bluuebunny/crossref_metadata_2025 huggingface dataset:
Involvement of Mechanistic Target of Rapamycin (mTOR) in Valine Orexigenic Effects in Rainbow Trout
Authors: Comesaña Sara , Chivite Mauro , Blanco Ayelén M. , Alborja-Valado María , Calo Jessica , Conde-Sieira Marta , Soengas José L.
Published: September 2022

This study was aimed at clarifying the importance of a mechanistic target of rapamycin (mTOR) in the central orexigenic effect of valine in fish. For this, rainbow trout (Oncorhynchus mykiss) were intracerebroventricularly (ICV) injected with valine alone or in the presence of rapamycin as the mTOR inhibitor, and two experiments were performed. In the first experiment, we evaluated feed intake levels. In the second experiment, we evaluated in the hypothalamus and telencephalon the following: (1) the phosphorylation status of mTOR and its downstream effectors ribosomal protein S6 and p70 S6 kinase 1 (S6K1), (2) the abundance and phosphorylation status of transcription factors involved in appetite regulation, and (3) the mRNA levels of key neuropeptides associated with homeostatic regulation of feed intake in fish. Rising central levels of valine clearly resulted in an orexigenic response in rainbow trout. This response occurred in parallel with mTOR activation in both the hypothalamus and telencephalon, as supported by depressant changes in proteins involved in mTOR signalling (S6 and S6K1). Also, these changes disappeared in the presence of rapamycin. However, it is not clear which precise mechanisms link the activation of mTOR and the alteration in feed intake levels since we did not observe changes in mRNA levels of appetite-regulatory neuropeptides as well as in the phosphorylation status and levels of integrative proteins.
Key Challenges for Indigenous Peoples of Canada in terms of Oral Health Provision and Utilization: A Scoping Review
Authors: Hussain Ahmed
Published: September 2022

Background. The oral health of Indigenous peoples in Canada is lacking compared with their non-Indigenous counterparts. This scoping assessment aimed to investigate the obstacles of providing and using oral healthcare among Indigenous peoples in Canada. Methods. The scoping review took place between December 15, 2021 and January 10, 2022. Five key databases were examined: PubMed, Scopus, ISI Web of Science, Embase, and PROQUEST. The data were analyzed using NVIVO software to facilitate understanding of the major themes, subthemes, and codes provided. Results. Seven major themes and eighteen subthemes were identified as impacting the oral health provision and utilization of Indigenous peoples in Canada. The major themes are individual characteristics, affordability, availability, accessibility, accommodation, acceptability, and public or government policy. Thus, to improve the oral health of the Indigenous peoples in Canada, an integrated approach is required to address these obstacles. Conclusions. To address the oral health disparities among Indigenous peoples in Canada, policymakers should adopt an integrated approach.
Effect of Serum Level of Vitamin D on External Apical Root Resorption in Maxillary Anterior Teeth in Patients under Fixed Orthodontic Treatment
Authors: Azizi Fatemeh , Karami Nasim , Golshah Amin , Imani Mohammad Moslem , Safari-Faramani Roya
Published: September 2022

Introduction. This study aimed to assess the effect of serum level of vitamin D on external apical root resorption (EARR) in maxillary anterior teeth in patients under fixed orthodontic treatment. Materials and Methods. This retrospective cohort was conducted on patients under fixed orthodontic treatment who were between 12 to 30 years of age. All patients underwent the same treatment technique by the same orthodontist using a 0.022 MBT system. EARR in maxillary anterior teeth was evaluated on pre- and postoperative panoramic radiographs. Blood samples were also collected from patients, and their serum level of vitamin D was measured after the completion of treatment. Data were analyzed by independent t-test and Chi-square test (alpha = 0.05). Results. A reduction in root length was noted in all patients, which was significant (

P
<
0.0001

); 75% of patients showed EARR in at least one maxillary incisor. EARR had no significant correlation with the serum level of vitamin D (

P
=
0.423

). Conclusions. Serum level of vitamin D had no significant correlation with the occurrence of EARR. However, the high prevalence of EARR calls for measures to minimize it.
Prediction of Unbalanced Financial Risk Based on GRA-TOPSIS and SMOTE-CNN
Authors: Li Huiru , Liu Hongjiu , Hu Yanrong
Published: September 2022

The financial status of an enterprise is related to its healthy and long-term development, and whether the interests of investors and bank loans can be guaranteed. To improve the prediction accuracy of corporate financial risk, this paper proposes a prediction model for corporate financial risk that integrates GRA-TOPSIS and SMOTE-CNN. First, using GRA-TOPSIS to make a comprehensive evaluation of the financial situation of listed companies. Second, the evaluation results are clustered to obtain the scientific level and interval of financial risk, which lays the foundation for the supervised learning of the convolutional neural network. Then, the SMOTE algorithm is introduced to solve the problem of data imbalance of enterprises at all levels, and the focal loss function is used instead of the cross-entropy loss function to further balance the data. Finally, the listed companies in A shares are randomly selected, and experiments were designed to verify the performance of the model built in this paper. The results show that the prediction accuracy of the financial risk prediction model based on GRA-TOPSIS and SMOTE-CNN is 98.57%, which indicates that the model is feasible and has certain reference value.
Hybrid Japanese Language Teaching Aid System with Multi-Source Information Fusion Mapping
Authors: Zhang Rui
Published: September 2022

Learning Japanese can enhance competitiveness in a globalized economy, and we address the problems of poor open-source Japanese language teaching, cumbersome teaching tasks, and a single teaching model. We propose a hybrid Japanese teaching aid system with multiple information fusion mapping, which can effectively improve the efficiency of Japanese teaching and reduce the tedious human teaching procedures. The system is divided into two branches of Japanese language recognition, namely, the Japanese text recognition branch and the Japanese voice sequence recognition branch. In the Japanese text recognition branch, we integrate attention mechanisms and long short-term memory networks as the basic network for Japanese character text recognition. In addition, we set up separate text feature recognition systems for Japanese computer writing and handwriting to prevent feature overlap problems. For Japanese voice sequence recognition, we used a combination of memory gating unit and encoder, based on the network still extending the structure of the deep neural network and using the residual structure connection in the gating unit to avoid the gradient disappearance problem. At the end of the system, we use a softmax layer to connect the text recognition and voice recognition networks to form a Japanese language teaching aid system. To verify the efficiency of our system, we selected the Japanese text recognition public dataset and voice recognition public dataset for experimental validation. To match the practical application of the system, we created our dataset based on the dataset standard and conducted experimental validation. To compare other Japanese recognition methods, we selected the six most representative Japanese recognition algorithms for experimental comparison. To ensure the balance of the experiments, each algorithm is trained in a separate experimental environment for modeling and tuning parameters. Experimental performance and the experimental results show that our method significantly outperforms the other methods and has better system stability.
Intelligent Generation and Analysis of the Municipal Road Construction Scheme Based on the KNN Algorithm
Authors: Chenzhong Ren , Wenliang Kan , Taihua Zhou , Dongdong Su , YongLi Geng , Wenzheng Wu
Published: September 2022

The construction of municipal road engineering is a complex system engineering, and its internal components are interconnected and mutually restricted, and the relationship is intricate. The quality of its construction plan directly affects the realization of the project's quality, safety, environment, progress, cost, and other goals, and the project construction plan occupies an important position in the construction of the project. The selection of construction plans for municipal road projects involves a wide range of areas. According to the characteristics of specific municipal road engineering projects, it is very important to establish a scientific construction scheme intelligent generation model and select the optimal construction scheme suitable for the project from many feasible construction schemes, which has very important theoretical research value and practical application value. After analyzing the knowledge characteristics of road construction technology and the content of road construction schemes, this study decomposes the knowledge of road construction schemes into two parts: case characteristics and solutions. Then, according to the needs of case retrieval technology, the data storage form of each subdivision index is proposed and the value range is explained, and a complete structure form of the road construction scheme case database is formed. Combined with actual engineering cases, the feasibility and applicability of the intelligent generation method of the road construction scheme based on the KNN algorithm is confirmed, which provides a new idea for the automation of road construction scheme preparation and the improvement of the scheme application effect.
Relaxin-3 Ameliorates Diabetic Cardiomyopathy by Inhibiting Endoplasmic Reticulum Stress
Authors: Pan Li-ya , Zhang Xiao-hui , Xia Wu-jie , Pan Jia-lin
Published: September 2022

Background. This study is aimed at investigating whether relaxin-3 exhibits protective effects against cardiomyopathy in diabetic rats by suppressing ERS. Methods. Eighty male SD rats were randomly divided into two groups: controls (

n
=
20

) and diabetes (

n
=
60

). The streptozotocin-treated rats were randomly divided into three groups: diabetic group (DM), low-dose relaxin-3 group (0.2 μg/kg/d), and high-dose relaxin-3 group (2 μg/kg/d). The myocardial tissues and collagen fiber were observed by hematoxylin and eosin (H&E) and Masson staining. Serum brain natriuretic peptide (BNP), troponin (TNI), myoglobin, interleukin (IL-17), interleukin (IL)-1α, and tumor necrosis factor (TNF)-α were determined by ELISA. The protein expression of glucose regulatory protein 78 (GRP78) and C/EBP homologous protein (CHOP) in the heart tissue of each group was detected by Western blot analysis. Results. (1) HE and Masson staining indicated that relaxin-3 could attenuate myocardial lesions and myocardial collagen volume fraction. (2) BNP, TnI, and myoglobin in the DM group at four and eight weeks were significantly higher than in the controls (

P
<
0.01

). The relaxin-3-treated groups showed significantly reduced serum BNP, TnI, and myoglobin levels compared with the DM group (

P
<
0.05

). (3) IL-17, IL-1α, and TNF-α levels in the DM rats at 4 weeks were higher than in the controls (

P
<
0.05

). Low or high dose of relaxin-3-treated groups showed reduced serum IL-17 and TNF-α levels compared with the DM group at four and eight weeks (

P
<
0.05

). (4) CHOP and GRP78 protein expression was increased in the DM group at four and eight weeks compared with the controls (

P
<
0.01

), and small and large doses of relaxin-3 significantly reduced GRP78 and CHOP protein expression. Conclusions. Exogenous relaxin-3 ameliorates diabetic cardiomyopathy by inhibiting ERS in diabetic rats.
CAN Signal Extinction-based DoS Attack on In-Vehicle Network
Authors: Lee Yousik , Woo Samuel
Published: September 2022

As automobiles become more electrified, more and more Electronic Control Units (ECU) are installed in vehicles. ECUs communicate with each other through dedicated protocols such as a controller area network (CAN), but these protocols do not have their own security measures. Many cyberattacks have exploited this weakness, but an intrusion detection system (IDS) is emerging as an effective countermeasure. In this study, we introduce a new attack method that existing IDS cannot detect. CAN signal extinction-based DoS attack (CEDA) is a new attack method that uses a voltage drop to erase the CAN signal. When the target ECU transmits a signal, adding a resister that lowers the differential voltage to an undefined gray zone causes the other ECU to ignore the signal being sent from the target ECU. In cybersecurity, denial of service (DoS) is defined as restricting an authorized entity from accessing a resource or delaying a time-critical system. This attack is a kind of a DoS attack since the adversary can make the target ECU bus-off through a CEDA. CEDA could be a serious problem as it has not been detected by any known IDS to date. In this study, we use laboratory and vehicle tests to detail the attack methods and introduce appropriate security measures.
Integrating Feature Engineering with Deep Learning to Conduct Diagnostic and Predictive Analytics for Turbofan Engines
Authors: Wang Chih-Hsuan , Liu Ji-Yu
Published: September 2022

The prediction of remaining useful life (RUL) is a critical issue in many areas, such as aircrafts, ships, automobile, and facility equipment. Although numerous methods have been presented to address this issue, most of them do not consider the impacts of feature engineering. Typical techniques include the wrapper approach (using metaheuristics), the embedded approach (using machine learning), and the extraction approach (using component analysis). For simplicity, this research considers feature selection and feature extraction. In particular, principal component analysis (PCA) and sliced inverse regression (SIR) are adopted in feature extraction while stepwise regression (SR), multivariate adaptive regression splines (MARS), random forest (RF), and extreme gradient boosting (XGB) are used in feature selection. In feature selection, the original 15 sensors can be reduced to only four sensors that accumulate more than 80% degrees of importance and not seriously decrease the predictive performances. In feature extraction, only the top three principal components can account for more than 80% variances of original 15 sensors. Further, PCA combined with RF is more recommended than PCA and CNN (convolutional neural network) because it can achieve satisfactory performances without incurring tedious computation.
A Novel B7-H6–Targeted IgG-Like T Cell–Engaging Antibody for the Treatment of Gastrointestinal Tumors
Authors: Zhang Wei , Auguste Aurélie , Liao Xiaoyun , Walterskirchen Christian , Bauer Kathrin , Lin Yu-Hsi , Yang Ling , Sayedian Farzaneh , Fabits Markus , Bergmann Michael , Binder Carina , Corrales Leticia , Vogt Anne B. , Hudson Lindsey J. , Barnes Martin P. , Bisht Arnima , Giragossian Craig , Voynov Vladimir , Adam Paul J. , Hipp Susanne
Published: September 2022

Purpose:

Advanced-stage gastrointestinal cancers represent a high unmet need requiring new effective therapies. We investigated the antitumor activity of a novel T cell–engaging antibody (B7-H6/CD3 ITE) targeting B7-H6, a tumor-associated antigen that is expressed in gastrointestinal tumors.

Experimental Design:

Membrane proteomics and IHC analysis identified B7-H6 as a tumor-associated antigen in gastrointestinal tumor tissues with no to very little expression in normal tissues. The antitumor activity and mode of action of B7-H6/CD3 ITE was evaluated in in vitro coculture assays, in humanized mouse tumor models, and in colorectal cancer precision cut tumor slice cultures.

Results:

B7-H6 expression was detected in 98% of colorectal cancer, 77% of gastric cancer, and 63% of pancreatic cancer tissue samples. B7-H6/CD3 ITE-mediated redirection of T cells toward B7-H6–positive tumor cells resulted in B7-H6–dependent lysis of tumor cells, activation and proliferation of T cells, and cytokine secretion in in vitro coculture assays, and infiltration of T cells into tumor tissues associated with tumor regression in in vivo colorectal cancer models. In primary patient-derived colorectal cancer precision-cut tumor slice cultures, treatment with B7-H6/CD3 ITE elicited cytokine secretion by endogenous tumor-infiltrating immune cells. Combination with anti-PD-1 further enhanced the activity of the B7-H6/CD3 ITE.

Conclusion:

These data highlight the potential of the B7-H6/CD3 ITE to induce T cell–redirected lysis of tumor cells and recruitment of T cells into noninflamed tumor tissues, leading to antitumor activity in in vitro, in vivo, and human tumor slice cultures, which supports further evaluation in a clinical study.
GSTA4 Governs Melanoma Immune Resistance and Metastasis
Authors: Ucche Sisca , Yokoyama Satoru , Mojic Marija , Oki Kohei , Ohshima Chikako , Tsuihiji Haruka , Takasaki Ichiro , Tahara Hideaki , Hayakawa Yoshihiro
Published: September 2022

Among factors involved in cancer cells escaping from immune responses, an intrinsic defect in the IFNγ response is considered to be one of the major players allowing cancer cells to evade the host immunity. In this study, we investigated how tumor cells escape from the IFNγ-dependent immune response through the immunoediting process by analyzing originally established immune-escape variants of melanoma cells. We found that the immune-escape melanoma variants gained resistance to the IFNγ-induced oxidative stress response and identified glutathione-S-transferase-4 (GSTA4) as a critical molecule in this process. Furthermore, the immune escape melanoma variants acquired a greater metastatic ability by a GSTA4-dependent mechanism.

Implications:

Considering the importance of GSTA4 in controlling IFNγ responsiveness and the metastatic potential of other melanoma cells, our results highlight a novel mechanism whereby cancer cells escape from host immunity and gain metastatic ability by acquiring resistance to oxidative stress responses through the upregulation of GSTA4.
Differences in Variants in the Structural Domain of BCR-ABL1 Kinase between Chinese Han and Minority Patients with Chronic Myeloid Leukemia by Sanger Sequencing and Next-Generation Sequencing
Authors: Abulaiti Dilinazi , Tuerxun Niluopaer , Wang Huan , Abulizi Patiguli , Zhao Fang , Liu Yang , Hao Jianping
Published: September 2022

This study aimed to detect differences in BCR-ABL1 kinase domain (KD) variants in patients with chronic myeloid leukemia (CML) who have been warned and failed in tyrosine kinase inhibitor (TKI) treatment among Chinese Han and ethnic minorities through Sanger sequencing (SS) and next-generation sequencing (NGS), and analyze the difference between SS and NGS detection. Peripheral blood samples from 51 CML patients with warning and failure of TKI therapy were analyzed using SS and NGS, and the detection differences between both sequencing types were compared. BCR-ABL1 KD variants were found in 23.53% of the cohort, including 7 Han Chinese (58.33%) and 5 ethnic minority cases (41.67%). Y253H, F317L, M244V, D276G, F359I, L387F, E459K, E255K, T315I, M351V, and heterozygous insertional mutated genes (ABL1 c.1068_1070dup) were detected. Comparison of the two sequencing assays revealed that NGS could detect compound variants and low frequency variants that were not detected by SS. More compound variants were detected in Han patients than in ethnic minority patients. In conclusion, there is no significant difference in BCR-ABL1 KD mutations between Han and ethnic minority patients. NGS has a higher mutation detection rate than SS, and can detect compound variants and genes with lower mutation frequency that are not detected by SS.
A Mechanistic Clinical Trial Using (
R
)- Versus
(S
)-Propafenone to Test RyR2 (Ryanodine Receptor) Inhibition for the Prevention of Atrial Fibrillation Induction
Authors: Shoemaker M. Benjamin , Yoneda Zachary T. , Crawford Diane M. , Akers Wendell S. , Richardson Travis , Montgomery Jay A. , Phillips Sharon , Shyr Yu , Saavedra Pablo , Estrada Juan C. , Kanagasundram Arvindh , Shen Sharon T. , Michaud Gregory F. , Crossley George , Ellis Christopher R. , Knollmann Bjorn C.
Published: September 2022

Background:

Experimental data suggest ryanodine receptor-mediated intracellular calcium leak is a mechanism for atrial fibrillation (AF), but evidence in humans is still needed. Propafenone is composed of two enantiomers that are equally potent sodium-channel blockers; however,
(R
)-propafenone is an ryanodine receptor inhibitor whereas
(S
)-propafenone is not. This study tested the hypothesis that ryanodine receptor inhibition with
(R
)-propafenone prevents induction of AF compared to
(S
)-propafenone or placebo in patients referred for AF ablation.

Methods:

Participants were randomized 4:4:1 to a one-time intravenous dose of
(R
)-propafenone,
(S
)-propafenone, or placebo. The study drug was given at the start of the procedure and an AF induction protocol using rapid atrial pacing was performed before ablation. The primary endpoint was 30 s of AF or atrial flutter.

Results:

A total of 193 participants were enrolled and 165 (85%) completed the study protocol (median age: 63 years, 58% male, 95% paroxysmal AF). Sustained AF and/or atrial flutter was induced in 60 participants (84.5%) receiving
(R
)-propafenone, 60 (80.0%) receiving
(S
)-propafenone group, and 12 (63.2%) receiving placebo. Atrial flutter occurred significantly more often in the
(R
)-propafenone (N=23, 32.4%) and
(S
)-propafenone (N=26, 34.7%) groups compared to placebo (N=1, 5.3%,
P
=0.029). There was no significant difference between
(R
)-propafenone and
(S
)-propafenone for the primary outcome of AF and/or atrial flutter induction in univariable (
P
=0.522) or multivariable analysis (
P
=0.199, adjusted for age and serum drug level).

Conclusions:

There is no difference in AF inducibility between
(R
)-propafenone and
(S
)-propafenone at clinically relevant concentrations. These results are confounded by a high rate of inducible atrial flutter due to sodium-channel blockade.

Registration:

https://clinicaltrials.gov
; Unique Identifier: NCT02710669.
Not the End of the Story
Authors: van Schaik Anne-Rieke
Published: September 2022

Central to this article are two maps by Floris Balthasarsz van Berckenrode, both on the siege of Grave (1602) by Maurice of Orange during the Dutch Revolt. The first map was in 1602 produced as a news map about the events, the second was a re-edition, published eight years later as a book illustration for Jan Jansz Orlers, Den Nassauschen Lauren-Crans (Leiden 1610). In this article, principles for a new method are introduced to analyse and compare these ‘story maps’ with particular attention to the narrative impact of the map. Using this method in combi-nation with (book) historical research, it argues that the 1610 map should be considered as a ‘memorial map’ that reframes the collective memory of the Dutch Revolt. It emphasizes the dynamic relationship between news, map and book publishing and pleads for a more prominent position of story maps and book illustrations in Early Modern memory landscapes.
Of Poets, Prophets, and Printers
Authors: Penman Leigh T.I.
Published: September 2022

This article identifies the personalities and circumstances behind two previously unknown heterodox religious publishing projects of the seventeenth century. The first was based in Leiden in the United Provinces, while the second originated in Dresden in Electoral Saxony. The Leiden project was likely led by the German jurist Johann Angelius Werdenhagen, who in 1628 had Jacob Böhme’s Weg zu Christo and Anna Ovena Hoyer’s Gespräch Eines Kindes mit seiner Mutter printed in Leiden at the presses of Govert Basson. This project demonstrates Werdenhagen’s centrality in the early distribution of Böhme’s theosophical doctrines in the United Provinces. The Dresden project was funded by Rosine Vogtin, who from 1642 commissioned the office of Gimel Bergen to print works by Jacob Böhme and Ludwig Friedrich Gifftheil.
Three new species of the genus Asceua Thorell, 1887 (Araneae: Zodariidae) from Yunnan Province, China
Authors: LI SONG-LIN , LIU PING , PENG XIAN-JIN
Published: September 2022

Three new species of the genus Asceua Thorell, 1887 are described and named as: A. calciformis sp. nov. (♂♀), A. digitata sp. nov. (♂) and A. forcipiformis sp. nov. (♂♀) from Yunnan province, China. Detailed descriptions, photos of somatic features and copulatory organs, as well as a distribution map are provided.
On the female gonocoxites of Asian, Arabian, and African Clivinini with realignment of the Thliboclivina-, Physoclivina-, and Eoclivina-species groups, and notes on the higher systematics of the tribe Clivinini Rafinesque, 1815 (Coleoptera, Carabidae)
Authors: BALKENOHL MICHAEL
Published: September 2022

Out of the Oriental, Arabian, and African Clivinini, the external female reproductive tracts of 32 genera and subgenera were investigated. Five different basic morphologies were found and within the basic plans, genus-specific variations. The data are compared with the current systematics of the Clivinini at a suprageneric level with focus on the Asian groups. One of the morphologies is completely unknown for Scaritinae. The sixteen species concerned are investigated in more detail and belong to the genus Thliboclivina Kult, the two subgenera Physoclivina Kult and Eoclivina Kult, and the Oriental Clivina attenuata-species group. For these groups, the new subtribe Thliboclivinina subtr. nov. is erected. This arrangement is based on the conspicuous and unique morphology of the female gonocoxite and epipleurite corresponding to several external characters, which are as well unique among the Clivinini. Ecological data support this arrangement. The subgenera Physoclivina and Eoclivina are elevated to genus level (stat. nov.); for the Oriental C. attenuata-species group, the genus Sulciclivina gen. nov. is described. An identification key to the four genera of the subtribe Thliboclivinina subtr. nov. is provided. For Asian, Arabian, and African Clivinini, an overview of the basic shapes of the external female genitalia is provided in the form of examples in a picture catalogue. The species Clivina svenssoni Basilewsky is arranged into the genus Ancus Putzeys (stat. nov.).
Cardiovascular Drug Therapy in Patients with Hepatic Diseases and Patients with Congestive Heart Failure
Authors: Sokol Seth I. , Cheng Angela , Frishman William H. , Kaza Chatargy S.
Published: September 2022

Hepatic impairment can alter the pharmacokinetic profiles of cardiovascular drugs, which can lead to unwanted toxicity. In the presence of cirrhosis, portosystemic shunting occurs and cytochrome P450 activity is reduced. Impaired oxygen uptake caused by changes in the liver's sinusoids, as proposed by the oxygen limitation theory, may also explain the alteration of drug metabolism seen in cirrhosis. With congestive heart failure, sinusoidal congestion and hypoperfusion of the liver are seen. Similar to cirrhosis, the common pathway for hepatic damage in congestive heart failure seems to be liver hypoxia, which may explain the disease's effect on drug metabolism. Since routine hepatic function tests do not always relate to the liver's ability to eliminate drugs, existing guidelines for dosing cardiovascular drugs in patients with hepatic impairment are limited. This article provides guidance for dosing cardiovascular drugs in cirrhotic and heart failure patients based on available research data. Altered drug metabolism, especially in congestive heart failure, tends to be overlooked or not realized in clinical practice. Therefore, further research is needed in congestive heart failure to better elucidate safe prescribing patterns.
Decreased EEG Sensitivity to Alprazolam in Subjects with a Parental History of Alcoholism
Authors: Sarid‐Segal Ofra , Knapp Clifford M. , Ciraulo Ann Marie , Greenblatt David J. , Shader Richard I. , Ciraulo Domenic A.
Published: September 2022

Altered benzodiazepine sensitivity in subjects with a history of parental alcoholism (PHP) compared to control subjects (NC) has been reported for regional brain blood volume, eye movement tasks, and subjective effects. This study tests the hypothesis that PHP subjects are less sensitive to benzodiazepine effects on EEG activity than are NC subjects. Frontal EEG activity was recorded in PHP and NC subjects after administration of the benzodiazepine, alprazolam (1 mg), or placebo. PHP subjects had decreased sensitivity to the EEG effects of alprazolam compared to NC subjects. Significant differences were detected for change in percent relative beta activity and alpha and theta band power. Pharmacokinetic parameters did not differ significantly between groups. These results suggest that PHP subjects are less sensitive to the effects of alprazolam on central electrophysiological activity than are NC subjects.
Lack of Pharmacokinetic Interaction between Sumatriptan and Naproxen
Authors: Srinivasu Poondru , Rambhau Devaraj , Rao Boinpally Ramesh , Rao Yamsani Madhusudan
Published: September 2022

Sumatriptan is a 5HT1D agonist used in the treatment of migraine. Nonsteroidal anti‐inflammatory drugs, β‐blockers, and calcium channel‐blocking antagonists are used in the prophylaxis of migraine. Hence, there is a need to investigate the interaction of these prophylactic drugs with sumatriptan. The interaction of sumatriptan with propranolol, flunarizine, pizotifen, and butorphanol were reported earlier. Naproxen is shown to be effective in prophylactic treatment of migraine. In this study, the authors have investigated the circadian rhythm effect of naproxen on the pharmacokinetics of sumatriptan at 1000 and 2200 hours. Twelve healthy volunteers were treated with 100 mg sumatriptan succinate either alone or along with 500 mg naproxen orally at either 1000 or 2200 hours in a randomized Latin square design with a washout period of 10 days. Serum samples were collected at predetermined time intervals and analyzed for unchanged sumatriptan by high‐performance liquid chromatography. The pharmacokinetic parameters were calculated by using model‐independent methods. Naproxen had no statistically significant (p > 0.05) effect on any pharmacokinetic parameters of sumatriptan both at 1000 and 2200 hours treatment. The results of this study suggest that no alteration in the sumatriptan dosage will be necessary for migraine patients taking naproxen prophylactic therapy.
An Evaluation of the Hemostatic Effect of Externally Applied Notoginseng and Notoginseng Total Saponins
Authors: White C. Michael , Fan Chengde , Chow Moses
Published: September 2022

No effective hemostatic agents are available for external use. This project was conducted to evaluate the hemostatic effects of notoginseng using a hemorrhagic rat model. Rats (n = 40) were divided into four groups, and their tails were transected 5 mm from the tip. Group 1 received no treatment (control), while the other groups received external powder applied to the wound. Group 2 received placebo (flour), group 3 received ground notoginseng, and group 4 received a saponin extract of notoginseng. The total bleeding time was determined and compared between groups. The notoginseng group had lower bleeding times (9.60 ± 1.50 min) than the control group (19.23 ± 4.09 min, p < 0.001) or the placebo group (15.18 ± 2.24 min, p < 0.001). Likewise, the saponin extract group had significantly lower bleeding times (11.70 ± 2.53 min) than the control and placebo groups (p < 0.001 for both comparisons). No differences were found between the notoginseng and the saponin extract groups (p = 0.35). Notoginseng and a saponin extract from notoginseng provide hemostatic effects when applied externally.
Pharmacokinetics, Pharmacodynamics, and Safety of Inhaled Cyclosporin A (ADI628) after Single and Repeated Administration in Healthy Male and Female Subjects and Asthmatic Patients
Authors: Rohatagi S. , Calic F. , Harding N. , Ozoux M‐L. , Bouriot J‐P. , Kirkesseli S. , DeLeij L. , Jensen B. K.
Published: September 2022

Severe asthmatics treated with oral/inhaled corticosteroids are at risk of side effects (adrenal suppression). Oral cyclosporin A has been effective in asthma treatment, and nebulized cyclosporin A has been administered for ∼6 months with no nephrotoxicity or hepatotoxicity, suggesting a wider therapeutic margin for an inhaled cyclosporin A for treatment of asthma. Single‐ and repeated‐dose studies in healthy and asthmatic male and female subjects were conducted to determine the pharmacokinetics, pharmacodynamics, and safety of a new formulation of inhaled cyclosporin A (ADI628) metered‐dose inhaler (MDI). ADI628 had roughly dose‐linear increases in blood concentrations with moderate variability after single and multiple administration in healthy subjects. Steady‐state ADI628 concentrations reflected an effective half‐life of 7.0 to 12.5 hours. No overt gender‐related differences were observed after single inhaled 10 mg ADI628 dose. However, asthmatics and females (20 mg dose group) had lower ADI628 concentrations as compared to healthy males, probably due to lower inspiratory flow rates and probably not due to disease‐ or gender‐related differences in metabolism/elimination of ADI628. Renal excretion was a minor route of elimination for ADI628 with no dose‐ or gender‐related differences. The blood ADI628 exposure in humans was 1/3‐ to 1/6‐fold lower than the no‐effect dose in dogs. Also, the blood ADI628 exposure after the highest inhaled dose was much lower than after the administration of the efficacious oral cyclosporin A dose (3 mg/kg) for treating asthma. The highest steady‐state dose (10 mg bid) resulted in ADI628 concentrations that are not typically associated with systemic nephrotoxicity or immunosuppression. Furthermore, repeated inhaled doses of ADI628 were safe and generally well tolerated with no apparent systemic immunosuppressive activity in healthy and asthmatic subjects.
Bioavailability and Metabolism of Mometasone Furoate following Administration by Metered‐Dose and Dry‐Powder Inhalers in Healthy Human Volunteers
Authors: Affrime Melton B. , Cuss Francis , Padhi Desmond , Wirth Mark , Pai Sudhakar , Clement Robert P. , Lim Josephine , Kantesaria Bhavna , Alton Kevin , Cayen Mitchell N.
Published: September 2022

These studies were conducted to assess the systemic bioavailability of mometasone furoate (MF) administered by both the dry‐powder inhaler (DPI) and the metered‐dose inhaler with an alternate propellant (MDI‐AP). The pharmacokinetics of single doses (400 μg) of MF administered by intravenous (IV) and inhalation routes was assessed in a randomized, three‐way crossover study involving 24 healthy volunteers. In a separate study, 6 healthy subjects were administered a single dose of tritiated (3H‐) MF by DPI, and the radioactivity in blood, urine, feces, and expired air was determined. Following IV administration, MF was detected in all subjects for at least 8 hours postdose. The half‐life (t1/2) following IV administration was 4.5 hours. In contrast, following DPI administration, plasma MF concentrations were below the limit of quantification (LOQ, 50 pg/mL) for many subjects (10 of 24), and the systemic bioavailability by this route was estimated to be less than 1%. Only two plasma samples following MDI‐AP administration had plasma concentrations of MF above the LOQ, indicating no detectable systemic bioavailability in 92% of the subjects. A separate study with 6 healthy male subjects administered a single dose of3H‐MF (200 μCi) by DPI revealed that much of the dose (∼ 41%) was excreted unchanged in the feces (0–72 hours), while that which was absorbed was extensively metabolized. These results indicate that inhaled MF has negligible systemic bioavailability and is extensively metabolized and should therefore be well tolerated in the chronic treatment of asthma.
Reactogenicity Profile of Tetanus‐Diphtheria (Adult‐Type) Vaccine: Results of a Naturalistic Study Performed at an Adult Vaccination Center
Authors: Vilella Ana , Dal‐Ré Rafael , Simó Dulcis , García‐Corbeira Pilar , Diego Pilar , Bayas José‐María
Published: September 2022

A prospective observational naturalistic study was conducted at a vaccination center to assess the reactogenicity of tetanus‐diphtheria (adult‐type) (Td) vaccine. In 1 year, 3072 adult subjects were invited to participate, of whom 1977 (62% women, mean age [± SD]: 39 [± 14.5] years [range: 18–85 years]) actively did so. A follow‐up diary card was provided to all subjects to record all local and general symptoms experienced during the following 4 days after vaccination. Of the study population (n = 1977), 280 received a second Td dose, and 30 received a third dose: the total number of diary cards collected was 2287. Td was always administered (i.m. route) in the left arm. The study population was grouped by age: 52%, 41%, and 7% were ages 18 to 35, 36 to 65, and > 65 years, respectively, most of them beingtravelers to developing countries. Close to two‐thirds of subjects received up to nine different vaccines (mainly hepatitis B, hepatitis A, and typhoid) in addition to Td. Adverse reactions were classified as mild, moderate, and severe. Overall, 50% of subjects reported some type of adverse reaction. Pain, discomfort with arm movement, swelling, malaise, and fever (axillary temperature ≥ 38°C) were recorded in 43%, 14%, 3.8%, 5.1%, and 1.7% of all diary cards, respectively. Local and general reactions were considered as mild by almost two‐thirds of vaccinees and lasted ≤ 48 hours in about three‐fourths of them. The incidence of moderate plus severe local reactions was significantly (p < 0.01) more commonly reported in the 18‐ to 35‐year‐old group than in the 36‐ to 65‐year‐old group. No statistically significant differences were observed when comparing the incidence of general adverse reactions of those receiving Td alone with those receiving additional vaccines or when comparing the duration and intensity by age groups. Only 5.2% of subjects required analgesic/antipyretic treatment. In conclusion, this study shows that Td vaccine is reasonably well tolerated when given alone or with other vaccines. Similar studies should be conducted with other vaccines routinely recommended to adults to assess how they are administered in usual clinical practice and the reactogenicity profile perceived by the vaccinees.
Simvastatin Does Not Affect CYP3A Activity, Quantified by the Erythromycin Breath Test and Oral Midazolam Pharmacokinetics, in Healthy Male Subjects
Authors: Prueksaritanont Thomayant , Vega José M. , Rogers J. Douglas , Gagliano Kathleen , Greenberg Howard E. , Gillen Lisa , Brucker Mary Jo , McLoughlin Debra , Wong Peggy H. , Waldman Scott A.
Published: September 2022

Potential for inhibition of CYP3A activity by simvastatin, an HMG‐CoA reductase inhibitor, was evaluated in 12 healthy male subjects who received placebo or 80 mg of simvastatin, the maximal recommended dose, once daily for 7 consecutive days. On day 7, an intravenous injection of 3 μCi [14C N‐methyl]erythromycin for the erythromycin breath test (EBT) was coadministered with a 2 mg oral solution of midazolam. The values for percent 14C exhaled during the first hour (for EBT) and the pharmacokinetic parameters of midazolam (AUC, Cmax, t1/2) were not affected following multiple once‐daily oral doses of simvastatin 80 mg. The 95% confidence interval was 0.97 to 1.18 for EBT and 0.99 to 1.23 for midazolam AUC. In addition, the total urinary recoveries of midazolam and its 1′‐hydroxy metabolites (free plus conjugate) obtained from both treatments were not statistically different (p > 0.200). These data demonstrate that multiple dosing of simvastatin, at the highest recommended clinical dose, does not significantly alter the in vivo hepatic or intestinal CYP3A4/5 activity as measured by the commonly used EBT and oral midazolam probes.
Rosiglitazone Does Not Alter the Pharmacokinetics of Metformin
Authors: Di Cicco Robert A. , Allen Ann , Carr Alison , Fowles Susan , Jorkasky Diane K. , Freed Martin I.
Published: September 2022

Rosiglitazone is a potent oral antidiabetic agent of the thiazolidinedione class that works through activation of the peroxisome proliferator‐activated nuclear receptor. It improves insulin sensitivity in peripheral tissues and effectively lowers blood glucose in patients with type 2 diabetes. Metformin is a dimethyl‐biguanide, also used in type 2 diabetes, that lowers fasting blood glucose primarily by decreasing hepatic glucose output. Rosiglitazone and metformin reduce plasma glucose concentrations via different mechanisms and thus could potentially be used in combination to optimize glycemic control. This study evaluated the effects of the coadministration of these two agents on the pharmacokinetics of both rosiglitazone and metformin. Sixteen male volunteers (22–55 years old) received oral metformin (500 mg every 12 hours), rosiglitazone (2 mg every 12 hours), or the combination each for 4 days. Plasma collected on day 4 of each regimen was assayed for rosiglitazone and metformin concentrations. Oral doses of rosiglitazone and metformin were safe and well tolerated when administered alone or in combination. There were no clinically significant episodes of hypoglycemia or increased blood lactic acid levels following treatment with any regimen. Coadministration of rosiglitazone and metformin had no significant effects on the steady‐state pharmacokinetics (AUC(0‐12h), Cmax, tmax, or t1/2) of either drug. The authors conclude that rosiglitazone can be safely administered with metformin and, due to the different mechanisms of action of these agents, may offer a therapeutic advantage in patients with type 2 diabetes mellitus.
Morphine‐Fluoxetine Interactions in Healthy Volunteers: Analgesia and Side Effects
Authors: Erjavec Miklavz K. , Coda Barbara A. , Nguyen Quynh , Donaldson Gary , Risler Linda , Shen Danny D.
Published: September 2022

The authors evaluated the ability of fluoxetine, a selective serotonin reuptake inhibitor (SSRI), to enhance the analgesic potency of morphine. Fifteen volunteers participated in this double‐blind crossover study. All received combinations of morphine or saline with either fluoxetine 30 mg or placebo. The authors used individual morphine pharmacokinetics to program an infusion pump to achieve plasma morphine levels of 15, 30, and 60 ng/ml. Analgesia during morphine infusion was assessed using a model of electrical tooth stimulation. Subjective side effects, measurements of end‐tidal CO2, O2 saturation, pupil size, and testing of psychomotor performance were obtained. Plasma morphine concentrations were not affected by fluoxetine. In comparison to placebo, oral fluoxetine resulted in less sedation during morphine infusion and less nausea during morphine washout. Morphine‐induced pruritus, psychomotor function, and respiratory depression were unaffected by fluoxetine. Acute administration of 30 mg oral fluoxetine augmented analgesia by approximately 3% to 8% and reduced morphine‐associated nausea, mood reduction, and drowsiness.
Optimizing the Use of Biomarkers, Surrogate Endpoints, and Clinical Endpoints for More Efficient Drug Development
Authors: Colburn Wayne A.
Published: September 2022

Biomarkers and surrogate endpoints are critical to the future of efficient drug development. Definitions, a conceptual model, and a conceptual framework for validating and bridging biomarkers to clinical endpoints are provided in this presentation. In addition, a few examples are provided to support the development concept. Poor correlation between a biomarker and its clinical endpoint may result from (1) poor measurement of one or both, (2) selection of an inappropriate biomarker, or, more important, (3) use of an inappropriate clinical endpoint. Pharmacokinetic/pharmacodynamic (PK/PD) modeling output can be no better than biomarkers or surrogate endpoints used for the modeling. As we increase our understanding of biomarkers, surrogate markers, and the mechanistic basis for the processes of interest, biomarker and surrogate endpoint predictive power will no longer be an issue and PK/PD modeling inputs and outputs will improve.
Pharmacokinetics of Pilocarpine in Subjects with Varying Degrees of Renal Function
Authors: Peter John V. St. , Lambrecht Lawrence J. , Gunderson Brent W. , Andersen Scott A. , Gallagher Susan C. , Swan Suzanne K.
Published: September 2022

Data from three separate single‐center studies were combined to assess the pharmacokinetics of orally administered pilocarpine. Pilocarpine concentration‐time data were used to generate a data set including 42 subjects (34 males, 8 females) with varying degrees of renal function (average of two estimated creatinine clearance rates of 10 to 112 mL/min). Age ranged from 19 to 88 years. Subjects received single oral doses (range: 2.5–20 mg) of pilocarpine. Plasma samples were collected at time 0; at 20 and 40 minutes; and at 1, 1.5, 2, 3, 4, 6, 8, 12, 16, and 24 hours following dose administration. Cmax and AUC were normalized to a 5 mg exposure in those subjects who received doses other than 5 mg. Plasma pilocarpine concentrations were determined by gas chromatography/mass spectrometry. The pharmacokinetic parameters (elimination rate constant, Cmax, tmax, AUC, Vd/F, and Cl/F) in subjects with impaired renal function were similar to results found in other pharmacokinetic studies involving normal healthy volunteers with only Cmax being significantly higher (p < 0.05). No significant regression relationships were noted between creatinine clearance and pilocarpine elimination rate constant, tmax, Vd/F, Cl/F, or AUC. Pilocarpine clearance does not appear to be impaired in patients with varying degrees of renal insufficiency.
Effects of Cholestyramine on Vitamin E Levels in Patients Treated with Statins
Authors: Kersting Friedrich , Selenka Angelika , Walch Stefan
Published: September 2022

The aim of this study was to investigate the effects of cholestyramine in combination with statins on vitamin E levels and their concentration related to LDL‐cholesterol (LDL‐C) in patients with hyperlipidemia. In an open‐label, randomized study of 25 patients with elevated LDL‐C, 12 received cholestyramine (12 g/d) in addition to chronic statin therapy, which had been started at least 8 weeks prior to the study in all patients. At the start and end of the 12‐week study period, vitamin E concentrations were measured by high‐performance liquid chromatography and cholesterol and triglycerides enzymatically in all patients. Vitamin E levels remained virtually unchanged within normal range before (11.90 ± 0.71 mg/l) and after 12 weeks (11.69 ± 0.82 mg/l) of concomitant therapy with cholestyramine. However, the ratio of vitamin E/LDL‐C increased from 7.48 ± 0.56 to 8.58 ± 0.75 (× 10−2) (p < 0.09) in the cholestyramine group but not in the control group. LDL‐C concentrations decreased from 162.00 ± 5.98 to 144.33 ± 12.48 mg/dl. The authors conclude that cholestyramine 12 g/d given for 12 weeks in addition to chronic statin therapy did not lower vitamin E levels in hyperlipemic patients. However, antioxidant status (vitamin E/LDL‐C ratio) seems to be improved by a cholestyramine‐associated LDL‐C decrease.