scholarly journals Hormones of Pituitary-Gonadal Axis and Histology of Pituitary Gland Following Oral Treatment of Male Wistar Rats with Glyphosate

2018 ◽  
Vol 1 (2) ◽  
pp. 164-169
Author(s):  
S O Popoola ◽  
C L Sakpa
Keyword(s):  
Pituitary Gland ◽  
Wistar Rats ◽  
Imaging Techniques ◽  
Oral Treatment ◽  
Reproductive Hormones ◽  
High Dose ◽  
Male Adult ◽  
Endocrine Disrupting Chemical ◽  
Endocrine Disrupting ◽  
Group B

There are numerous endocrine disrupting chemicals across the globe among which is the contentious organophosphate called glyphosate. The aim was to analyze the effects of glyphosate on Wistar rat’s pituitary gland and pituitary-gonadal axis. Specific objectives determined male reproductive hormones of Wistar rats exposed to glyphosate; demonstrated possible endocrine disruptive action of glyphosate on Wistar rats and determined effects of glyphosate on histology of pituitary gland. Fifteen male adult Wistar rats of 200g and above used for the study were randomly assigned into three groups A, B and C of 5 rats in each. Group A (control) gavaged with only distilled water. Group B (low dose) and Group C (high dose) were gavaged with 400mg and 2000mg of glyphosate/kg body weight/day respectively. All the rats were treated for 60 days before sacrificing, collection of blood sample and harvesting of tissue for analysis. Collated data were entered into Statistical Package for Social Scientists (version 21) for t-test and test of significance (p<0.05).  Both follicle stimulating hormone and testosterone were significantly decreased in treated rats. The levels of luteinizing hormone, prolactin, oestrogen, progesterone and testosterone/oestrogen ratio statistically increased among treated groups. Adenohypophysis in Group B rats illustrated cellular hyperplasia with mitotic bodies while those of Group C demonstrated fewer cells that are widely separated by connective tissue. This study established glyphosate as an endocrine disrupting chemical. Histological slides of the pituitary gland of treated rats showed some level of abnormality. High-resolute imaging techniques were suggested for better imaging.

scholarly journals The fertility assessment of normal cyclic Wistar rats following the administration of methanolic extract of Portulaca oleracea: an experimental study

2021 ◽  
Vol 26 (1) ◽  
Author(s):  
Izuchukwu Azuka Okafor ◽  
Uchenna Somtochukwu Nnamah ◽  
Jude Nnaka
Keyword(s):  
Estrous Cycle ◽  
Adult Female ◽  
Wistar Rats ◽  
Major Effect ◽  
Reproductive Hormones ◽  
Portulaca Oleracea ◽  
High Dose ◽  
Methanolic Extracts ◽  
Cycle Arrest ◽  
Female Wistar Rats

Abstract Background Purslane is a widely distributed shrub used for the treatment of different ailments. The increasing reproductive complications associated with herbal treatments have led to the need to critically evaluate the safety and/or reproductive potentials of commonly used plant extracts. This study investigated the reproductive effect of methanolic extracts of Portulaca oleracea (MEPO) in adult female Wistar rats. Results Group C showed a significant decrease both in relative ovarian weight (p = 0.000), and relative uterine weight (p = 0.037), when compared with the control. There were no significant (p ˃ 0.05) changes in the levels of follicle-stimulating hormone, luteinizing hormone, progesterone, and estradiol. When compared to the control, groups B and C showed abnormal estrous cycle and cycle arrest especially at the metestrus phase with mild congestion of a few blood vessels in the ovary and uterus. Conclusions MEPO may possess some anti-fertility effect, as it disrupts the estrous cycle of adult female Wistar rats; although it has no major effect on the reproductive hormones, uterus, and ovarian histology of adult female Wistar rats. However, high dose consumption should be taken with precaution.

scholarly journals Effects of Tetracarpidium Conophorum on Iron Overload-Induced Cardiac Toxicity in Wistar Rats

2021 ◽  
Vol 16 ◽  
pp. 33-41
Author(s):  
Silvanus Olu Innih ◽  
Ebehiremen Bridget Iorliam ◽  
Tracy Edoghogho Lawal
Keyword(s):  
Iron Overload ◽  
Wistar Rats ◽  
Cardiac Toxicity ◽  
Heart Weight ◽  
High Dose ◽  
Time Interval ◽  
Iron Level ◽  
Standard Drug ◽  
Significant Change ◽  
Group B

This study was carried out to investigate the effects of Tetracarpidium conophorum on iron overload-induced cardiac toxicity in wistar rats. A total of 30 rats weighing between 170-245g were divided into six groups (A, B, C, D, E and F) of five per group. Group A (control) was administered 1ml of distilled water, group B, C, D, E, and F were induced with iron (II) chloride for thirty days and treated with different doses of the extract except group B for thirty days, group F was treated with standard drugs at the same time interval, using orogastric tube. After last day of administering drugs, the rats were left for an overnight fast and then sacrificed 24 hours later. Blood tissue samples were collected through cardiac puncture and immediately transferred to EDTA sample bottles for iron level and total iron concentration tests. 2ml was transferred into plain sample bottles for oxidative stress test analysis. Free radical scavenging activities, lipid peroxidation, haematological indices, body and heart weight and histological studies analysis were accessed. Results shows that there was significant increase (p<0.05) in body weight and no significant change in organ weight. These show that Tetracarpidium conophorum extract when mildly consumed has healing effect on damages heart induced by iron (II) chloride. It also proves anti-inflammatory activity of walnut. Histological slides showed vascular ulceration, erosion and stenosis of coronary artery in group B treated with only iron (II) chloride while other groups were normal. There was no significant change in anti-oxidant enzymes activities, except glutathione peroxidase that significantly increased in group F treated with high dose of the extract. However, graded doses of Tetracarpidium conophorum and standard drug reversed the lesions induced by iron (II) choride. Tetracarpidium conophorum extract has ameliorating effects on iron (II) chloride-induced heart damage.

scholarly journals Low dose bitter leaf improves sperm quality disrupted in immunosuppressed Wistar rats: An experimental study

2020 ◽  
Author(s):  
Risikat Eniola Kadir ◽  
Abdulmumin Ibrahim ◽  
Balkis Abimbola Ibrahim ◽  
Sadiya Musa Gwadabe ◽  
Rukayat Jaji-Sulaimon ◽  
...  
Keyword(s):  
Wistar Rats ◽  
Low Dose ◽  
Sperm Quality ◽  
Hematological Parameters ◽  
Immunosuppressive Agents ◽  
Sperm Parameters ◽  
Male Adult ◽  
Sperm Counts ◽  
Group A ◽  
Group B

Background: Synthetic prednisolone (PRED) is a widely used over-the-counter glucocorticoid. Glucocorticoids have inhibitory effects on the immune system and are often used as immunosuppressive agents. Suppressed immunity may impact fertility via the hypothalamic-pituitary-adrenal axis. Bitter leaf (BL) has been shown to improve sperm parameters, but its effects on immunosuppression-associated infertility have not yet been documented. Objective: To determine the fertility effects of bitter leaf on immunosuppressed Wistar rats. Materials and Methods: A total of 30 male adult Wistar rats were randomly assigned to 6 groups (n = 5/each). Group A served as a control and were given distilled water in addition to normal feeds, group B received 2 mg/kg PRED for 14 days and served as the standard immunosuppressed group, and groups C-F were immunosuppressed as in B but in addition received 50 mg/kg levamisole, low-dose (250 mg/kg) BL, highdose (375 mg/kg) BL, and low-dose BL + levamisole, respectively. The CD4 counts, hematological parameters, and sperm parameters were analyzed and compared. Results: There were significant decreases in sperm motility, progressive motility, morphology, and life/death ratio in the animals given PRED only compared to the controls (p = 0.002, 0.001, 0.001, and 0.01, respectively). These were significantly increased in the treated groups, and animals given levamisole and 250 mg/kg BL showed significantly increased sperm counts compared to the controls (p = 0.04 and p = 0.04, respectively). Conclusion: Low-dose BL (250 mg/kg) restored the sperm parameters altered by prednisolone administration. Key words: Bitter leaf, Immunosuppression, Infertility, Prednisolone, Rats.

scholarly journals EFEK PEMBERIAN ANABOLIK ANDROGENIK STEROID INJEKSI DOSIS RENDAH DAN TINGGI TERHADAP GAMBARAN HISTOPATOLOGI HATI DAN OTOT RANGKA TIKUS WISTAR (Rattus Novergicus)

2015 ◽  
Vol 3 (1) ◽  
Author(s):  
Pamela K. Sari ◽  
Poppy M. Lintong ◽  
Lily L. Loho
Keyword(s):  
Protein Synthesis ◽  
Wistar Rats ◽  
Low Dose ◽  
Anabolic Steroids ◽  
Inflammatory Cells ◽  
High Dose ◽  
Group A ◽  
Androgenic Anabolic Steroids ◽  
Group B ◽  
Group D

Abstract: Androgenic-anabolic steroids (AAS) are synthetic derivatives of the male hormone endogenous testosterone that stimulates anabolic (protein synthesis) and androgenic effects (masculinization). Long-term usage of AAS can result in liver damage. However, physiological concentrations of testosterone can stimulate protein synthesis which lead to an increase in muscle size, body mass, and endurance. This study aimed to determine the histopathology of liver and skeletal muscles of wistar rats that were given low dose and high dose injection of AAS. Subjects were 21 wistar rats divided into 7 groups. Group A was given standard pellets for 56 days (negative control), terminated on days 29,43, and 57. Group B was treated with low-dose AAS injection and standard pellets for 28 days, terminated on day 29. Group C was treated with low-dose AAS injection and standard pellets for 42 days, terminated on day 43. Group D was treated with low-dose AAS injection and standard pellets for 56 days, terminated on day 57. Group E was treated with high-dose AAS injection and standard pellets for 28 days, terminated on day 29. Group F was treated with high-dose AAS injection and standard pellets for 42 days, terminated on day 43. Group G was treated with high-dose AAS injection and standard pellets for 56 days, terminated on day 57. The results showed that the histopathology of liver and muscles in group A was still normal. In group B, the architecture of liver was still normal with a few inflammatory cells around the Kiernan triangle while in muscle the ratio of myofibril diameter was 1.28:1. In group C and group D, there were widening of the hepatic artery, bile duct, and portal vein containing blood fibrin, and inflammatory cells around the Kiernan triangle. The ratio of myofibril diameter was 1.43:1 in group C and 2.14:1 in group D. In group E, F and G, there were micro-vesicular fatty cells in the peripheral part of the liver meanwhile the myofibril diameter ratio of the muscles in group E was 1.43:1, group F 2.1:1, and group G 2.28:1. Conclusion: Administration of AAS injection of low dose and high dose for less than 4 weeks could result in inflammation, dilation of the portal vein, hepatic artery and bile duct meanwhile administration of AAS for over 4 weeks could ressult in focal fatty liver (steatosis). The administration of AAS injection of low dose and high dose for 4,6 and 8 weeks reslutid in enlargement of skeletal muscle (muscle hypertrophy).Keywords: androgenic-anabolic steroids, liver, skeletal muscleAbstrak: Anabolik Androgenik Steroid (AAS) adalah derivat sintetis dari hormon sex testosteron endogen pria, yang merangsang efek anabolik (sintesis protein) dan androgenik (maskulinisasi). Penggunaan AAS jangka panjang dapat mengakibatkan terjadinya kerusakan hati namun secara fisiologi testosteron dapat menstimulasi sintesis protein sehinggaberdampak pada peningkatan ukuran otot, massa tubuh dan ketahanan tubuh. Penelitian ini bertujuan untuk mengetahui gambaran histopatologi hati dan otot rangka wistar yang diberikan AAS injeksi dosis rendah dan dosis tinggi. Subjek penelitian 21 ekor wistar yang dibagi menjadi 7 kelompok. Kelompok A diberi pelet standar selama 56 hari (kontrol negatif), terminasi pada hari ke-29, 43, dan 57. Kelompok B diberi perlakuan AAS injeksi dosis rendah dan pelet standar selama 28 hari, terminasi hari ke-29. Kelompok C diberi AAS injeksi dosis rendah dan pelet standar selama 42 hari, terminasi hari ke-43. Kelompok D diberi AAS injeksi dosis rendah dan pelet standar selama 56 hari, terminasi hari ke-57. Kelompok E diberi perlakuan AAS injeksi dosis tinggi dan diberi pelet standar selama 28 hari, terminasi hari ke-29. Kelompok F diberi perlakuan AAS injeksi dosis tinggi dan diberi pelet standar selama 42 hari, terminasi hari ke-43. Kelompok G diberi perlakuan AAS injeksi dosis tinggi dan diberi pelet standar selama 56 hari, terminasi hari ke-57. Hasil penelitian menunjukkan pada kelompok A didapatkan gambaran histopatologi hati normal sedangkan pada otot tidak terdapat perubahan. Pada kelompok B didapatkan arsitektur hati masih normal dengan sedikit sel radang disekitar segitiga Kiernan sedangkan pada otot terlihat diameter miofibril ratio 1,28:1. Pada kelompok C dan D terlihat pelebaran arteri hepatika, duktus biliaris, dan vena porta yang berisi fibrin darah, serta sel-sel radang di sekitar segitiga Kiernan. Pada kelompok C diameter miofibril ratio 1,43;1 dan pada kelompok D 2,14:1. Pada kelompok E, F dan G terdapat sel-sel perlemakan mikrovesikuler di perifer sedangkan pada otot diameter miofibril ratio kelompok E 1,43:1, kelompok F 2,1:1, dan kelompok G 2,28:1. Simpulan: Pada pemberian AAS injeksi dosis rendah dan dosis tinggi kurang dari 4 minggu terjadi peradangan hati, pelebaran vena porta, arteri hepatika dan duktus biliaris sedangkan lebih dari 4 minggu terdapat perlemakan (steatosis) fokal hati. Pemberian AAS injeksi dosis rendah dan tinggi dalam waktu 4,6 dan 8 minggu menunjukkan pembesaran otot rangka (hipertrofi otot).Kata kunci: AAS, hati, otot rangka

scholarly journals Effect of Smokeless Tobacco Product, Afzal, on the Reproductive Hormones and Gonadal Pathology of Wistar Rats

2020 ◽  
Vol 25 (1) ◽  
pp. 1
Author(s):  
Nawal Al-Mukhaini ◽  
Taher Ba Omar ◽  
Elsadig Eltayeb ◽  
Aisha Al Khayat Al-Shehi ◽  
Jamila Al-Belushi ◽  
...  
Keyword(s):  
Body Weight ◽  
Smokeless Tobacco ◽  
Wistar Rats ◽  
Reproductive Function ◽  
Tobacco Product ◽  
Reproductive Hormones ◽  
Albino Rats ◽  
High Dose ◽  
Frequent Use ◽  
Smokeless Tobacco Product

Afzal is a common smokeless tobacco product (STP) in Oman, and it is believed to contain toxins that may affect the reproductive hormones and hence reproductive function. This study assessed the effect of  Afzal  on the gonads of Wistar rats.  In order to assess gonad toxicity induced by this STP, an aqueous extract of Afzal was added to drinking water to be administrated orally to Wistar albino rats (n = 72) classified as young (4 weeks old) and adult (20 weeks old) of both genders weighing between 60-80 g and 150-240 g respectively for 8 weeks. The rats were divided into 3 groups; control (received distilled water instead of Afzal extract), low-dose (received 3 mg nicotine/kg body weight/day) and high-dose (received 6 mg nicotine/kg body weight/day). At the termination of the study, the rats were euthanized and their blood samples and ovaries were collected for biochemical and histopathological investigations. Testosterone and estradiol hormones showed a significant decrease (P<0.05( in Afzal-treated groups (low and high doses) compared with the control. Histopathological findings revealed the damaging effects manifested as a reduction in the number of the germ cells with deformed organization and in fatty and fibrous degenerations in testes and ovaries. Afzal was found to have adverse effect on the reproductive hormones and gonadal pathology in Wistar rats of both genders, and hence users of Afzal need to consider the risk associated with its frequent use.

scholarly journals Gambaran histopatologik lambung tikus Wistar (Rattus norvegicus) yang diberikan air perasan jeruk nipis (Citrus aurantifolia)

2016 ◽  
Vol 4 (2) ◽  
Author(s):  
Suhaidir Laomo ◽  
Lily L. Loho ◽  
Carla F. Kairupan
Keyword(s):  
Vitamin C ◽  
Rattus Norvegicus ◽  
Wistar Rats ◽  
Herbal Remedy ◽  
Gastric Gland ◽  
High Dose ◽  
Gastric Glands ◽  
Histopathological Features ◽  
Group A ◽  
Group B

Abstract: Lime squash is often used as a herbal remedy for gastritis, even though it is acidic. It contains citric acid and vitamin C which in certain doses can be irritant to the stomach. Nevertheless, lime squash also contains antioxidants such as limonene, flavonoids, and vitamin C, that play certain roles in improving the protection of the stomach and the ability of cell regeneration, and as anti-inflammatory agents. This study aimed to reveal the histopathological features of the gaster of Wistar rats (Rattus norvegicus) treated with lime squash. This was an experimental laboratory study using 15 adult Wistar rats divided into three groups (five rats in each group). Group A (negative control) was given no treatment; group B and C were treated with lime squash 0.5 and 1.56 ml/day, respectively. Lime squash was given in a single dose for seven consecutive days. Rats were terminated on day eight. The results revealed that the gaster of Wistar rats in group A were similar to that of the normal gaster, while group B and C showed no signs of inflammation and the gastric gland cells appeared enlarged and dense. Conclusion: Histopathological features of the gaster of Wistar rats, treated with either low or high dose (three-fold) lime squash, showed no signs of abnormalities such as inflammation, however, there were enlarged glandular cells which might be related to increased gastric mucosal defence.Keywords: lime, gastric histopathological features, inflammatory cells, gastric glands Abstrak: Air perasan jeruk nipis sering digunakan sebagai obat herbal terhadap gastritis, meskipun bersifat asam. Air perasan jeruk nipis mengandung asam sitrat yang pada dosis tertentu menjadi bahan iritan terhadap lambung. Namun demikian, kandungan antioksidan seperti limonene, flavonoid dan vitamin C berperan dalam meningkatkan proteksi lambung dan kemampuan regenerasi sel, serta sebagai anti inflamasi. Penelitian ini bertujuan untuk mengetahui gambaran histopatologik lambung tikus wistar yang diberikan air perasan jeruk nipis. Jenis penelitian ialah eksperimental menggunakan 15 ekor tikus Wistar yang dibagi dalam tiga kelompok (lima ekor tikus tiap kelompok). Kelompok A (kontrol negatif) tidak diberi perlakuan; kelompok B dan C masing-masing diberi air perasan jeruk nipis 0,5 ml/hari dan 1,56 ml/hari dosis tunggal selama tujuh hari, Semua tikus diterminasi pada hari ke-8. Hasil yang didapatkan pada gambaran histopatologik lambung tikus wistar yaitu: kelompok A sesuai dengan gambaran lambung normal; kelompok B dan C tidak menunjukkan tanda-tanda peradangan namun sel-sel kelenjar lambung tampak membesar dan padat. Simpulan: Gambaran histopatologik lambung tikus wistar yang diberi air perasan jeruk nipis, baik dosis rendah maupun tinggi (tiga kali lipat) tidak menunjukkan tanda-tanda kelainan seperti peradangan, melainkan tampak terjadi pembesaran sel-sel kelenjar lambung yang mungkin berhubungan dengan peningkatan pertahanan mukosa lambung. Kata kunci: jeruk nipis, gambaran histopatologik lambung, sel radang, kelenjar lambung

scholarly journals Morphological and Biochemical Effects of Aqueous Extract of Moringa oleifera Leaf on Cobalt Chloride-Induced Cerebral Damage in Adult Wistar Rats

2021 ◽  
pp. 46-57
Author(s):  
A. J. Ajibade ◽  
A. E. Okeleye ◽  
I. A. Ogunmola
Keyword(s):  
Cerebral Cortex ◽  
Wistar Rats ◽  
Moringa Oleifera ◽  
Cobalt Chloride ◽  
High Dose ◽  
Male Wistar Rats ◽  
Group A ◽  
Group B ◽  
Group D ◽  
The Brain

Cobalt induces hypoxia in the brain which leads to oxygen deprivation resulting in cognitive disturbance and decreased motor control. This study evaluated the effect of Moringa oleifera extract on the cobalt chloride-induced cerebral cortex of adult male wistar rats.  40 male wistar rats weighing (90 ± 120g) were used for the study and they were divided into 5 groups with each group containing 8 rats. Group A served as control which received distilled water, Group B was treated orally with Cobalt chloride at dose 45 mg/kg, Group C received cobalt chloride 45 mg/kg + low dose of Moringa oleifera extract 250 mg/kg for 52 days, Group D treated with cobalt chloride 45 mg/kg + high dose of Moringa oleifera extract 500 mg/kg and Group E treated with 500 mg/kg Moringa oleifera extract only and rats were sacrificed on the 53rd day by cervical dislocation. The brain of each rat was removed and weighed before half was fixed in formol calcium for histological analysis and the second half was used for oxidative stress parameters. The mean body weight of the wistar rats in group C and E increased significantly (P <0.05) while it decreased significantly (P <0.05) in group D. The biochemical analysis shows a significant increase (P<0.05) in the level of MDA in group B and a significant decrease (P<0.05) in group E. additionally, NO level shows a significant increase (P<0.05) in group B compared with control. SDH activity decreased significantly in group C, D, and E. Microscopic examination of the cerebral cortex in group B, C and D showed degenerative changes compared with normal histological features in A and E. The study concluded that cobalt chloride induced cerebral cortical damage while administration of Moringa oleifera extract attenuated the toxic effect of cobalt chloride in wistar rats.

Histomorphometric Alterations in Hepatic Tissue from Malathion-Induced Toxicity: An Experimental Animal Study

2021 ◽  
Vol 10 (1) ◽  
pp. 370-375
Author(s):  
Shazia Parveen Channar ◽  
Nasreen Qazi ◽  
Sajjad Ali Almani ◽  
Sehar Gul Memon ◽  
Mansoor Mukhtar Qazi ◽  
...  
Keyword(s):  
Wistar Rats ◽  
Low Dose ◽  
The Body ◽  
Hepatic Tissue ◽  
Control Group ◽  
High Dose ◽  
Dependent Manner ◽  
Histopathological Changes ◽  
Group A ◽  
Group B

Background: Malathion, a widely used insecticide readily absorbed through skin and seriously affects different tissues and organs of the body. The main objective of this study was to compare the histomorphometric alterations resulting from hazardous effects of different doses of Malathion on hepatic tissue of male albino Wistar rats. Material and Methods: This animal experimental study was conducted at the Department of Anatomy and Postgraduate Research Laboratory at the Isra University, Hyderabad, Sindh Pakistan from February to July 2019. Thirty male albino Wistar rats between 250-300 grams weight were distributed equally into group A (control), group B (low-dose Malathion group; 27mg/kg 1/50 of LD50), and group C (high-dose Malathion group; 50mg/kg). Bodyweight of all rats was taken twice, before and after the experiment. The liver was dissected out, washed and weighed. Histopathological examination was done under the light microscope. Grading was done for severity in histopathological changes in each group. Data was analyzed using one-way ANOVA and Post-hoc Tukey test for comparison with the level of significance set at P-value ≤ .05. Results: Statistically significant (P < .05) decline in body weight was observed in groups B and C in comparison with group A. The relative weight of the liver was increased significantly (P < .05) in the experimental groups, when compared with the control group. Mild-to-moderate histopathological changes were observed in the low-dose Malathion group (Group B) while moderate-to-severe histopathological changes were demonstrated in the high-dose group (Group C). Conclusions: Malathion is a potent toxic pesticide and its exposure can exhibit damage to the hepatic tissues in a dose-dependent manner.

Pharmacokinetics and Safety Assessment of Anti-HIV Dapivirine Vaginal Microbicide Rings with Multiple Dosing

2020 ◽  
Author(s):  
Lungwani Muungo
Keyword(s):  
Ex Vivo ◽  
Oral Treatment ◽  
Plasma Concentrations ◽  
Vaginal Ring ◽  
Vaginal Fluid ◽  
Cervical Tissue ◽  
Double Blind ◽  
Group A ◽  
Group B ◽  
Anti Hiv

Objectives: Self-administered vaginal rings are a promising method for delivery of topical anti-HIV microbicidesand might offer an adherence advantage over daily or coitally-dependent dosage forms such as gels. This trialassessed the safety and pharmacokinetic aspects of the Dapivirine Vaginal Ring-004 when worn as multiple rings oversequential periods of ring use by healthy, sexually-active, HIV-negative women.Methods: This double-blind trial was conducted among 48 women (18-40 years). Participants were randomlyassigned to two groups (A or B) and received (3:1) either the dapivirine or a placebo vaginal ring. Group A used tworings over a 56-day period and Group B used three rings over a 57-day period. Safety evaluations were conductedthroughout the trial. Dapivirine concentrations were measured in plasma, vaginal fluid and cervical tissue samplescollected during and after the 56 days (Group A) or 57 days (Group B) of vaginal ring use.Results: Ring-004 was safe and well tolerated in all participants. The pharmacokinetic profile demonstrated arapid increase in plasma and vaginal fluid concentrations and achieved concentrations in vaginal fluids and cervicaltissue well above the in vitro IC99 in cervical tissue (3.3 ng/mL) that were sustained for a 28 to 35-day ring use period(approximately 3000 times higher in vaginal fluids and 14 -1000 times higher in cervical tissue). Drug levels wereassociated with significant inhibitory activity of genital secretions against HIV ex vivo, a biomarker of pharmacodynamics.Individual plasma dapivirine concentrations did not exceed 553 pg/mL and were well below plasma concentrations atthe maximum tolerated dose for oral treatment (mean Cmax 2286 ng/mL).Conclusions: The consecutive use of several rings over a period of up to 57 days was safe and well tolerated, andPK data indicate that a single Ring-004 is likely to be protective for at least 35 days.

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