the assessment of mouse models of cardiovascular diseases and the determination of functional parameters as the left ventricular volume. As the current gold standard, the phase-correlated Feldkamp reconstruction (PCF), shows poor performance in case of low dose scans, more sophisticated reconstruction algorithms have been proposed to enable low-dose imaging. In this study, the authors focus on the McKinnon-Bates (MKB) algorithm, the low dose phase-correlated (LDPC) reconstruction, and the high-dimensional total variation minimization reconstruction (HDTV) and investigate their potential to accurately determine the left ventricular volume at different dose levels from 50 to 500 mGy. The results were verified in phantom studies of a five-dimensional (5D) mathematical mouse phantom. Methods: Micro-CT data of eight mice, each administered with an x-ray dose of 500 mGy, were acquired, retrospectively gated for cardiac and respiratory motion and reconstructed using PCF, MKB, LDPC, and HDTV. Dose levels down to 50 mGy were simulated by using only a fraction of the projections. Contrast-to-noise ratio (CNR) was evaluated as a measure of image quality. Left ventricular volume was determined using different segmentation algorithms (Otsu, level sets, region growing). Forward projections of the 5D mouse phantom were performed to simulate a micro-CT scan. The simulated data were processed the same way as the real mouse data sets. Results: Compared to the conventional PCF reconstruction, the MKB, LDPC, and HDTV algorithm yield images of increased quality in terms of CNR. While the MKB reconstruction only provides small improvements, a significant increase of the CNR is observed in LDPC and HDTV reconstructions. The phantom studies demonstrate that left ventricular volumes can be determined accurately at 500 mGy. For lower dose levels which were simulated for real mouse data sets, the

Assessment of dedicated low-dose cardiac micro-CT reconstruction algorithms using the left ventricular volume of small rodents as a performance measure.

Science.gov (United States)

Maier, Joscha; Sawall, Stefan; Kachelrieß, Marc

2014-05-01

Phase-correlated microcomputed tomography (micro-CT) imaging plays an important role in the assessment of mouse models of cardiovascular diseases and the determination of functional parameters as the left ventricular volume. As the current gold standard, the phase-correlated Feldkamp reconstruction (PCF), shows poor performance in case of low dose scans, more sophisticated reconstruction algorithms have been proposed to enable low-dose imaging. In this study, the authors focus on the McKinnon-Bates (MKB) algorithm, the low dose phase-correlated (LDPC) reconstruction, and the high-dimensional total variation minimization reconstruction (HDTV) and investigate their potential to accurately determine the left ventricular volume at different dose levels from 50 to 500 mGy. The results were verified in phantom studies of a five-dimensional (5D) mathematical mouse phantom. Micro-CT data of eight mice, each administered with an x-ray dose of 500 mGy, were acquired, retrospectively gated for cardiac and respiratory motion and reconstructed using PCF, MKB, LDPC, and HDTV. Dose levels down to 50 mGy were simulated by using only a fraction of the projections. Contrast-to-noise ratio (CNR) was evaluated as a measure of image quality. Left ventricular volume was determined using different segmentation algorithms (Otsu, level sets, region growing). Forward projections of the 5D mouse phantom were performed to simulate a micro-CT scan. The simulated data were processed the same way as the real mouse data sets. Compared to the conventional PCF reconstruction, the MKB, LDPC, and HDTV algorithm yield images of increased quality in terms of CNR. While the MKB reconstruction only provides small improvements, a significant increase of the CNR is observed in LDPC and HDTV reconstructions. The phantom studies demonstrate that left ventricular volumes can be determined accurately at 500 mGy. For lower dose levels which were simulated for real mouse data sets, the HDTV algorithm shows the

Deformable Nanovesicles Synthesized through an Adaptable Microfluidic Platform for Enhanced Localized Transdermal Drug Delivery

Directory of Open Access Journals (Sweden)

Naren Subbiah

2017-01-01

Full Text Available Phospholipid-based deformable nanovesicles (DNVs that have flexibility in shape offer an adaptable and facile method to encapsulate diverse classes of therapeutics and facilitate localized transdermal delivery while minimizing systemic exposure. Here we report the use of a microfluidic reactor for the synthesis of DNVs and show that alteration of input parameters such as flow speeds as well as molar and flow rate ratios increases entrapment efficiency of drugs and allows fine-tuning of DNV size, elasticity, and surface charge. To determine the ability of DNV-encapsulated drug to be delivered transdermally to a local site, we synthesized, characterized, and tested DNVs carrying the fluorescently labeled hydrophilic bisphosphonate drug AF-647 zoledronate (AF647-Zol. AF647-Zol DNVs were lyophilized, resuspended, and applied topically as a paste to the calvarial skin of mice. High-resolution fluorescent imaging and confocal microscopy revealed significant increase of encapsulated payload delivery to the target tissue—cranial bone—by DNVs as compared to nondeformable nanovesicles (NVs or aqueous drug solutions. Interestingly, NV delivery was not superior to aqueous drug solution. Our studies show that microfluidic reactor-synthesized DNVs can be produced in good yield, with high encapsulation efficiency, reproducibility, and stability after storage, and represent a useful vehicle for localized transdermal drug delivery.

Hydrogels containing redispersible spray-dried melatonin-loaded nanocapsules: a formulation for transdermal-controlled delivery

Science.gov (United States)

Hoffmeister, Cristiane RD; Durli, Taís L.; Schaffazick, Scheila R.; Raffin, Renata P.; Bender, Eduardo A.; Beck, Ruy CR; Pohlmann, Adriana R.; Guterres, Sílvia S.

2012-05-01

The aim of the present study was to develop a transdermal system for controlled delivery of melatonin combining three strategies: nanoencapsulation of melatonin, drying of melatonin-loaded nanocapsules, and incorporation of nanocapsules in a hydrophilic gel. Nanocapsules were prepared by interfacial deposition of the polymer and were spray-dried using water-soluble excipients. In vitro drug release profiles were evaluated by the dialysis bag method, and skin permeation studies were carried out using Franz cells with porcine skin as the membrane. The use of 10% ( w/ v) water-soluble excipients (lactose or maltodextrin) as spray-drying adjuvants furnished redispersible powders (redispersibility index approximately 1.0) suitable for incorporation into hydrogels. All formulations showed a better controlled in vitro release of melatonin compared with the melatonin solution. The best controlled release results were achieved with hydrogels prepared with dried nanocapsules (hydrogels > redispersed dried nanocapsules > nanocapsule suspension > melatonin solution). The skin permeation studies demonstrated a significant modulation of the transdermal melatonin permeation for hydrogels prepared with redispersible nanocapsules. In this way, the additive effect of the different approaches used in this study (nanoencapsulation, spray-drying, and preparation of semisolid dosage forms) allows not only the control of melatonin release, but also transdermal permeation.

Antioxidant protection of LDL by physiological concentrations of 17 beta-estradiol. Requirement for estradiol modification.

Science.gov (United States)

Shwaery, G T; Vita, J A; Keaney, J F

1997-03-18

Exposure to estrogens reduces the risk for coronary artery disease and associated clinical events; however, the mechanisms responsible for these observations are not clear. Supraphysiological levels of estrogens act as antioxidants in vitro, limiting oxidation of low-density lipoprotein (LDL), an event implicated in atherogenesis. We investigated the conditions under which physiological concentrations of 17 beta-estradiol (E2) inhibit oxidative modification of LDL. Plasma incubated with E2 (0.1 to 100 nmol/L) for 4 hours yielded LDL that demonstrated a dose-related increase in resistance to oxidation by Cu2+ as measured by conjugated diene formation. This effect was dependent on plasma, because incubation of isolated LDL with E2 at these concentrations in buffered saline produced no effect on Cu(2+)-mediated oxidation. Incubation of plasma with E2 had no effect on LDL alpha-tocopherol content or cholesteryl ester hydroperoxide formation during the 4-hour incubation. Plasma incubation with [3H]E2 was associated with dose-dependent association of 3H with LDL. High-performance liquid chromatographic analysis of LDL derived from plasma incubated with [3H]E2 indicated that the majority of the associated species were not detectable as authentic E2 but as nonpolar forms of E2 that were susceptible to base hydrolysis consistent with fatty acid esterification of E2. Plasma-mediated association of E2 and subsequent antioxidant protection was inhibited by 5,5'-dithiobis(2-nitrobenzoic acid), an inhibitor of plasma acyltransferase activity. Exposure of LDL to physiological levels of E2 in a plasma milieu is associated with enhanced resistance to Cu(2+)-mediated oxidation and incorporation of E2 derivatives into LDL. This antioxidant capacity may be another means by which E2 limits coronary artery disease in women.

Micro-dose hCG as luteal phase support without exogenous progesterone administration

DEFF Research Database (Denmark)

Andersen, C Yding; Fischer, R; Giorgione, V

2016-01-01

RHa trigger to induce ovulation showed that exogenous progesterone administration without hCG supplementation was insufficient to obtain satisfactory pregnancy rates. This has prompted development of alternative strategies for LPS. Augmenting the local endogenous production of progesterone by the multiple......For the last two decades, exogenous progesterone administration has been used as luteal phase support (LPS) in connection with controlled ovarian stimulation combined with use of the human chorionic gonadotropin (hCG) trigger for the final maturation of follicles. The introduction of the Gn...... corpora lutea has been one focus with emphasis on one hand to avoid development of ovarian hyper-stimulation syndrome and, on the other hand, to provide adequate levels of progesterone to sustain implantation. The present study evaluates the use of micro-dose hCG for LPS support and examines the potential...

Amphiphilic poly{[α-maleic anhydride-ω-methoxypoly(ethylene glycol]-co-(ethyl cyanoacrylate} graft copolymer nanoparticles as carriers for transdermal drug delivery

Directory of Open Access Journals (Sweden)

Jinfeng Xing

2009-10-01

Full Text Available Jinfeng Xing, Liandong Deng, Jun Li, Anjie DongDepartment of Polymer Science and Engineering, School of Chemical Engineering and Technology, Tianjin University, Tianjin, People’s Republic of ChinaAbstract: In this study, the transdermal drug delivery properties of D,L-tetrahydropalmatine (THP-loaded amphiphilic poly{[α-maleic anhydride-ω-methoxy-poly(ethylene glycol]-co-(ethyl cyanoacrylate} (PEGECA graft copolymer nanoparticles (PEGECAT NPs were evaluated by skin penetration experiments in vitro. The transdermal permeation experiments in vitro were carried out in Franz diffusion cells using THP-loaded PEGECAT NPs as the donor system. Transmission electron microscopy and Fourier transform infrared spectroscopy were used to characterize the receptor fluid. The results indicate that the THP-loaded PEGECAT NPs are able to penetrate the rat skin. Fluorescent microscopy measurements demonstrate that THP-loaded PEGECAT NPs can penetrate the skin not only via appendage routes but also via epidermal routes. This nanotechnology has potential application in transdermal drug delivery. Keywords: poly{[α-maleic anhydride-ω-methoxy-poly(ethylene glycol]-co-(ethyl cyanoacrylate}, nanoparticles, transdermal drug delivery, D,L-tetrahydropalmatine

Preparation and the in vitro evaluation of nanoemulsion system for the transdermal delivery of granisetron hydrochloride.

Science.gov (United States)

Zheng, Wen-wu; Zhao, Ling; Wei, Yu-meng; Ye, Yun; Xiao, Shun-han

2010-08-01

The objective of this study was to develop and evaluate nanoemulsion system for transdermal delivery of granisetron hydrochloride. Pseudo-ternary phase diagram was constructed to ascertain the concentration range of components of nanoemulsion composed of isopropyl myristate (IPM) as an oil phase, tween 85 as surfactant, ethanol as cosurfactant, water as aqueous phase. The effects of the content of IPM as an oil phase and n-methyl pyrrolidone (NMP) as transdermal enhancer on rat skin permeation of granisetron hydrochloride nanoemulsion were studied in vitro. The results showed that the mean particle size of nanoemulsion ranged from 50.4+/-1.5 to 82.4+/-0.9 nm with homogeneous size distribution. The resulted optimum formulation composed of 2.5% granisetron hydrochloride, 4% IPM, 40% tween 85/ethanol (1 : 1) and 10% NMP showed that the skin permeation rate was the highest (85.39+/-2.90 microg/cm(2)/h) and enhancement of drug permeability was 4.1-fold for transdermal delivery of granisetron hydrochloridein comparison with the control group (20% of tween 85 and 20% of ethanol micelle solution containing 2.5% of granisetron hydrochloride without IPM), and cumulative permeation amount was the highest (891.8+/-2.86 microg/cm(2)) with the shortest lag time (0.11+/-0.02 h) and was stable for at least 12 months. Therefore, the nanoemulsion system developed in this study offers a promising vehicle for the transdermal delivery system of granisetron hydrochloride, which may be as effective as oral or intravenous dosage forms and avoid some difficulties associated with these dosage forms.

Ethinyl Estradiol and Etonogestrel Vaginal Ring

Science.gov (United States)

... or infection of the vagina white or yellow vaginal discharge vaginal bleeding or spotting when it is not time ... Follow your doctor's directions for examining your breasts; report any lumps ... and ethinyl estradiol vaginal ring.Do not let anyone else use your ...