Rker-050 Rescued Ruxolitinib (Rux)-Associated Reductions in Red Blood Cell Volume

Abstract Myelofibrosis (MF) is characterized by the dysfunctional Janus kinase/signal transducers and activators of transcription signaling (JAK/STAT) pathways leading to progressive proliferation of granulocytic and megakaryocytic cells in the bone marrow at the expense of other hematopoietic lineages. Clinical signs of MF include cytopenias, splenomegaly and transformation to acute leukemia. Jakafi® (ruxolitinib, or rux), a JAK2 inhibitor, is a therapeutic for MF and functions to impair the activated mutations that cause the expansion of megakaryocytic precursors. However, JAK2 also transduces signals of the erythropoietin receptor, thrombopoietin receptor, and the granulocyte colony-stimulating factor receptor. Therefore, individuals being treated with rux are susceptible to treatment-associated effects on normal hematopoiesis resulting in thrombocytopenia, neutropenia and anemia. The TGF-β superfamily plays a vital role in the regulation of hematopoiesis; specifically, SMAD 2/3 activation results in cell quiescence and inhibits precursors from progressing through later stages of hematopoiesis. KER-050, a modified ActRIIA extracellular domain fused to the Fc of human IgG1, is designed to inhibit ligands including activin A, activin B, GDF8 and GDF11, that activate SMAD 2/3. In a preclinical study, administration of KER-050 in mice led to upregulation of erythropoiesis by mobilizing early- and late-stage erythroid precursors and facilitating their terminal maturation into red blood cells (RBCs). In a Phase 1 clinical study, administration of KER-050 to healthy volunteers led to sustained increases in RBCs and hemoglobin (HGB) along with increases in platelets. Given the observed effect of KER-050 on increasing RBCs, we evaluated whether treatment with a research form of KER-050 (RKER-050) could reverse rux-associated reductions in RBCs. Additionally, preclinical studies have shown that KER-050 potentially functioned as a muscle anabolic by increasing lean mass in rodents. We first established anemia in C57Bl/6 mice by dosing with rux before administering RKER-050. Anemia was confirmed on study day 37; mice receiving 120 mg/kg rux via oral gavage (PO) BID had significantly lower RBC (-7.4%, p=0.0001), HGB (-4.0%, p=0.002) and hematocrit (HCT; -5.7%, p=0.0006) levels compared to the control group. Treatment with RKER-050 was initiated on study day 41 and mice received 7.5 mg/kg RKER-050 or vehicle intraperitoneally (IP) twice weekly for approximately 14 days. Mice receiving rux alone continued their decline in RBCs and, on day 55, continued to have significant reductions in RBC (-6.7%, p<0.0001), HGB (-6.0, p<0.00001) and HCT (-5.6%, p=0.0002) levels compared to the control group. These findings are consistent with the progressive effect of JAK2 inhibition on suppressing erythrocyte development and production. In contrast, treatment with RKER-050 abrogated the observed rux-associated reductions in RBCs, HGB, and HCT in the rux-RKER-050 cohort with significant observed increases (+15.8%, +12.2%, +11.2%, respectively, all p<0.0001) when compared to the rux-vehicle group. The rux-RKER-050 cohort also had significantly increased body mass, measured between study day 41 and study day 55 versus the rux-vehicle group (+9.9%, p= 0.006, and +0.69%, respectively). These data demonstrate that rux treatment reduced RBCs, HGB, and HCT in mice, and that coadministration of RKER-050 reversed rux-associated reductions in RBC parameters. Therefore, treatment with KER-050 has the potential to mitigate the dose limiting effects of rux and enhance duration of therapy in MF patients. RKER-050 also increased body weight in mice receiving rux through its anabolic effect on muscle, a potential benefit in elderly MF patients. These data support the potential benefit of KER-050 as a monotherapy and in combination with rux in patients with MF and anemia. KER-050 will be assessed in a Phase 2 clinical trial (KER050-MF-301), which we expect to commence in 2021. Disclosures Nathan: Keros Therapeutics: Current Employment, Current equity holder in publicly-traded company. Feigenson: Keros Therapeutics: Current Employment, Current equity holder in publicly-traded company. Lamora: Keros Therapeutics: Current Employment. Tseng: Keros Therapeutics: Current Employment, Current equity holder in publicly-traded company. Fisher: Keros Therapeutics: Current Employment, Current equity holder in publicly-traded company. Seehra: Keros Therapeutics: Current Employment, Current equity holder in publicly-traded company. Lachey: Keros Therapeutics: Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees.

Download Full-text

A Phase 1 Study of INCB057643 Monotherapy in Patients with Relapsed or Refractory Myelofibrosis (INCB 57643-103)

Blood ◽

10.1182/blood-2020-134604 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 16-17

Author(s):

Christine Lihou ◽

Gongfu Zhou ◽

Fred Zheng

Keyword(s):

Transcription Factors ◽

Group Performance ◽

Phase 1 ◽

Study Drug ◽

Janus Kinase ◽

Primary Study ◽

Publicly Traded ◽

Bet Inhibitor ◽

Laboratory Values ◽

Consensus Report

Background: Activation of transcription factors that regulate oncogenic processes is frequently observed in cancers such as myelofibrosis (MF). In preclinical studies, tumors associated with dysregulation of transcription factors appear to be responsive to inhibition of bromodomain and extra-terminal motif (BET) protein [Delmore JE, et al. Cell 2011; Shimamura T, et al. Clin Cancer Res 2013]. In addition to exerting a direct effect on tumor cells, BET inhibitors may also modulate tumorigenic inflammation; in a mouse model of MF, BET inhibition in combination with the Janus kinase inhibitor ruxolitinib resulted in decreased inflammation and reduced disease burden [Kleppe M, et al. Cancer Cell 2018]. In the first-in-human study INCB 57643-101, the small-molecule BET inhibitor INCB057643, was safe and generally well tolerated as monotherapy, and demonstrated preliminary efficacy in 2 out of 3 patients with MF when administered alone or in combination with ruxolitinib [Falchook G, et al. Clin Cancer Res 2020]. The INCB 57643-103 trial is designed to further evaluate the safety and tolerability of INCB057643 monotherapy in patients with relapsed or refractory MF. Methods: INCB 57643-103 (NCT04279847) is a phase 1, single-arm, open-label, two-part dose confirmation and expansion study evaluating INCB057643 in patients with measurable histologically or cytologically confirmed (World Health Organization criteria 2016), relapsed or refractory primary MF or secondary MF (post-polycythemia vera, post-essential thrombocythemia). Patients must be ≥18 years of age, have received ≥1 line of prior therapy including ruxolitinib and have no option for therapy known to provide clinical benefit, have a risk category of intermediate-2 or high according to the Dynamic International Prognostic Scoring System, have an Eastern Cooperative Oncology Group performance status 0-2, have a life expectancy of 24 weeks or more, and be willing to provide a pretreatment bone marrow biopsy and/or aspirate at baseline (or an archival sample obtained after most recent therapy). Patients will be excluded if they have received prior treatment with a BET inhibitor; received anticancer treatment within specified intervals before the first administration of study drug or receiving concurrent anticancer therapy; received allogeneic hematopoietic stem cell transplant (6 months or less before enrollment) or have active graft versus host disease or received immunosuppressive therapy after allogeneic transplant 2 weeks or less before study drug treatment; have significant and uncontrolled medical events such as gastrointestinal or cardiovascular; have a history of bleeding disorder or at a high risk of bleeding; or have abnormal hematologic, hepatic, renal, coagulation, or metabolic laboratory values. Approximately 15 patients will be enrolled. Part 1 will evaluate initial safety and tolerability of INCB057643. Up to 6 patients will self-administer oral INCB057643 4 mg once daily (QD) continuously. Doses will be declared tolerable if dose-limiting toxicities (DLT) occur in ≤2 patients and discontinuation due to treatment-related adverse events (TRAEs) occurs in ≤2 patients during the DLT evaluation period. Part 2 will further characterize safety and tolerability as well as evaluate preliminary efficacy. Up to 9 patients will receive INCB057643 at 4 mg QD if the dose is deemed tolerable in Part 1; if not, the starting dose will be 2 mg QD. Treatment may continue as long as benefit is derived and discontinuation criteria are not met. The primary study objective is assessment of safety and tolerability of INCB057643 monotherapy by monitoring the frequency and severity of AEs, performing physical examinations, and collecting vital signs and laboratory values. Secondary objectives include evaluation of anemia response by International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) and European LeukemiaNet (ELN) Consensus Report, red blood cell transfusion dependence, spleen volume, rate of spleen response and duration of spleen response by IWG-MRT and ELN Consensus Report, and impact on quality of life. Patients will be assessed every 3 cycles and will receive follow-up for safety for 30-35 days after last dose of study drug. Disclosures Lihou: Incyte: Current Employment, Current equity holder in publicly-traded company. Zhou:Incyte: Current Employment, Current equity holder in publicly-traded company. Zheng:Incyte: Current Employment, Current equity holder in publicly-traded company.

Download Full-text

Thirteen-Week Oral Toxicity Study of l-Arginine in Rats

International Journal of Toxicology ◽

10.1080/10915810490435622 ◽

2004 ◽

Vol 23 (2) ◽

pp. 101-105 ◽

Cited By ~ 17

Author(s):

Shoji Tsubuku ◽

Kazuhisa Hatayama ◽

Kazunori Mawatari ◽

Miro Smriga ◽

Takeshi Kimura

Keyword(s):

Amino Acid ◽

Group Treatment ◽

Clinical Signs ◽

Female Rats ◽

Male Rats ◽

Control Group ◽

Standard Diet ◽

Male And Female ◽

Cell Counts ◽

Male And Female Rats

The amino acid l-arginine (Arg) has been used extensively in dietary and pharmacological products. This study evaluated toxicological and behavioral effects of Arg produced by Ajinomoto Co. (Tokyo, Japan) during a dosing study with male and female Sprague-Dawley rats. The amino acid was incorporated into a standard diet at doses equal to 1.25%, 2.5%, and 5.0% ( w/w). A control group of rats received only a standard diet. All diets were administered ad libitum for 13 continuous weeks. To examine recoverability of any potential effects, the administration period was followed by a 5-week-long recovery, during which only a standard diet was provided. In male and female rats in each concentration group, treatment-related changes were not observed for clinical signs, body weights, diet consumption, ophthalmology, gross pathology, organ weight, or histopathology. An elevated level of plasma glucose was detected in some male rats (5.0%, w/ w) during the analysis conducted in the fifth week of administration; however, the degree of the change was within the physiological range, and no changes were observed at the end of the administration period. In the same group, an increase in hemoglobin, together with a tendency toward an increase in the red blood cell counts, was found, but the change was considered toxicologically insignificant. The no-observed-adverse-effect level (NOAEL) for Arg was estimated at 5.0% ( w/w) for both genders (males, 3.3 ±0.1 g/kg/day; females, 3.9 ±0.2 g/kg/day).

Download Full-text

Ker-050, an Inhibitor of TGF- β Superfamily Signaling, Promoted Thrombopoiesis and Reversed Immune Thrombocytopenia in a Mouse Model of Disease

Blood ◽

10.1182/blood-2021-152814 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2068-2068

Author(s):

Marina Feigenson ◽

Remya Nathan ◽

Joshua Lamora ◽

Ffolliott Fisher ◽

Claire C Tseng ◽

...

Keyword(s):

Mouse Model ◽

Immune Thrombocytopenia ◽

Phase 1 ◽

Fold Increase ◽

Treated Group ◽

Vehicle Group ◽

Preclinical Model ◽

Publicly Traded ◽

Post Dose ◽

Multiple Stages

Abstract KER-050 is a modified ActRIIA ligand trap that is designed to inhibit the activity of the TGF-β ligands, including activin A, activin B, GDF8 and GDF11, that act through the SMAD2/3 signaling cascade. Notably, in a Phase 1 clinical study we observed that, in addition to increases in red blood cells and hemoglobin, treatment with KER-050 elicited a robust and sustained increase in platelets (PLTs) in healthy volunteers. While ActRII ligand traps have been shown to increase erythropoiesis in preclinical and clinical studies, their role in thrombopoiesis has not yet been well-elucidated. A variety of conditions exist where hematopoiesis is impaired and cytopenia persists, including comorbidities associated with aging, diseases causing ineffective hematopoiesis such as myelodysplastic syndrome (MDS) and myelofibrosis (MF), and acute bleeding. Thrombocytopenia can arise from primary or secondary causes due to multiple etiologies and treatments are limited, aiming at treating the root cause of disease or replacing PLTs through transfusion. Therefore, there is an unmet medical need for more targeted treatments to correct thrombocytopenia. Here, in a series of preclinical studies, we investigated the mechanism of action of KER-050 on thrombopoiesis and evaluated its ability to accelerate recovery from acute platelet depletion. First, we examined how RKER-050 (a research form of KER-050) affected thrombopoiesis under homeostatic conditions. We observed that a single intraperitoneal dose of RKER-050 (10 mg/kg) to 11-week-old mice resulted in a 2-fold increase in PLTs compared to vehicle-treated mice 12 hours after treatment. The timing of the effect is suggestive of a direct effect of RKER-050 on terminal platelet maturation. Additionally, there was a 35% increase in the number of bone marrow (BM) megakaryocyte (Mk) progenitors (Lin -; sca1 -; cKit -; CD41 + cells), demonstrating that RKER-050 affected earlier stages of the PLT formation process. We also evaluated the effect of RKER-050 on the polyploidization of Mks, a hallmark of Mk differentiation. At 24 hours after treatment with RKER-050, there was an increase in BM CD41 + cells with ploidy greater than 16N compared to vehicle-treated mice, demonstrating that RKER-050 treatment resulted in a greater number of Mk that are potentially primed for platelet production. Taken together, these data are consistent with RKER-050 affecting multiple stages of thrombopoiesis in a preclinical model. We next tested whether RKER-050 affects PLTs in a mouse model of immune thrombocytopenia (IT) where antibodies directed against mouse GPIbα result in acutely reduced PLT numbers. In this model, mice receiving anti-GPIbα had a 25% reduction in PLT number at 4 days post-dose compared to IgG control-treated mice. At this point, the anti-GPIba cohort was divided into receiving either a single dose of vehicle or RKER-050. On day 7 following anti-GPIbα treatment, PLT counts in vehicle-treated mice were 62% lower compared to IgG-control-treated mice. In contrast, the GPIbα-mediated effect on PLT count was stabilized in the anti-GPIbα + RKER-050 group, which had 55% more platelets compared to the anti-GPIba + vehicle group. These data suggest that RKER-050 promoted thrombopoiesis in mice even under conditions when the system is acutely challenged and potentially could promote faster recovery from thrombocytopenia. Additionally, we observed a 25% increase in the number of CD41 + cells in the BM of the RKER-050-treated group compared to the vehicle-treated group at day 10 after PLT depletion, suggesting that under acute thrombocytopenia, RKER-050 treatment promoted differentiation of Mks as a mechanism of the accelerated recovery in platelet-depleted mice. In summary, our preclinical data demonstrate a potentially novel effect of RKER-050 on thrombopoiesis. RKER-050 treatment resulted in a rapid increase in PLTs, consistent with an effect on terminal maturation. Treatment also increased the number of Mk progenitors and increased the number of polyploid Mks, demonstrating an effect on early stages of thrombopoiesis. These findings support that RKER-050-targeted ligands regulate multiple stages of the thrombopoiesis pathway in mice. Additionally, our data demonstrate that KER-050 has the potential to accelerate the rate of PLT recovery due to acute depletion, and could represent a potential novel treatment option for thrombocytopenia in patients with MDS, MF and IT. Disclosures Feigenson: Keros Therapeutics: Current Employment, Current equity holder in publicly-traded company. Nathan: Keros Therapeutics: Current Employment, Current equity holder in publicly-traded company. Lamora: Keros Therapeutics: Current Employment. Fisher: Keros Therapeutics: Current Employment, Current equity holder in publicly-traded company. Tseng: Keros Therapeutics: Current Employment, Current equity holder in publicly-traded company. Seehra: Keros Therapeutics: Current Employment, Current equity holder in publicly-traded company. Lachey: Keros Therapeutics: Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees.

Download Full-text

Thirteen-Week Oral Toxicity Study of L-Lysine Hydrochloride in Rats

International Journal of Toxicology ◽

10.1080/10915810490444415 ◽

2004 ◽

Vol 23 (2) ◽

pp. 113-118 ◽

Cited By ~ 18

Author(s):

Shoji Tsubuku ◽

Masahiro Mochizuki ◽

Kazunori Mawatari ◽

Miro Smriga ◽

Takeshi Kimura

Keyword(s):

Amino Acid ◽

Group Treatment ◽

Recovery Period ◽

Clinical Signs ◽

Female Rats ◽

Control Group ◽

Standard Diet ◽

Oral Toxicity ◽

Male And Female ◽

Male And Female Rats

l-Lysine hydrochloride (Lys) is an essential amino acid in humans and animals, and it is used in animal feeds, in prevention of herpes simplex recurrence, and cereal fortification in some developing countries. This study evaluated toxicological and behavioral effects of Lys during a dosing study with male and female Sprague-Dawley rats. The amino acid was incorporated into a standard diet at doses equal to 1.25%, 2.5%, and 5.0% ( w/ w). A control group of rats received a standard diet. All diets were administered ad libitum for 13 consecutive weeks. To examine stability of any potential effects, the administration period was followed by a 5-week recovery period, during which only the standard diet was provided to all animals. In male and female rats in each concentration group, treatment-related changes were not observed in the clinical signs, body weights, diet consumption, water intake, ophthalmology, gross pathology, organ weights, or histology. A Lys-related drop in serum concentration and an increase in urine excretion of chlorides was a compensatory reaction to the ingested hydrochloride. No functional, biochemical, or histological changes in renal function were found. The no-observed-adverse-effect level (NOAEL) for Lys was estimated at 5.0% for both genders (male, 3.36 ± 0.12 g/kg/day; female, 3.99 ± 0.28 g/kg/day).

Download Full-text

Perbandingan Efek Suplementasi Tablet Tambah Darah Dengan Dan Tanpa Vitamin C Terhadap Kadar Hemoglobin Pada Ibu Hamil Dengan Usiakehamilan 16-32 Minggu Di Desa Keniten Kecamatan Mojo Kabupaten Kediri

Jurnal Ilmu Kesehatan ◽

10.32831/jik.v3i1.49 ◽

2017 ◽

Vol 3 (1) ◽

pp. 76

Author(s):

Siti Asiyah ◽

Dwi Estuning Rahayu ◽

Wiranti Dwi Novita Isnaeni

Keyword(s):

Treatment Group ◽

Vitamin C ◽

Gestational Age ◽

Group Treatment ◽

Sampling Technique ◽

Hemoglobin Level ◽

The Body ◽

Control Group ◽

Fetal Organ ◽

And Control

The needed of Iron Tablet in pregnancy was increase than mother who not pregnant. That cause of high metabolism at the pregnancy for formed of fetal organ and energy. One of effort for prevent anemia in mother pregnant with giving the Iron tablet and vitamin c. The reason of this research in 4 June – 11 July 2014 is for compare the effect of iron tablet suplementation with and without vitamin C toward Hemoglobin level in mother pregnant With Gestational Age Of 16-32 Weeks In Desa Keniten Kecamatan Mojo Kabupaten Kediri. This research method using comparative analytical. Research design type of Quasy Eksperiment that have treatment group and control group. Treatment group will giving by Iron tablet and 100 mg vitamin C, and control group just giving by iron tablet during 21 days. Population in this research are all of mother pregnant with Gestational Age Of 16-32 Weeks with Sampling technique is cluster random sampling is 29 mother pregnant. Comparison analysis of iron tablet suplementation effect with and without vitamin C toward Hemoglobin level in mother pregnant With Gestational Age Of 16-32 Weeks, data analysis using Mann Whitney U-test and the calculated U value (44,5) less than U-table (51). So there was difference of iron tablet suplementation effect with and without vitamin C toward Hemoglobin level in mother pregnant With Gestational Age Of 16-32 Weeks Therefore, the addition of vitamin C on iron intake is needed to increase the uptake of iron tablets. When the amount of iron uptake increases, the reserves of iron in the body will also increase, so as to prevent anemia in pregnant women; Keywords : Iron Tablet (Fe), Vitamin C, Hemoglobin level, Mother Pregnant

Download Full-text

Modern approaches to the treatment of mastitis in women of reproductive age

HEALTH OF WOMAN ◽

10.15574/hw.2016.111.101 ◽

2016 ◽

pp. 191-108

Author(s):

A.A. Sukhanova ◽

◽

Yu.M. Melnik ◽

O.O. Karlova ◽

◽

...

Keyword(s):

Ultrasound Examination ◽

Clinical Signs ◽

Reproductive Age ◽

Herbal Remedies ◽

Control Group ◽

Women Of Reproductive Age ◽

Clinical Method ◽

Gynecological Examination ◽

Study Results ◽

Observation Period

The aim of the study: to study the efficacy and safety of use Mastofemin in the treatment of various forms of mastitis in women of reproductive age. Materials and methods. The study included 62 women of reproductive age (mean age of 33.5±2.3 years) who were screened in the Kiev city center reproductive and perinatal medicine. Women were divided into 2 groups. The first (main) group consisted of 32 patients who received the proposed treatment using herbal remedies Mastofemin 1 capsule 2 times per day for 3 months; 30 patients of the second (control) group were under observation and received no treatment. These groups were representative and homogeneous on age, clinical symptoms and sonographic characteristics. The clinical method included evaluation of complaints of patients, anamnesis, presence of concomitant gynecologic pathology, inspection, palpation of the lymph nodes and the breast and obtaining a discharge from the nipples to conduct cytological examination, which allowed excluding from the study women with suspected malignancy of the process. All the patients were performed ultrasound examination of the breast. The review was supplemented with vaginal gynecological examination and ultrasound examination of small pelvis organs to assess the condition of the uterus and its appendages, the diagnosis of gynecological diseases. Results. Summarizing obtained in this study results one should stress the positive long-term effect of applying Mastofemin for the treatment of proliferative changes of the breast in women of reproductive age. This is manifested by a decrease in the intensity of clinical signs of mastitis, consistent with the results of sonographic control. Established positive dynamics in the treatment of cystic mastitis, dectective and when combined cystic mastopathy with dectective. In the control group of patients for a given observation period (6 months) no significant changes in clinical signs of mastitis and sonographic characteristics. Regression of disease has not occurred in any of the patients, in 2 patients increased sensitivity of the breast after 6 months moved to the soreness. Sonographic characteristics of mastitis during the observation period did not change. Thus, the use of Mastofemin aimed at pathogenetic treatment of mastitis and prevention of breast cancer. Conclusion. Application of Mastofemin during the treatment of mastitis in women of reproductive age significantly improves the clinical condition of patients; reduce the subjective and objective symptoms of the disease. The positive effect of the treatment with Mastofemin proved in the case of the treatment of sonographic following forms of mastitis: cystic mastopathy, cystic mastopathy with dectectasy. Mastofemin may be the drug of choice for complex conservative monotherapy in women of reproductive age with proliferative changes in the breast, and can also be used as part of complex treatment in patients with diffuse changes of the breast when combined with hyperplastic processes of the myometrium and endometrium. Keywords: mastopathy, breast gland, herbal medicine, herbal remedies, Mastofemin.

Download Full-text

New opportunities of drug delivery in oncology

ZHurnal «Patologicheskaia fiziologiia i eksperimental`naia terapiia» ◽

10.25557/0031-2991.2018.03.120-127 ◽

2018 ◽

pp. 120-127

Author(s):

А.В. Бойко ◽

Н.Д. Олтаржевская ◽

В.И. Швец ◽

Л.В. Демидова ◽

Е.А. Дунаева ◽

...

Keyword(s):

Clinical Signs ◽

Supportive Therapy ◽

Main Group ◽

Radiation Proctitis ◽

Control Group ◽

Vaginal Mucosa ◽

Zone Method ◽

Radiation Cystitis ◽

Grade Ii ◽

Grade Iii

Цель исследования. Разработка методов сопроводительной терапии для защиты нормальных органов и тканей, входящих в зону облучения. Методы. В исследование включено 112 больных раком шейки и тела матки после комбинированного или самостоятельного лучевого лечения с 2012 по 2016 гг. У 71 пациентки основной группы в качестве терапии сопровождения применяли гидрогель с деринатом и у 41 больной группы контроля - традиционные методы профилактики (масло оливковое, подсолнечное, метилурациловая мазь). Для профилактики эпителиита слизистой влагалища и шейки матки в основной группе использовали гидрогель в виде аппликаций с первого дня облучения. Для профилактики лучевого ректита гидрогель вводили в прямую кишку 1 раз в день с первого дня облучения. Инстилляции гидрогеля в мочевой пузырь начинали только при развитии первых признаков клинической картины цистита. Пациенткам контрольной группы для профилактики лучевых реакций проводились масляные, мазевые аппликации во влагалище, масляные микроклизмы в прямую кишку с первого дня облучения. Лечение лучевого цистита проводили с помощью растительных диуретиков, уросептиков. Результаты. Применение гидрогеля с деринатом позволило провести курс лучевой терапии без перерыва у 84,5% (60/71) больных, в контрольной группе - лишь у 48,8% (20/41). Лучевые циститы возникали в 2,5 раза реже (25,3% ± 3,3 против 63,4% ± 2,7, р<0,01). Анализ степени выраженности лучевого цистита по RTOG в двух группах показал, что у 75% больных основной группы наблюдалась I степень, у 25% - II степень, III и IV степени не отмечено, тогда как в контрольной группе лучевой цистит I степени развился у 44% пациенток, II - 40% и III - 16% больных. Применение гидрогеля снизило частоту лучевых ректитов в 2 раза (26,7% ± 3,3 против 53,7% ± 3,2 р<0,1).При использовании ежедневных аппликаций гидрогеля с деринатом со стороны слизистой оболочки влагалища и шейки матки преобладали эпителииты I степени (53,5%), II степень наблюдалась у 29,5% и III степень лучевой реакции - лишь в 16,9% случаев, IV степень реакции не отмечена. В контрольной группе эти показатели составили 26,8%, 24,3%, 31,7% и 17,2% соответственно. Разработаны цитологические критерии оценки течения лучевых реакций слизистой влагалища. Выделены три степени изменения цитограммы, которые коррелировали с клинической картиной. В основной группе лучевые изменения I степени зафиксированы в 4,5 раза чаще (52 ± 9,9% против 11,5 ± 6,3%, р<0,002), а III степень представлена в 3,8 раза реже, чем в контрольной группе (12 ± 6,5% против 46,1 ± 9,8%, р<0,003). Заключение. Применение гидрогелевого материала с деринатом в качестве препарата сопроводительной терапии во время курса облучения позволяет уменьшить частоту и степень выраженности лучевых повреждений со стороны слизистой влагалища, мочевого пузыря и прямой кишки, провести курс лучевой терапии без перерыва и улучшить качество жизни пациенток. Objective. Development of methods for accompanying therapy to protect normal organs and tissues in the irradiation zone. Method. The study included 112 patients with cervical and endometrial cancer after combined or independent radiotherapy from 2012 to 2016. In 71 female patients of the main group, Derinat with hydrogel was applied as a supportive therapy and in 41 patients of the control group, conventional prevention methods (olive oil, sunflower oil, methyluracyl ointment) were applied. For prevention of vaginal mucosal and cervical epitheliitis in the main group, hydrogel was used as applications from the first radiation day. For prevention of radiation proctitis, hydrogel was injected into the rectum once daily from the first radiation day. Hydrogel instillations into the bladder were started only with the first clinical signs of cystitis. For prevention of radiation reactions, vaginal oil and ointment and rectal oil micro-enema were administered to patients of the control group from the first day of irradiation. Radiation cystitis was treated with vegetable diuretics and uroseptic drugs. Results. Using the hydrogel with Derinat allowed to administer a course of radiotherapy without interruption in 84.5% (60/71) of patients and only in 48.8% (20/41) in the control group. Radiation cystitis occurred 60% less frequently (25.3% ± 3.3 versus 63.4% ± 2.7, p <0.01). Analysis of radiation cystitis severity in two groups (according to RTOG) showed that 75% of patients in the main group had grade I and 25% had grade II. Grade III and grade IV did not occur. At the same time, in the control group, grade I radiation cystitis developed in 44% of patients, grade II - in 40%, and grade III - in 16% of patients. The hydrogel treatment halved the frequency of radiation proctitis (26.7% ± 3.3 vs. 53.7% ± 3.2 p <0.1). With daily application of the hydrogel with Derinat, grade I epitheliitis (53.5%) predominated in vaginal and cervical mucosa, grade II was observed in 29.5%, and grade III radiation reaction - only in 16.9% of cases; grade IV reaction was not observed. In the control group, these proportions were 26.8%, 24.3%, 31.7%, and 17.2%, respectively. Cytological criteria were developed to evaluate the course of radiation reactions in the vaginal mucosa. Three degrees of change in the cytogram were identified, which correlated with clinical picture. In the main group, incidence of grade I radiation-induced changes was increased by more than 350% (52 ± 9.9% vs. 11.5 ± 6.3%, p <0.002), and incidence of grade III was decreased by more than 70% compared to the control group (12 ± 6.5% vs. 46.1 ± 9.8%, p <0.003). Conclusion. Using the hydrogel material with Derinat as an accompanying therapy during the course of irradiation allows to reduce frequency and severity of radiation injuries of the vaginal mucosa, bladder, and rectum, administer an uninterrupted course of radiotherapy, and improve the quality of life of patients.

Download Full-text

Comparison of the Effects of Fenugreek Vaginal Cream and Ultra Low- Dose Estrogen on Atrophic Vaginitis

Current Drug Delivery ◽

10.2174/1567201817666200708112655 ◽

2020 ◽

Vol 17 (9) ◽

pp. 815-822

Author(s):

Maryam Safary ◽

Sevil Hakimi ◽

Noushin Mobaraki-Asl ◽

Paria Amiri ◽

Habib Tvassoli ◽

...

Keyword(s):

Postmenopausal Women ◽

Low Dose ◽

Intervention Group ◽

Clinical Signs ◽

Control Group ◽

Conjugated Estrogens ◽

Atrophic Vaginitis ◽

Vaginal Cream ◽

Intergroup Comparison ◽

Significant Difference

Introduction: Atrophic vaginitis is a common problem in postmenopausal women and results from decreased levels of blood estrogen. It is associated with symptoms of itching, burning, dyspareunia, and postmenopausal bleeding. The present study evaluated the effects of fenugreek extract on atrophic vaginitis. Materials and Methods: This randomized controlled clinical trial was performed on 60 postmenopausal women in Ardabil, Iran, in 2018. The participants were selected using block randomization with the allocation ratio 1:1. Those in the intervention group received 0.5g (the applicator filled to the half-full mark) fenugreek vaginal cream 5% twice a week for 12 weeks. The control group received conjugated estrogens vaginal cream at the dose of 0.625 mg (the applicator filled to the half-full mark) containing 0.3 mg of conjugated estrogens. Atrophic vaginitis was evaluated before and after the treatment through clinical examination, clinical signs, and measurement of Vaginal Maturation Index (VMI). Findings: After the 12-week intervention and modification of the baseline score, the mean (standard error) score for atrophic vaginitis signs was 3.100 (1.43-4.75). This difference was statistically significant in intragroup comparison and in favor of the control group in intergroup comparison (p=0.001). VMI was less than 49% in 86.7% and 46.7% of the participants in the intervention and control groups, respectively. This was a significant difference in favor of the control group (p=0.001). Conclusion: The results of this study showed that total fenugreek extract could be effective in treating signs of atrophic vaginitis, but it was not as effective as ultra-low-dose estrogen.

Download Full-text

Human Monoclonal Antibody Cocktail for the Treatment or Prophylaxis of Middle East Respiratory Syndrome Coronavirus

The Journal of Infectious Diseases ◽

10.1093/infdis/jiab036 ◽

2021 ◽

Author(s):

Sumathi Sivapalasingam ◽

George A Saviolakis ◽

Kirsten Kulcsar ◽

Aya Nakamura ◽

Thomas Conrad ◽

...

Keyword(s):

Middle East ◽

Adverse Events ◽

Phase 1 ◽

Human Monoclonal Antibody ◽

Preclinical Study ◽

Middle East Respiratory Syndrome ◽

Lung Pathology ◽

Phase 1 Study ◽

Serious Adverse Events ◽

Dipeptidyl Peptidase 4

Abstract Background REGN3048 and REGN3051 are human monoclonal antibodies (mAb) targeting the spike glycoprotein on the Middle East respiratory syndrome coronavirus (MERS-CoV), which binds to the receptor dipeptidyl peptidase-4 (DPP4) and is necessary for infection of susceptible cells. Methods Preclinical study: REGN3048, REGN3051 and isotype immunoglobulin G (IgG) were administered to humanized DPP4 (huDPP4) mice 1 day prior to and 1 day after infection with MERS-CoV (Jordan strain). Virus titers and lung pathology were assessed. Phase 1 study: healthy adults received the combined mAb (n = 36) or placebo (n = 12) and followed for 121 days. Six dose levels were studied. Strict safety criteria were met prior to dose escalation. Results Preclinical study: REGN3048 plus REGN3051, prophylactically or therapeutically, was substantially more effective for reducing viral titer, lung inflammation, and pathology in huDPP4 mice compared with control antibodies and to each antibody monotherapy. Phase 1 study: REGN3048 plus REGN3051 was well tolerated with no dose-limiting adverse events, deaths, serious adverse events, or infusion reactions. Each mAb displayed pharmacokinetics expected of human IgG1 antibodies; it was not immunogenic. Conclusions REGN3048 and REGN3051 in combination were well tolerated. The clinical and preclinical data support further development for the treatment or prophylaxis of MERS-CoV infection.

Download Full-text

Safety evaluation of an antimalarial herbal product from Andrographis paniculata (AS201-01) in healthy volunteers

Journal of Basic and Clinical Physiology and Pharmacology ◽

10.1515/jbcpp-2020-0381 ◽

2021 ◽

Vol 0 (0) ◽

Author(s):

Aty Widyawaruyanti ◽

Arijanto Jonosewojo ◽

Hilkatul Ilmi ◽

Lidya Tumewu ◽

Ario Imandiri ◽

...

Keyword(s):

Blood Glucose ◽

Healthy Volunteers ◽

Day Treatment ◽

Phase 1 ◽

Andrographis Paniculata ◽

Control Group ◽

Healthy Human ◽

Double Blind ◽

Random Blood Glucose ◽

Significant Difference

Abstract Objectives Andrographis paniculata tablets (AS201-01) have previously been shown to have potent bioactivity as an antimalarial and to produce no unwanted side effects in animal models. Here, we present the phase 1 clinical trial conducted to evaluate the safety of AS201-01 tablets in healthy volunteers. Methods The study was a randomized, double-blind controlled cross-over, a placebo-controlled design consisting of a 4-day treatment of AS201-01 tablets. A total of 30 healthy human volunteers (16 males and 14 females) were divided into two groups, and each group was given 4 tablets, twice daily for 4 days. Group 1 received AS201-01, while group 2 received placebo tablets. Volunteers were given a physical examination before the treatment. The effects of AS201-01 on random blood glucose, biochemical, and hematological as well as urine profiles were investigated. Results There were no changes in observed parameters as a result of AS201-01 being administered. Statistical analysis showed no significant difference (p>0.05) between the test and control group regarding hematology profile, biochemical profile, and random blood glucose. Increased appetite and better sleep, which categorized as grade 1 adverse event was reported after treatment with AS201-01 tablet Conclusions The outcome supports our previous observation that the AS201-01 tablet, given twice a day for 4 days, is safe and nontoxic.

Download Full-text