Single Daily Oral Administration Research Articles

Istradefylline Improves Impaired Smooth Pursuit Eye Movements in Parkinson's Disease.

Patients with Parkinson's disease (PD) exhibit alterations in eye movement control, primarily diverse oculomotor deficits which include hypometric saccade and impaired smooth pursuit with reduced pursuit-gain necessitating catch-up saccades. The effects of dopaminergic treatment of PD on eye movements are controversial. Previous studies suggest that smooth pursuit eye movements (SPEMs) are not directly influenced by the dopaminergic system. The nondopaminergic drug istradefylline, a selective adenosine A2A receptor antagonist, reduces the OFF time and improves somatomotor function in levodopa-treated PD. Here, we investigated whether istradefylline improves SPEMs in PD, and determined whether oculomotor performance is associated with somatomotor performance. Using an infrared video eye tracking system, we quantified horizontal SPEMs in six patients with PD before and 4-8weeks after initiation of istradefylline administration. A further five patients with PD were tested before and after a 4-week interval without istradefylline to control for practice effects. We evaluated smooth pursuit gain (eye velocity/target velocity), accuracy of smooth pursuit velocity, and saccade rate during pursuitbefore and after istradefylline administration during the ON state. Patients received istradefylline by single daily oral administration at 20 to 40mg. Eye tracking data were obtained 4-8weeks after initiation of istradefylline administration. Istradefylline increased smooth pursuit gain and the accuracy of smooth pursuit velocity, and tended to decrease saccade rates during pursuit. Istradefylline ameliorated the oculomotor deficit in SPEM of patients with PD, although differences in somatomotor performance before and after istradefylline treatment were not significant during ON periods. The discrepancy observed between the oculomotor and somatomotor responses to istradefylline supports previous findings that SPEM is at least partially under nondopaminergic control.

Выбор антибактериального препарата при инфекциях мочевыделительной системы у детей

Инфекции мочевыделительной системы в детском возрасте занимают второе место по частоте обращений за первичной медицинской помощью. Escherichia coli — наибольший причинно-значимый возбудитель внебольничных форм инфекций мочевыделительной системы, которые, как правило, носят неосложненный характер и чаще диагностируются у девочек после трехмесячного возраста. Klebsiella pneumoniae превалирует при нозокомиальных формах инфекций мочевыводящих путей, характеризующихся осложненным течением и чаще диагностируемых у мальчиков до трехмесячного возраста. Одной из причин повторных эпизодов инфекций мочевыводящих путей является формирование антибиотикорезистентности за счет действия β-лактамаз микроорганизмов к наиболее часто используемым антибактериальным препаратам группы аминопенициллинов. В литературном обзоре обоснован выбор антибактериальной терапии инфекций мочевыделительной системы в детском возрасте с учетом клинической эффективности, безопасности и чувствительности основных уропатогенов. Обобщены результаты рандомизированных клинических исследований эффективности и безопасности использования цефалоспорина III поколения цефиксима у детей с инфекциями мочевыделительной системы. Особое внимание уделено сохранению бактериальной чувствительности на уровне свыше 90 % к действию цефиксима у Escherichia coli и Klebsiella pneumoniae и высокой комплаентности при возможности однократного ежедневного перорального применения в качестве самостоятельной терапии на амбулаторном этапе и потенциального перехода от парентерального использования цефалоспоринов III поколения к менее инвазивному — пероральному приему, особенно у детей.

Abstract 3011: Phase I study of TT-00420, a multiple kinase inhibitor, in patients with triple negative breast cancers and other advanced solid tumors

Abstract Background: TT-00420, a multikinase inhibitor, targets cell proliferation, angiogenesis, and immunomodulatory pathways by inhibiting the mitotic kinases Aurora A/B, Janus kinases (JAK) involved in cytokine signalling, and receptor tyrosine kinases involved in angiogenesis (FGFRs and VEGFRs). These pathways are important in the pathogenesis of triple negative breast cancer (TNBC) and TT-00420 has shown preclinical efficacy against multiple subtypes of TNBC. Methods: This phase I, open-label, first-in-human study is enrolling adult patients with advanced or metastatic TNBC and other advanced solid tumors. The study contains a dose escalation phase (N=22), followed by dose expansion in two parallel cohorts, a TNBC cohort (N=22) and a selected advanced tumor (SAT) cohort (N=22). The provisional dose range for dose escalation is 1 mg/d to 20 mg/d. Dose escalation is guided by Bayesian modeling with overdose control until a dose recommended for dose expansion is determined. Adverse events (AE) are evaluated per CTCAE v5.0 criteria, and tumor response is evaluated per RECIST v1.1 criteria. Patients receive a single daily oral administration of TT-00420 continuously for 28-day cycles. The primary endpoint is to evaluate dose limiting toxicity (DLT) and identify a maximum tolerated dose (MTD). Secondary objectives include evaluating the efficacy and pharmacokinetic profile of TT-00420. Results: As of the data cut-off date on September 26, 2019, 11 patients have received TT-00420 treatment in 4 dose levels, 1 mg/d (N=1), 3 mg/d (N=1), 5 mg/d (N=3), and 8 mg/d (N=6). No DLTs have been observed at any of the tested dose levels. Commonly reported suspected AEs across all tested dose levels were grades 1 or 2 diarrhea (n=4, 36.4%), myalgia (n=2, 18.2%) and hypertension (n=2, 18.2%). Two suspected serious adverse events reported were grade 2 hypertension (8 mg/d) and grade 3 nausea (5 mg/d). No grade 3 AEs have occurred in more than one subject. Stable disease has been observed in 4 patients, including a metastatic TNBC patient treated at 8 mg/d, who received 9 lines of prior antineoplastic therapy. Per RECIST v1.1 criteria, this TNBC patient had a 21% decrease in target lesions observed on restaging after two cycles of TT-00420 treatment. Interestingly, significant clinical improvement in the skin lesions were observed as well. More detailed data from this TNBC patient and other patients treated in the study will be presented. Enrollment in dose escalation is currently ongoing. Clinical trial information: NCT03654547 Citation Format: Sarina A. Piha-Paul, Ecaterina Ileana-Dumbrava, Filip Janku, Daniel D. Karp, Funda Meric-Bernstam, Jordi Rodon, Brenda Ngo, Peng Peng, Frank Wu. Phase I study of TT-00420, a multiple kinase inhibitor, in patients with triple negative breast cancers and other advanced solid tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3011.

The efficacy of axitinib as a first‐line treatment for metastatic renal cell carcinoma

To evaluate predictive factors which associated with oncological outcomes to first-line axitinib for metastatic renal cell carcinoma (mRCC). A retrospective chart review was conducted patients who had been treated with axitinib as first-line therapy for the treatment of mRCC from September 2013 to February 2018. Axitinib was given by single daily oral administration at a dose of 10mg, which was reduced according to adverse events (AEs). We investigated progression-free survival (PFS), overall survival (OS), objective response rate (ORR) and AEs. Thirty-eight mRCC patients were enrolled. The median follow-up duration of axitinib treatment was 11.3 months (range = 1.0-56.9). ORR was 28.9%. Median PFS and OS was 12.8, and 17.9 months, respectively. In univariate analysis, baseline lactate dehydrogenase (LDH), neutrophil, corrected calcium (Ca), platelets (Plt) and time from diagnosis were selected as potential predictive factors. Multivariate Cox's proportional hazards model analysis showed that the number of risk factors were associated with PFS (P=0.03) and OS (P=0.02). Baseline LDH, neutrophil, Ca, Plt and time from diagnosis are predictive factors for both PFS and OS in first-line treatment with axitinib for metastatic renal cell carcinoma.

A phase I, first-in-human, dose-escalation and dose-expansion study of the multitarget kinase inhibitor TT-00420 in patients with advanced solid tumors.

TPS3168 Background: Multi-target kinase inhibitors have gained increasing attention in the past few years due to their capabilities of simultaneously targeting several hallmarks of cancer. Triple negative breast cancer (TNBC), the most aggressive type of breast cancer, is a highly heterogeneous disease composed of several subtypes with distinct genomic profiles and activating pathways. TT-00420 is a multi-target kinase inhibitor that targets Aurora A/B, receptor tyrosine kinases (RTKs) involved in angiogenesis, and other kinases involved in tumor-associated inflammation and immune escape. Preclinical studies have established signs of efficacy for TT-00420 in TNBC. Targets inhibited by TT-00420 are among the key dysregulated pathways directly involved in the tumorigenesis of TNBC. TT-00420 is efficacious against most subtypes of TNBC cell lines. This anti-TNBC activity is confirmed in both cell line derived xenograft (CDX) and patient derived xenograft (PDX) TNBC model in vivo, in which TT-00420 is active both as first-line and second-line treatment. TT-00420 demonstrated good oral bioavailability and pharmacokinetic properties in mice, rats and dogs, and revealed mechanism-related but manageable toxicities. The IND approval of TT-00420 was granted by the FDA on Sept. 27, 2018. Methods: TT420X2101 is an open-label, first-in-human, multicenter, phase I study including a dose escalation portion in adult patients with advanced solid tumors, followed by dose expansion in two parallel cohorts, TNBC cohort (N=22) and selected advanced tumor (SAT) cohort (N=22). Adverse events will be evaluated per CTCAE v5.0 criteria, and tumor responses will be evaluated per RECIST v1.1 criteria. Patients aged 18-75 with measurable target lesion(s) at baseline and ECOG status of 0 or 1 will be enrolled. Patients are treated with a single daily oral administration of TT-00420 continuously for a 28-day cycle. Dose escalation is driven by Bayesian modeling with over-dose control. Approximately 66 patients are expected to be enrolled and treated in this study. Primary endpoint is to evaluate dose limiting toxicity (DLT) and identify maximum tolerate dose (MTD), if feasible, or establish recommended dose for Dose Expansion. Preliminary efficacy and PK profile will be evaluated as well. Enrollment is currently ongoing. Clinical trial information: NCT03654547.

An open label, non-comparative pilot study to assess the efficacy and safety of a food supplement containing manna in pediatric functional constipation

Objective. The primary objective of this study was to evaluate the efficacy and safety of the food supplement Physiomanna Baby® in pediatric patients with a history of functional constipation defined by Rome III criteria; secondary objective was to evaluate the adherence to the tested product in the enrolled children. Methods. The trial was designed as an open label, non-comparative pilot trial. In 3 Romanian sites (one community hospital and two private medical practice offices) 49 children (20 males, 29 females) aged 0 - 8 years were enrolled. The study was conducted between February 2016 and April 2016. The investigational product was administered as 1 g/kg in single daily oral administration from the first day and continued for a maximum of 3 days in the first week. If the constipation symptoms persisted, the children were treated in an additional cycle of treatment for a maximum of 3 days. Results. The number of Spontaneous Bowel Movements (SBM) per week has increased to normal after Physiomanna Baby® administration (from 1.80 ± 0.41 at baseline to 6.04±1.54 at day 8) evidencing a statistically significant difference (P-value <0.0001). The efficacy was also demonstrated in the subpopulation of children <4 years where the mean values per week increased from 1.69±0.47 at baseline to 6.15±1.59 SBM at day 8 (P-value <0.0001). According to Investigator Global Assessment of Efficacy (IGAE), Physiomanna Baby® shows immediate and excellent efficacy after one or two doses for 79.60% of the children, a very good efficacy after three doses for 12.24% and good efficacy after the second cycle of administration for 6.12% of children. Both Investigator Global Assessment for Safety (IGAS) and Patient Global Assessment for Safety (PGAS) were rated as 100% excellent for all patients. Conclusions. The food supplement Physiomanna Baby® provided immediate efficacy, offering to pediatricians a safe solution in the care of mild to moderate functional constipation, even if the study design characteristics were limited (pilot trial with a small sample size and without control group).

The long-term effects of probiotics in the therapy of ulcerative colitis: A clinical study.

Intestinal dysbiosis seems to be the leading cause of inflammatory bowel diseases, and probiotics seems to represent the proper support against their occurrence. Actually, probiotic blends and anti-inflammatory drugs represent a weapon against inflammatory bowel diseases. The present study evaluates the long-term (2 years) effects of combination therapy (mesalazine plus a probiotic blend of Lactobacillus salivarius, Lactobacillus acidophilus and Bifidobacterium bifidus strain BGN4) on ulcerative colitis activity. Sixty patients with moderate-to-severe ulcerative colitis were enrolled: 30 of them were treated with a single daily oral administration of mesalazine 1200 mg; 30 patients received a single daily oral administration of mesalazine 1200 mg and a double daily administration of a probiotic blend of Lactobacillus salivarius, Lactobacillus acidophilus and Bifidobacterium bifidus strain BGN4. The treatment was carried out for two years and the clinical response evaluated according to the Modified Mayo Disease Activity Index. All patients treated with combination therapy showed better improvement compared to the controls. In particular, the beneficial effects of probiotics were evident even after two years of treatment. A long-term treatment modality of anti-inflammatory drugs and probiotics is viable and could be an alternative to corticosteroids in mild-to moderate ulcerative colitis.

Chronic oral administration of pine bark extract (flavangenol) attenuates brain and liver mRNA expressions of HSPs in heat-exposed chicks

Exposure to a high ambient temperature (HT) can cause heat stress, which has a huge negative impact on physiological functions. Cellular heat-shock response is activated upon exposure to HT for cellular maintenance and adaptation. In addition, antioxidants are used to support physiological functions under HT in a variety of organisms. Flavangenol, an extract of pine bark, is one of the most potent antioxidants with its complex mixture of polyphenols. In the current study, chronic (a single daily oral administration for 14 days) or acute (a single oral administration) oral administration of flavangenol was performed on chicks. Then the chicks were exposed to an acute HT (40±1°C for 3h) to examine the effect of flavangenol on the mRNA expression of heat-shock protein (HSP) in the brain and liver. Rectal temperature, plasma aspartate aminotransferase (AAT), a marker of liver damage, and plasma corticosterone as well as metabolites were also determined. HSP-70 and -90 mRNA expression, rectal temperature, plasma AAT and corticosterone were increased by HT. Interestingly, the chronic, but not the acute, administration of flavangenol caused a declining in the diencephalic mRNA expression of HSP-70 and -90 and plasma AAT in HT-exposed chicks. Moreover, the hepatic mRNA expression of HSP-90 was also significantly decreased by chronic oral administration of flavangenol in HT chicks. These results indicate that chronic, but not acute, oral administration of flavangenol attenuates HSP mRNA expression in the central and peripheral tissues due to its possible role in improving cellular protective functions during heat stress. The flavangenol-dependent decline in plasma AAT further suggests that liver damage induced by heat stress was minimized by flavangenol.

Abstract 922: ABTL0812: A new drug class with oral antitumor action inhibiting mTOR activity and DHFR expression

Abstract ABTL0812* is a lipid analogue that has shown high efficacy by the oral route in mouse models of cancer. Here we show that two clinically validated targets are responsible for the cytotoxic effect of ABTL0812: mTOR (mammalian target of rapamycin), as shown by the dramatic reduction in S6 phosphorylation, and dihydrofolate reductase (DHFR), as shown by its reduced expression, resulting in autophagic cell death. Moreover, the compound's cellular potency increases with incubation time, and it has a long lasting cytotoxic effect after removing the compound from the incubation medium. In vivo efficacy was determined in a human lung cancer xenograft model by subcutaneously injecting A549 human lung adenococarcinoma cells into nu/nu mice. ABT0812 was administered daily at two dose levels and its impact on tumor volume was measured. ABT0812 showed a similar efficacy to docetaxel but with much lower toxicity, and better efficacy than erlotinib. Histological analysis of the tumors revealed increased necrotic area, more inflammatory cells and fewer cells undergoing mitosis. Additionally, plasma levels of ABTL0812 were inversely correlated with tumor volume, reinforcing the concentration-effect relationship. A parallel study was performed to evaluate ABTL0812 efficacy in a pancreatic cancer model. Nu/nu mice were subcutaneously injected with MiaPaCa-2 cells and the volume of xenograft was used as a measurement of efficacy. Again, ABTL0812 showed a statistically significant reduction of tumor volume, increased tumor cell death, and better tolerance than gemcitabine in the mice. DMPK properties in rats and dogs showed very low in vitro hepatic metabolism, ∼50% bioavailability and half lives that calculate to single daily oral administration. Safety pharmacology studies with very high doses of the compound showed no impact on the central nervous system. Ongoing toxicological studies show that the margin between efficacy and toxicity is broad. In conclusion, ABTL0812 is a lipid analogue that hits two clinically validated targets: mTOR and DHFR. This multitarget property increases antitumor efficacy and reduces drug resistance. In addition, preliminary in vivo results indicate that the potential therapeutic margin will be high. * Protected by PCT WO 2010/106211, by Escribá Ruiz PV, et al., licensed to AB-Therapeutics, SL. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 922. doi:1538-7445.AM2012-922

Enhanced bioavailability and retinal accumulation of lutein from self-emulsifying phospholipid suspension (SEPS)

Ability of any formulation to keep the drug in solubilized form in vivo is essential for bioavailability (BA) enhancement rather than the solubility of drug in the formulation vehicle/matrix itself. Besides, utilization of an excess amount of surfactants/co-surfactants to solubilize the drug in the lipid formulation poses potential pharmaceutical as well as health problems. To address this problem, self-emulsifying phospholipid suspension (SEPS) consisting of high amount of phospholipid (an endogenous lipid with efficient in vivo emulsification capability) and relatively low amount of surfactant/co-surfactant has been proposed to enhance the bioavailability (BA) of lutein. In this study, the ability of SEPS formulation to enhance the BA of lutein was assessed from three SEPS formulations with various amounts of phospholipid (SEPS-0, SEPS-I, and SEPS-II with 0 mg, 250 mg, and 500 mg of Phosal ® 53 MCT, respectively) in beagle dogs following a single oral administration of lutein equivalent to 100 mg, and were compared with commercial formulation (CF). In addition, the retinal accumulation of lutein in Sprague Dawley (SD) rats’ eyes from SEPS-II formulation (lutein dose of 100 mg/kg/day) was investigated following single daily oral administration for a period of 14 days. CF and placebo (vegetable oil without lutein) were also administered for the same period of time and were compared with the SEPS-II formulation. In the relative BA study in beagle dogs, no significant differences were observed between the pharmacokinetic (PK) parameters of formulation SEPS-O and CF. However, the C max in comparison to CF was 3.70 folds and 11.76 folds higher for SEPS-I and SEPS-II, respectively. Relative BA compared to CF was 178.88% and 473.13% for SEPS-I and SEPS-II, respectively. The retinal lutein accumulation was 0.91 ± 0.31 ng/g, 3.45 ± 1.63 ng/g, and 14.72 ± 2.02 ng/g for placebo, CF, and SEPS-II, respectively. This enhancement was about 16.1 folds and 4.27 folds compared to placebo and CF, respectively. The relative BA study in dogs and retinal accumulation study in rats demonstrated the excellent ability of SEPS to enhance the BA of lutein. For this reason, SEPS containing lutein could be a promising lipid based delivery system for the prevention of ocular diseases.

Early Post-Natal Iron Administration Induces Astroglial Response in the Brain of Adult and Aged Rats

This study was aimed to investigate neuropathological changes in adult and aged rats subjected to supplementary iron administration in a critical postnatal period to study the contribution of environmental risk factors to the pathogenesis of neurodegenerative disorders. Ten rats received a single daily oral administration of iron (10mg/kg) between 12th and 14th post-natal days; nine rats received vehicle (sorbitol 5% in water) in the same period. Five iron-treated and three sorbitol-treated rats were killed at the age of 3months while five iron-treated and six sorbitol-treated rats were killed at age of 24months and their brains processed for immunohistochemistry. Increased astrocytosis, revealed by densitometry of GFAP-immunoreactive astrocytes, was found in aged (24months) iron-treated rats in the substantia nigra and striatum and in the hippocampus of adult (3months) iron-treated rats when compared to age-matching controls. Decreased densitometry of neurons, revealed by neuronal nucleus immunohistochemistry, was found in aged (24months) iron-treated rats in substantia nigra and striatum when compared to age-matching controls. These findings suggest that transient dietary iron supplementation during the neonatal period is associated to cellular imprinting in the brain later in life.

Stimulation of vascular dopamine receptors: status and future strategies.

The ability to stimulate dopamine receptors in the heart and blood vessels with selective receptor agonists, such as fenoldopam, has been an important advance. Fenoldopam is a selective DA1 receptor agonist and is currently in clinical trials for cardiovascular disease therapy. An alternative approach to stimulating dopamine receptors, while at the same time blunting sympathetic nervous system activity, would be by inhibiting the enzyme dopamine beta-hydroxylase (D beta H), thus increasing the cardiovascular and renal ratio of dopamine to norepinephrine. SK&F 102698, (1-[3',5'-difluorobenzyl]-2-mercaptoimidazole), is a potent inhibitor of D beta H with a Ki of 40 nM against D beta H in vitro. In the spontaneously hypertensive rat SK&F 102698 100 mg/kg orally, increases the dopamine/norepinephrine ratio approximately 5-fold and lowers blood pressure approximately 30 mmHg to normotensive levels. Antihypertensive activity can be achieved with single daily oral administration and neither tolerance nor reflex tachycardia occur. Stimulation of dopamine receptors by inhibition of dopamine beta-hydroxylase is a unique approach toward cardiovascular and renal therapeutics.

Endocrinological effects of single daily ketoconazole administration in male beagle dogs.

Some endocrinological effects of single daily oral administration of 150 mg ketoconazole for 15 days were investigated in 4 male beagle dogs. Plasma testosterone fell markedly within 3-4 h and then progressively returned to control concentrations by 10 h after drug administration. On the other hand, plasma 17 alpha-hydroxyprogesterone, progesterone and 17 alpha, 20 alpha-dihydroxyprogesterone increased within 3-10 h before returning to basal values after 24 h. Plasma LH did not rise significantly though some high individual levels were noted. Plasma cortisol and oestradiol-17 alpha levels were not significantly modified by the treatment. These results confirm that a high therapeutic dose of ketoconazole, given orally once a day, transiently inhibits in vivo the 17-20 lyase enzyme of the testis, without modifying basal cortisol and oestradiol-17 beta plasma concentrations and that enzymatic inhibition still occurs after daily treatment for up to 2 weeks but remains transient and parallels the resorption profile of the drug so that normal plasma testosterone levels are observed from 10 to 24 h after drug intake. However, permanent inhibition of androgen biosynthesis might be obtained by the administration of high doses of ketoconazole given several times a day.