bluuebunny/crossref_metadata_2025 huggingface dataset:
Examination of the Healthy Caregiver Effect among Older Adults: Findings from the Canadian Longitudinal Study on Aging
Authors: Li Lun , Wister Andrew Victor , Mitchell Barbara A.
Published: September 2022

Introduction: The Healthy Caregiver Hypothesis (HCH) suggests that caregiving is associated with beneficial health impacts for family caregivers. However, mixed results have been reported, particularly when different levels of caregiving intensity were examined. This study analyzes the relationship between caregiving intensity and three health indicators (functional health, chronic illness, and self-rated general health) among Canadian older adults over 3 years. Methods: We drew upon a subsample of 11,344 participants aged 65 years and older from the Baseline and Follow-up 1 data of the Canadian Longitudinal Study on Aging and used linear mixed models to test the hypothesis based on different levels of caregiving intensity. Results: Older adults who provided low-intensity care recently or continuously reported better functional health and self-rated health than noncaregivers. In contrast, older adults with low-intensity caregiving responsibility reported more chronic conditions over time compared to noncaregivers, but this association was not found for high-intensity caregivers. Discussion/Conclusion: This study elucidates the HCH by incorporating caregiving intensity to understand patterns of better functional health and perceived health but more chronic conditions. The findings yielded from different health indicators suggest the impact of caregiving on health may be domain specific.
Efficacy and Safety of Vagus Nerve Stimulation in Stroke Rehabilitation: A Systematic Review and Meta-Analysis
Authors: Ananda Roshan , Roslan Mohd Hariz Bin , Wong Lin Ling , Botross Nevein Philip , Ngim Chin Fang , Mariapun Jeevitha
Published: September 2022

Introduction: Recent randomized controlled trials (RCTs) have assessed the role of vagus nerve stimulation (VNS) when paired with standard rehabilitation in stroke patients. This review aimed to evaluate the efficacy and safety of VNS as a novel treatment option for post-stroke recovery. Methods: We searched PubMed, EMBASE, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials (CENTRAL), and CINAHL Plus for articles published from their date of inception to June 2021. RCTs investigating the efficacy or safety of VNS on post-stroke recovery were included. The outcomes were upper limb sensorimotor function, health-related quality of life, level of independence, cardiovascular effects, and adverse events. The risk of bias was assessed using the Cochrane risk-of-bias tool, while the certainty of the evidence was assessed using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) criteria. Review Manager 5.4 was used to conduct the meta-analysis. Results: Seven RCTs (n = 236 subjects) met the eligibility criteria. Upper limb sensorimotor function, assessed by the Fugl-Meyer Assessment for Upper Extremity (FMA-UE), improved at day 1 (n = 4 RCTs; standardized mean difference [SMD] 1.01; 95% confidence interval [CI]: 0.35–1.66) and day 90 post-intervention (n = 3 RCTs; SMD 0.64; 95% CI: 0.31–0.98; moderate certainty of evidence) but not at day 30 follow-up (n = 2 RCTs; SMD 1.54; 95% CI: −0.39 to 3.46). Clinically significant upper limb sensorimotor function recovery, as defined by ≥6 points increase in FMA-UE, was significantly higher at day 1 (n = 2 RCTs; risk ratio [RR] 2.01; 95% CI: 1.02–3.94) and day 90 post-intervention (n = 2 RCTs; RR 2.14; 95% CI: 1.32–3.45; moderate certainty of the evidence). The between-group effect sizes for upper limb sensorimotor function recovery was medium to large (Hedges’ g 0.535–2.659). While the level of independence improved with VNS, its impact on health-related quality of life remains unclear as this was only studied in two trials with mixed results. Generally, adverse events reported were mild and self-limiting. Conclusion: VNS may be an effective and safe adjunct to standard rehabilitation for post-stroke recovery; however, its clinical significance and long-term efficacy and safety remain unclear.
An Extremely Rare Case of Thyroid Metastasis from Advanced Gastric Cancer
Authors: Lee Woo Yong , Yoon Byung Woo
Published: September 2022

Metastases to the thyroid area are extremely rare in cancer, more specifically, in gastric cancer, where intraperitoneal metastases are absent. Herein, we describe a case of a 41-year-old man who had advanced gastric cancer with metastasis to the right thyroid area, which was found 6 years after curative surgery. The patient presented with multiple enlarged right cervical lymph nodes and a right thyroid mass of 1.2 cm. We assumed that the patient had primary thyroid cancer as he had no signs of other metastases. We performed fine-needle cytology under ultrasonography on the thyroid nodule. However, with a positive carcinoembryonic antigen and a negative thyroid transcription factor 1 immunohistochemical staining results, the patient was diagnosed with metastatic adenocarcinoma that was of gastric origin. Subsequently, the patient was treated with radiotherapy and chemotherapy. This report aimed to raise the concern that gastric cancer may cause metastasis to the peri-thyroid area, involving the thyroid, parathyroid, and regional lymph nodes.
Calcified Epidural Hematoma after Conservative Treatment of Acute Epidural Hematoma in the Pediatric Population: A Systematic Review
Authors: D’Andrea Marcello , Mongardi Lorenzo , Cultrera Francesco , Fuschillo Dalila , Peraio Simone , Roblot Paul , Musio Antonio , Tosatto Luigino , Giordano Flavio
Published: September 2022

Background: Acute traumatic epidural hematoma (EDH) is a complication in 2–3% of pediatric head injuries. Surgery is mandatory in symptomatic cases; otherwise, conservative treatment is a valid approach, especially in the pediatric population. Ossified epidural hematomas (OEHs) have been reported in the pediatric population as a rare complication of conservative EDH management, although the exact incidence remains unknown. The progressive increase in conservative management may lead to increases in the OEH incidence over the next few years. Our study aimed to systematically review OEH incidence, management strategies, characteristics (thickness, inner/outer calcifications), complication rates, time to surgery after the EDH diagnosis, and clinical outcomes. Summary: A systematic review was conducted in accordance with the PRISMA guidelines. Studies reporting diagnoses and clear descriptions of OEH after EDH in pediatric patients were considered eligible. Sixteen studies, including 18 pediatric patients aged 0–18 years, were included. Head trauma was the most common cause of OEH. Seven (38.8%) OEHs were treated less than 1 month after EDH diagnosis. Surgery was performed in 17 cases (94.44%), while 1 asymptomatic case (5.56%) was managed conservatively. Key Messages: Surgery was the most commonly used treatment for OEH. Data for conservative treatment of OEH are limited. Magnetic resonance imaging or ultrasound within the first 2 months, to check for EDH resolution, may be crucial to rule out complications in pediatric patients.
Left Bundle Branch Pacing Postatrioventricular Junction Ablation for Atrial Fibrillation: Propensity Score Matching With His Bundle Pacing
Authors: Cai Mengxing , Wu Shengjie , Wang Songjie , Zheng Rujie , Jiang Limeng , Lian Liyou , He Yanlei , Zhu Ling , Xu Lei , Ellenbogen Kenneth A. , Whinnett Zachary I. , Su Lan , Huang Weijian
Published: September 2022

Background:

Left bundle branch pacing (LBBP) has emerged as a promising pacing modality to preserve physiological left ventricular activation; however, prospective data evaluating its long-term safety and efficacy in pacemaker-dependent patients following atrioventricular junction (AVJ) ablation are lacking. This study aimed to examine the feasibility, safety, and efficacy of LBBP in patients with atrial fibrillation and heart failure (HF) after AVJ ablation and compare LBBP with His bundle pacing (HBP) through a propensity score (PS) matching analysis.

Methods:

We prospectively enrolled patients with atrial fibrillation and HF referred for AVJ ablation and LBBP between July 2017 and December 2019. The control group was patients selected from HBP implants performed from 2012 to 2019 using PS matching with a 1:1 ratio.

Results:

A total of 99 patients were enrolled in the study. The LBBP implant success rate was 100%. Left ventricular ejection fraction improved from baseline 30.3±4.9 to 1-year 47.3±14.5 in HF patients with reduced ejection fraction and from baseline 56.3±12.1 to 1-year 62.3±9.1 in HF patients with preserved ejection fraction (both
P
<0.001), and left ventricular ejection fraction in both groups remained stable for up to 3 years of follow-up. A threshold increase >2 V at 0.5 ms occurred in only one patient. Of 176 (81.9%) of 215 patients who received permanent HBP post-AVJ ablation, 86 were matched to the LBBP group by 1:1 PS (propensity score matched His bundle pacing, N=86; propensity score matched left bundle branch pacing, N=86). No significant differences in echocardiographic or clinical outcomes were observed between the 2 groups (
P
>0.05), whereas lower thresholds, greater sensed R-wave amplitudes, and fewer complications were observed in the propensity score matched left bundle branch pacing group (
P
<0.05).

Conclusions:

LBBP is feasible, safe, and effective in patients with atrial fibrillation and HF post-AVJ ablation and has similar clinical benefits, a higher implant success rate, better pacing parameters, and fewer complications compared with HBP.
The etymology of three enigmatic (sub-)specific names clarified
Authors: Klaver Charles
Published: September 2022

Consulting the Reptile Database disclosed the absence of an etymology of three enigmatic reptilian (sub-) specific names. An elucidation on behalf of especially non-German-speaking colleagues is provided.
Wolfeniana, a new replacement name for fossil Pteridophyte genus Gillespiea Erwin & Rothwell (Stauropteridales)
Authors: DESHMUKH UMAKANT BHOOPATI
Published: September 2022

N/A
Two new genera and six new species of Terrestrial Hydrometridae (Hemiptera: Heteroptera) from French Polynesia
Authors: POLHEMUS DAN A.
Published: September 2022

The family Hydrometridae (Hemiptera: Heteroptera) has been previously recorded from French Polynesia based on three species in three genera: Chaetometra robusta (Hungerford, 1939) and Dolichocephalometra pacifica (Van Duzee, 1934) from the Marquesas Islands, and Hydrometra gagnei J. Polhemus & D. Polhemus, 1995 from Tahiti in the Society Islands. Based on recent surveys from montane cloud forest habitats, two new genera and and six new species of Hydrometridae are described from the Marquesas and Society Islands as follows: Marquesametra n. gen. from the Marquesas Islands, containing M. hivaoa n. sp. from Hiva Oa (Mt. Temetiu); and Prohydrometra n. gen. from the Society Islands, containing the previously described P. gagnei n. comb. from Tahiti (Tahiti Nui), and the five new species P. johnpolhemi n. sp. and P. englundi n. sp. from Raiatea (Trois Cascade and Mt. Toomaru respectively); P. tohiea n. sp. and P. moorea n. sp. from Moorea (both from Mt. Tohiea); and P. teatara n. sp. from Tahiti (Mts. Teatara). All of these new species are terrestrial, and with the exception of P. johnpolhemi, which inhabits rheocrenes, represent specialized inhabitants of upland wet forest habitats. This indicates that terrestrial ecologies have evolved multiple times within the Hydrometridae, and are the typical mode of life for species of this family occurring in the insular eastern Pacific.
A new species of the genus Achalinus (Squamata: Xenodermidae) from Ningshan County, Shaanxi Province, China
Authors: YANG DIAN-CHENG , HUANG RU-YI , JIANG KE , BURBRINK FRANK T. , GONG YAN-AN , YU JING , ZHANG YI , HUANG TIAN-QI , HUANG SONG
Published: September 2022

A new species of odd-scaled snake in the genus Achalinus is described from Ningshan County, Shaanxi Province, China, based on seven female specimens. Morphologically, the new species can be distinguished from its congeners by the following combination of characters: (1) dorsum iridescent and uniformly dark brown in preservative, longitudinal vertebral line absent; (2) light brown beneath; (3) dotted black streak in the middle of the subcaudals absent; (4) tail length relatively short, TaL/ToL 12–16%, in females; (5) fewer subcaudals, 41–46 in females; (6) dorsal scales 23 rows throughout, strongly keeled; the outer-most rows on both sides are also keeled and slightly enlarged; (7) one loreal; (8) internasal not fused to prefrontal; (9) suture between internasals is similar in size when compared to the suture between prefrontals; (10) preocular and postocular absent; (11) 6 supralabials; (12) 5 infralabials, the first 3 (rarely 2) touching the first pair of chin shields; (13) 3 pairs of chin shields. A phylogenetic analysis using mitochondrial gene, cytochrome c oxidase subunit 1 (CO1), showed that this new species forms a monophyletic group with strong support. In addition, the uncorrected p-distances between the new species and other known congeners ranged from 3.4% to 13.0%. The recognition of the new species increases the number of described Achalinus species to 21.
Description of Maghreboniscus rojasi sp. nov. from Southern Spain and validation of the genus by the designation of a type species (Isopoda: Oniscidea: Spelaeoniscidae)
Authors: GARCIA LLUC
Published: September 2022

A new species of terrestrial isopod genus Maghreboniscus Vandel, 1959, from the southernmost Iberian Peninsula, is described and illustrated: Maghreboniscus rojasi sp. nov. The finding represents the first record on the European continent of a representative of this genus, of which only three species had been described so far, all of them known from Africa. This paper also validates the genus Maghreboniscus and designates M. palmetensis Vandel, 1959 as its type species. A key to distinguishing the species of this genus is also provided.
Two new synonyms among Panchaetothripinae (Thysanoptera: Thripidae) with three species newly recorded from China
Authors: WANG ZHAOHONG , MOUND LAURENCE , MAO RUNQIAN , TONG XIAOLI
Published: September 2022

Helionothrips mube and Panchaetothrips bifurcus are here recognized as new synonyms of Helionothrips aino and Panchaetothrips timonii based on large numbers of specimens and continuous morphological differences. Three species, Caliothrips insularis, Hercinothrips femoralis and Phibalothrips rugosus are newly recorded from China and the previous record of Caliothrips indicus from China is here considered incorrect. Illustrations of males and larvae of Hercinothrips femoralis are also provided.
CYP2D6 Inhibition by Fluoxetine, Paroxetine, Sertraline, and Venlafaxine in a Crossover Study: Intraindividual Variability and Plasma Concentration Correlations
Authors: Alfaro Cam L. , Lam Y. W. Francis , Simpson Joseph , Ereshefsky Larry
Published: September 2022

The authors report the CYP2D6 inhibitory effects of fluoxetine, paroxetine, sertraline, and venlafaxine in an open‐label, multiple‐dose, crossover design. Twelve CYP2D6 extensive metabolizers were phenotyped, using the dextromethorphan/dextrorphan (DM/DX) urinary ratio, before and after administration of fluoxetine 60 mg (loading dose strategy), paroxetine 20 mg, sertraline 100 mg, and venlafaxine 150 mg. Paroxetine, sertraline, and venlafaxine sequences were randomized with 2‐week washouts between treatments; fluoxetine was the last antidepressant (AD) administered. Comparing within groups, baseline DM/DX ratios (0.017) were significantly lower than DM/DX ratios after treatment (DM/DXAD) with fluoxetine (0.313, p < 0.0001) and paroxetine (0.601, p < 0.0001) but not for sertraline (0.026, p = 0.066) or venlafaxine (0.023, p = 0.485). Between groups, DM/DXAD ratios were significantly higher for fluoxetine and paroxetine compared to sertraline and venlafaxine. No differences between DM/DXAD ratios were found for fluoxetine and paroxetine although more subjects phenocopied to PM status after receiving the latter (42% vs. 83%; χ2 = 4.44, p = 0.049, df = 1). Similarly, no differences between DM/DXAD ratios were found for sertraline and venlafaxine. Of note, the DM/DXAD for 1 subject was much lower after treatment with paroxetine (0.058) compared to fluoxetine (0.490), while another subject exhibited a much lower ratio after treatment with fluoxetine (0.095) compared to paroxetine (0.397). Significant correlations between AD plasma concentration and DM/DXAD were found for paroxetine (r2 = 0.404, p = 0.026) and sertraline (r2 = 0.64, p = 0.002) but not fluoxetine or venlafaxine. In addition, DM/DXAD correlated with baseline isoenzyme activity for paroxetine, sertraline, and venlafaxine groups. These results demonstrate the potent, but variable, CYP2D6 inhibition of fluoxetine and paroxetine compared to sertraline and venlafaxine. CYP2D6 inhibition may be related, in part, to dose, plasma concentration, and baseline isoenzyme activity, and these correlations merit further investigation.
Rizatriptan, a Novel 5‐HT1B/1D Agonist for Migraine: Single‐ and Multiple‐Dose Tolerability and Pharmacokinetics in Healthy Subjects
Authors: Goldberg Michael R. , Lee Yih , Vyas Kamlesh P. , Slaughter Donald E. , Panebianco Deborah , Ermlich Susan J. , Shadle Craig R. , Brucker Mary Jo , McLoughlin Debra A. , Olah Timothy V.
Published: September 2022

Rizatriptan is a novel 5‐HT1D/1B agonist for relief of migraine headache. The pharmacokinetics, metabolite profiles, and tolerability of rizatriptan were examined in a multiple‐dose study in healthy subjects. Rizatriptan (N = 24) (orplacebo, N = 12) was administered as a single 10 mg dose, followed 48 hours later by administration of one 10 mg dose every 2 hours for three doses on 4 consecutive days, corresponding to the maximum daily dose for a migraine attack. The AUC of rizatriptan and its active N‐monodesmethyl metabolite after three 10 mg doses was approximately threefold greater than the plasma concentrations following a single 10 mg dose. Metabolite profiles were similar after single and multiple doses. Adverse events during rizatriptan were mild and transient; similar events occurred during placebo, with a somewhat reduced incidence. Diastolic blood pressure tended to increase compared with placebo (∼5 mmHg), particularly on the first multiple‐dose day (p < .01 vs. placebo). In conclusion, rizatriptan is well tolerated by healthy subjects during multiple‐dose administration, with no unexpected accumulation of drug in plasma.
Adverse Drug Reactions: A Review of Relevant Factors
Authors: Ajayi Funmilayo O. , Sun He , Perry Julie
Published: September 2022

We examined some of the factors that contribute to the development of adverse drug reactions (ADRs) and analyzed postmarketing ADR reports for 22 drugs. The role of metabolic‐based drug‐drug interaction in the development of ADRs can not be overstated. Assessment of the postmarketing ADR data for 22 drugs revealed that drugs with high potential for eliciting clinically significant ADRs are usually detected and either withdrawn from the market or placed on restricted use within the first year or two of marketing. Postmarketing data could be a useful tool for understanding the ADR profile of drugs if reporting can be adequately monitored and verified. It is hoped that early evaluation of the clinically meaningful factors such as metabolism, pharmacogenetics, and effect of physiologic and pathophysiologic states on the clinical effect of a drug during drug development would significantly reduce the incidence and severity of post‐marketing ADRs.
A Contract Research Organization's Response to the New FDA Guidances for Bioequivalence/Bioavailability Studies for Orally Administered Drug Products
Authors: Kimanani Ebi , Stypinski Daria , Curtis Gary , Stiles Mark , Heessels Peter , Logan Scott , Nelson Kim , Germain Ellen St. , Boswell Garry
Published: September 2022

The new FDA Guidance for Industry BA and BE Studies for Orally Administered Drug Products ‐ General Considerations and Average, Population, and Individual Approaches to Establishing Bioequivalence imply significant changes in the areas of enrollment, cost, ethics, time, entry, validation applications (EVAs), and statistical and pharmacokinetic methods. The changes from three‐period to two‐period design for food effect studies, the elimination of most steady state studies, and the analyses of only the active moiety or ingredient are welcome. However, if the current guidances are adopted, additional time will be needed for participants, and more participants will be needed, resulting in higher costs to drug developers. The PK parameters needed to assess BE and the need for replicate designs for drugs with long t1/2 are still unclear. Finally, the advantages of the aggregate property of the FDA metric versus the disaggregate criteria are challenged, and four bioequivalence criteria are proposed.
The Relationship between Terazosin Dose and Blood Pressure Response in Hypertensive Patients
Authors: Achari Ramanuj , Hosmane Balakrishna , Bonacci Ernimio , O'Dea Robert
Published: September 2022

A double‐blind, randomized, placebo‐controlled, multicenter study was conducted to describe the dose‐response curve for terazosin on blood pressure. A total of 128 patients with mild to moderate essential hypertension (supine diastolic blood pressure, 100 to 114 mmHg) participated in the study. The study consisted of a 4‐week single‐blind placebo lead‐in period and a 14‐week double‐blind treatment period. Patients were randomized in equal numbers to four parallel treatment groups: terazosin 1, 2, and 5 mg; terazosin 2, 5, and 10 mg; terazosin 20, 40, and 80 mg; and placebo. The 24‐hour ambulatory blood pressure measurements were performed at the end of the placebo lead‐in period and at the end of each 4‐week fixed‐dose period. The nonlinear, mixed‐effect model computer program was used to analyze the dose‐response relationship. There was a strong dose‐response relationship between fall in blood pressure and the 1 to 10 mg terazosin dose, as well as a plateauing of response for terazosin doses above 10 mg. The maximum antihypertensive response (Emax) to terazosin was 10.7 mmHg for systolic blood pressure and 8.0 mmHg for diastolic blood pressure. The daily dose of terazosin, which produced 50% of the maximum response (ED50), was 3.0 mg for systolic blood pressure and 1.5 mg for diastolic blood pressure. The results of this study suggest that although some patients may benefit from terazosin doses of greater than 10 mg, doses up to 10 mg will maximize therapeutic benefit for most patients, with acceptable side effects.
The Pursuit of Clinical Truth: Role of Epidemiology/Observation Studies
Authors: Spector Reynold , Vesell Elliot S.
Published: September 2022

The need for evidence‐based medicine as a foundation for optimal patient care requires application of the best scientific methods. Various methods used in the search for clinical truth are discussed. The most powerful method to test a clinical hypothesis is the randomized, controlled clinical trial. By contrast, epidemiology/observation studies (EOS) have inherent weaknesses that can lead to erroneous conclusions. Five such examples, two older and three very recent, are discussed to provide historical perspective and demonstrate potential problems with EOS. Each incident has produced widespread consternation or confusion among physicians. Types of bias leading to errors in EOS are discussed, and the need is emphasized for more rigorous evaluation of EOS by investigators, as well as editors, to avoid repetition of past mistakes and to ensure publication of correct medical information.
Pharmacokinetics, Pharmacodynamics, and Safety of a Platelet GPIIb/IIIa Antagonist, RGD891, following Intravenous Administration in Healthy Male Volunteers
Authors: Zannikos Peter N. , Rohatagi Shashank , Jensen Bradford K. , DePhillips Susan L. , Massignon Denis , Calic Francoise , Sibille Michel , Kirkesseli Stephane
Published: September 2022

The pharmacokinetics (PK), pharmacodynamics (PD), and safety of a platelet GPIIb/IIIa receptor antagonist, RGD891, and its active metabolite, RGD039, were evaluated after administration of various intravenous regimens of RGD891 to healthy male volunteers in two Phase I studies. Plasma and urine concentrations of RGD891 and RGD039 were measured by validatedLC/MS/MS methods with minimum quantifiable limit (MQL) of 1 ng/mL and 10 ng/mL, respectively. PD activity was assessed by percent inhibition of ADP (20 μM)‐induced platelet aggregation. Following intravenous dosing, the RGD891 was the predominant compound in plasma. The PK of RGD891 was dose independent associated with modest between‐subject variability. RGD891 was rapidly cleared (Cl, 11.2–15.5 L/h), exhibited a restricted distribution (Vss, 23.0–25.9L) and a short terminal t1/2ΛXz (1.2‐2.1 h). Plasma concentrations of the metabolite (RGD039) increased with dose but were variable. RGD039 had longer t1/2Λz of 4.5 to 6.6hours. Renal excretion of unchanged drug played an important role in the elimination of the parent compound. Both RGD891 and RGD039 exhibited renal clearance values that were comparable to the glomerular filtration rate. Intravenous administration of RGD891 effectively inhibited platelet aggregation in a dose‐dependent and reversible manner. At the highest dose (60 μg/kg bolus dose + 336 μg/kg 8‐h infusion) > 90% inhibition of platelet aggregation was achieved. PD activity was primarily attributed to the parent compound. Inhibition of platelet aggregation was dependent on the anticoagulant present, with samples containing PPACK showing 20% to 30% lower activity as compared to citrate. RGD891 was safe and well tolerated across the various regimens studied.
Effect of Chlorpromazine and Clozapine on Plasma Concentrations of Haloperidol in a Patient with Schizophrenia
Authors: Allen Sharon A.
Published: September 2022

A 40‐year‐old patient being treated for schizophrenia developed elevated plasma levels of haloperidol (HAL) in combination with chlorpromazine (CPZ) and during overlap treatment with clozapine. Competitive inhibition of HAL by first CPZ and then clozapine is discussed as a possible mechanism.
Pharmacokinetics of Acetaminophen and Ibuprofen When Coadministered with Telmisartan in Healthy Volunteers
Authors: Stangier Joachim , Su Chung‐An P. F. , Fraunhofer A. , Tetzloff W.
Published: September 2022

Two open‐label, two‐way, crossover studies were performed to assess any pharmacokinetic interaction of telmisartan with either acetaminophen oribuprofen. Healthy male adult volunteers (n = 12) received a single oral dose of acetaminophen 1 g alone and with oral telmisartan 120 mg in one study. Oral ibuprofen 400 mg three times daily with and without oral once‐daily telmisartan 120 mg was given for 7 days in the other study conducted in 6 males and 6 females. In both studies, there was a washout period of ≥ 13 days between single and combination medication administration. The primary end points Cmax and AUC were compared between combination (acetaminophen or ibuprofen + telmisartan) and single‐agent medications (acetaminophen or ibuprofen). Pharmacokinetic drug interaction was assessed by analysis of variance (ANOVA) and calculation of 90% confidence intervals (CI) for treatment ratios using log‐transformed parameters. Bioequivalence (i.e., lack of interaction) was concluded ifthe90% CI of the ratios for both Cmax and AUC were within the acceptance limit of 0.80 to 1.25. Geometric mean Cmax values for acetaminophen and R‐(−)‐ and S‐(+)‐ibuprofen enantiomers were similar with and without telmisartan coadministration (12.6 μg/mL vs. 14.1 μg/mL; 17.3 μg/mL vs. 16.7 μg/mL; 19.4 μg/mL vs. 19.5 μg/mL, respectively), and values for R‐(−)‐ as well as S‐(+)‐ibuprofen were bioequivalent. Geometric mean AUC values for acetaminophen and R‐(−)‐ and S‐(+)‐ibuprofen were also bioequivalent with and without telmisartan. The distribution and elimination parameters of both acetaminophen and ibuprofen were comparable in the presence or absence of telmisartan. The concomitant and single‐agent medications were all well tolerated. In conclusion, the long half‐life and excellent safety profile of telmisartan were unaffected by concurrent acetaminophen or ibuprofen medication; thus, once‐daily dosing of telmisartan can be maintained, which may help to optimize patient compliance, and patients may self‐administer concomitant acetaminophen or ibuprofen.
Pharmacokinetics of Repeated Oral Doses of Amlodipine and Amlodipine plus Telmisartan in Healthy Volunteers
Authors: Stangier Joachim , Su Chung‐An P. F.
Published: September 2022

This open‐label, crossover study was performed to establish if there is evidence for interaction between telmisartan, an angiotensin II antagonist, and amlodipine, a class II (dihydropyridine) calcium channel antagonist, on the basis of pharmacokinetics and safety. In a two‐way crossover trial, 12 healthy Caucasian males were randomized to receive once daily for 9 days oral amlodipine 10 mg with or without oral telmisartan 120 mg. After a washout period of ≥ 13 days, the subjects were switched to the other medication regimen. The geometric means of the primary pharmacokinetic parameters at steady state (day 9) for amlodipine when given alone were the following: maximum plasma concentration (Cmax) 17.7 ng/mL, area under the plasma concentration‐time curve (AUC) 331 ng•h/mL, and renal clearance 39.5 mL/min, with 8% of the total amlodipine dose being excreted. When concomitant telmisartan was given, the respective values were 18.7 ng/mL, 352 ng•h/mL, and 43.0 mL/min, with 9.4% of the total amlodipine dose being excreted renally The limits of the 90% confidence intervals (CIs) for the ratios of these steady‐state parameters were 0.97 to 1.14 for Cmax and 0.98 to 1.16 for AUC; both were within the predefined reference range (0.8 to 1.25) for bioequivalence. The high intersubject variability in urinary amlodipine excretion resulted in bioequivalence not being demonstrated for renal clearance. Adverse effects were few, mild to moderate in intensity, and transient whether amlodipine was given alone or with telmisartan. Vital signs, except for blood pressure, and clinical laboratory values were unaffected by either medication. The findings of this study show that concomitant telmisartan and amlodipine may be administered as there is no clinically significant variation in primary pharmacokinetic parameters of amlodipine in the presence of telmisartan, and the safety of the combination is comparable to that of amlodipine alone.
Altered Phenytoin Pharmacokinetics in Children with Severe, Acute Traumatic Brain Injury
Authors: Stowe Cindy D. , Lee Kelley R. , Storgion Stephanie A. , Phelps Stephanie J.
Published: September 2022

The purpose of this study was to determine if phenytoin protein binding and metabolism were altered in prepubescent pediatric patients within the first 10 days following severe, acute traumatic brain injury. Patients (n = 10) received phenytoin loading doses (15–20 mg/kg) followed by a maintenance regimen (7 mg/kg/day) initiated within 12 hours of the loading dose. Phenytoin serum concentrations were measured serially on days 1, 2, 3, 5, 7, 9, and 10 at 1, 6, and 12 hours. Time‐invariant and time‐variant Michaelis‐Menten pharmacokinetic models were fit to the unbound phenytoin concentration‐time data (ADAPT II™). Albumin concentrations significantly decreased over time (p < 0.001) and were predictive of the phenytoin binding ratio (r2 = 0.373, p < 0.0001). The time‐variant model provided a superior fit of the data in 7 patients with no difference between models in 3 patients. Rapid inhibition of metabolism (Vmaxbaseline = 2.82 ± 2.35 mg/kg/day) was observed initially following injury. This was followed by induction of metabolism as reflected by a Vmaxinduced of 20.79 ± 13.71 mg/kg/day, which was approximately twofold higher than reported values for nonstressed children. Children with severe, acute neurotrauma were found to have markedly altered protein binding and phenytoin metabolism.
Pharmacokinetics and Bioavailability of a Metformin/Glyburide Tablet Administered Alone and with Food
Authors: Marathe P. H. , Arnold M. E. , Meeker Jeff , Greene D. S. , Barbhaiya R. H.
Published: September 2022

Two randomized crossover studies were conducted to evaluate the pharmacokinetics (including food effect) of fixed‐combination metformin/glyburide tablets. Pharmacokinetics and bioavailability of two strengths (500 mg/2.5 mg and 500 mg/5 mg) of metformin/glyburide tablets were assessed relative to coadministered metformin and glyburide tablets in study 1. The effect of a high‐fat meal on the bioavailability of a metformin/glyburide (500 mg/5 mg) tablet was assessed relative to the fasted condition in study 2. The fixed combination metformin/glyburide tablets showed bioequivalence for the metformin component with the reference metformin tablet and comparable bioavailability for the glyburide component with the reference glyburide tablet. Food does not appear to affect the bioavailability of either component to an appreciable extent.
Evaluating Possible Pharmacokinetic Interactions between Tobramycin, Piperacillin, and a Combination of Piperacillin and Tazobactam in Patients with Various Degrees of Renal Impairment
Authors: Dowell James A. , Korth‐Bradley Joan , Milisci Mark , Tantillo Kathryn , Amorusi Peter , Tse Susanna
Published: September 2022

A study was performed to further investigate the apparent instability of tobramycin when coadministered with piperacillin/tazobactam in subjects with renal impairment. Twenty‐six otherwise healthy volunteers between 23 and 74 years of age were studied. Eight subjects had moderate renal impairment, 10 had mild renal impairment, and 8 had normal renal function. Each subject received single doses of piperacillin/tazobactam and tobramycin alone as well as combined doses in a randomized, three‐way crossover design. The subjects with normal renal function also received combined doses of piperacillin and tobramycin. Considerable care was taken to protect against in vitro inactivation of plasma and urine samples after collection. No systematic changes in pharmacokinetic parameters were observed. It is concluded that piperacillin, either alone or with tazobactam, did not change the pharmacokinetics of tobramycin in subjects with renal impairment. The apparent in vivo inactivation of tobramycin in the presence of piperacillin or piperacillin/tazobactam reported by others may be an artifact of ex vivo inactivation.
Which Studies of Therapy Merit Credence? Vitamin E and Estrogen Therapy as Cautionary Examples
Authors: Spector Reynold , Vesell Elliot S.
Published: September 2022

A vast and continuously growing amount of material on drugs exists in the literature to read and evaluate. Frequently, the papers and their recommendations are conflicting and contradictory. Readers are faced with the dilemma of deciding what to believe. The need for evidence‐based medicine as a foundation for optimal clinical research and patient care requires application of the best scientific methods. Various methods are discussed. Generally the most powerful method to test a clinical hypothesis is the randomized, controlled clinical trial. By contrast, epidemiology/observation studies have certain inherent weaknesses that can lead to erroneous conclusions. The examples of estrogen therapy in postmenopausal women and of vitamin E therapy to reduce cardiovascular risk are discussed extensively to provide historical perspective and to demonstrate erroneous conclusions reached using epidemiology/observation studies. The sociology of journal publication is briefly described, and an attempt is made to assess who benefits and who is harmed when leading medical journals publish erroneous results. Types of bias and confounding issues leading to errors are discussed, and the need is emphasized for publication of rigorous studies after careful evaluation by editors to avoid repetition of past mistakes and to ensure publication of correct medical information.
Evaluation of Highly Bound Drugs: Interspecies, Intersubject, and Related Comparisons
Authors: Collins Jerry M. , Klecker Raymond W.
Published: September 2022

Free (unbound) drug is generally the pharmacologically relevant param eter for drug exposure. Thus, comparisons among species, among individuals, and in other situations such as cell culture or drug metabolism experiments in vitro should be based on free drug. Although the traditional focus has been on the absolute value for free drug, the applications for the data in this study are primarily comparative. Therefore, the authors evaluated direct dialysis of one plasma sample versus another. At equilibrium, the total concentration of valproate in human plasma was 3‐fold higher than in rat plasma. The total concentration of monoacetyl dapsone was 10‐fold higher in human plasma than in rat plasma and 18‐fold higher in human plasma than in dog plasma. These results confirm predictions derived from conventional dialysis of each plasma sample separately versus buffer. These data can be interpreted directly, without interspecies correction factors for binding, especially for the most important cases—drugs that are highly protein‐bound.
Novel Formulations of Cetrorelix Acetate in Healthy Men: Pharmacodynamic Effects and Noncompartmental Pharmacokinetics
Authors: Erb Katharina , Junge Klaus , Pechstein Birgit , Schneider Edith , Derendorf Hartmut , Hermann Robert
Published: September 2022

The objective of this study was to investigate the effects on the phaimacodj/namics and noncompartmental pharmacokinetics after weekly subcutaneous administration of novel formulations of cetrorelix acetate in healthy men. In a randomized parallel‐group study; single subcutaneous doses of cetrorelix acetate (concentration: 2.5 mg peptide base/ml) dissolved in aqueous gluconic acid (CET/glu, dose: 5 or 10 mg peptide base) or in water (CET/wat, dose: 10 mg peptide base) were given to 36 subjects once weekly in the morning for 4 weeks. Cetrorelix plasma, serum testosterone, luteinizing hormone, and follicle‐stimulating hormone concentrations were monitored after each administration for 1 week, with extensive profiling after the first and fourth administration. Cetrorelix plasma concentrations were analyzed by radioimmunoassay and serum hormone concentrations by enzyme immunoassays. At least half‐maximum testosterone suppression started with all treatments within less than 1 day. Deepest and longest testosterone suppression was acmevea oy iu mg CET/glu. Duration of at least half‐maximum suppression was after the first dose median of 82 hours and after the fourth dose median of 122 hours, respectively. Substantial suppression was also evident for luteinizing hormone (LH) and, to a lesser extent, for follicle‐stimulating hormone (FSH). On average, Cmax was nearly doubled after single and multiple doses, and AUCt was increased by about 50% after single doses and about 30% after multiple doses of 10 mg CET/glu as compared to 10 mg CET/wat. For tmax and t1/2′no significant differences were found between formulations. It was concluded that testosterone suppression increased with weekly subcutaneous administrations of 10 mg CET/glu. Compared to CET/wat, bioavailability and duration of suppression were increased with CET/glu.
An Evaluation of Bioequivalence of Two 7‐Day 17β‐Estradiol Transdermal Delivery Systems by Anatomical Site
Authors: Harrison Lester I. , Harari David
Published: September 2022

An open‐label, randomized, crossover study was conducted to assess the bioequivalence of two 7‐day transdermal 17β‐ estradiol delivery systems following application to the buttock in 42 postmenopausal women. The systems tested were a generic Estradiol Transdermal System (Mylan Pharmaceuticals, Inc.) and Climara (Berlex Laboratories, Inc.), the reference product. Each system was labeled to deliver 17β‐ estradiol 0.1 mg/day and was applied for 7 days. Serial serum samples were assayed for estradiol, estrone, and estrone sulfate using validated assays. The bioequivalence confidence intervals for the ratio of log‐transformed 17β‐estradiol Cmax values for the Estradiol Transdermal System and Climara were outside the interval of 0.80 to 1.25, indicating that the products were not bioequivalent. Application site reactions and skin irritation were more common with the Estradiol Transdermal System than with Climara. The odds of patch lifting or detachment were 6.95 times higher with the Estradiol Transdermal System than with Climara. Because these two transdermal delivery systems had been previously shown to be bioequivalent after application to the abdomen, the findings of this study suggest that bioequivalence at one anatomical site is not indicative of bioequivalence at another.
Single Plasma Concentrations of 1′‐Hydroxymidazolam or the Ratio of 1′‐Hydroxymidazolam: Midazolam Do Not Predict Midazolam Clearance in Healthy Subjects
Authors: Rogers Janyce F. , Nafziger Anne N. , Kashuba Angela D. M. , Streetman Daniel S. , Rocci Mario L. , Choo Edna F. , Wilkinson Grant R. , Bertino Joseph S.
Published: September 2022

The 30‐minute ratio of 1′‐hydroxymidazolam: midazolam plasma concentrations has been used as a measure of midazolam clearance in liver transplant patients. This study determined if a single concentration of 1′‐hydroxymidazolam or the ratio of 1′‐hydroxymidazolam: midazolam could be used to predict midazolam clearance in healthy subjects. Plasma midazolam and 1′‐hydroxymidazolam concentrations from three previous studies were used for analyses. Data obtained predose and at 5,30, 60,120,240, 300, and 360 minutes following intravenous doses of midazolam in 61 adults were divided and used to derive and validate equations to predict midazolam clearance. Equations were derived using linear regression and then validated by comparing predicted to observed clearance. Only one equation was related to midazolam clearance as a function of 1′‐hydroxymidazolam, but it did not predict midazolam clearance (r = 0.29, p = 0.31). Single sampling of 1′‐hydroxymidazolam or 1′‐hydroxymidazolam: midazolam plasma concentrations cannot be used to predict midazolam clearance in healthy adults.
No Effect of Age or Gender on the Pharmacokinetics of Rosuvastatin: A New HMG‐CoA Reductase Inhibitor
Authors: Martin Paul D. , Dane Aaron L. , Nwose Olise M. , Schneck Dennis W , Warwick Mike J.
Published: September 2022

The effects of age and gender on the pharmacokinetics of rosuvastatin (Crestor™) were assessed in healthy young (18–35 years) and elderly (< 65 years) males and females in this open, nonrandomized, noncontrolled, parallel‐group trial. Sixteen males and 16 females (8 young and elderly volunteers per gender group) were enrolled. Mean (range) ages were 24 (18–33) and 68 (65–73) years for young and elderly volunteers, respectively. Volunteers were given a single oral 40 mg dose of rosuvastatin. Blood samples for measurement of rosuvastatin plasma concentration were collected up to 96 hours following dosing. Age and gender effects were assessed by constructing 90% confidence intervals (CIs) around the ratios of young/elderly and male/female geometric least square means (glsmeans) for AUC(0‐t) and Cmax (derived from ANOVA of log‐transformed parameters). Small differences in rosuvastatin pharmacokinetics were noted between age and gender groups. Glsmean AUC(0‐t) was 6% higher (90% CI = 0.86‐1.30) and glsmean Cmax 12% higher (90% CI= 0.83‐1.51) in the young compared with the elderly group. Glsmean AUC(0‐t) was 9% lower (90% CI= 0.74‐1.12) and glsmean Cmax 18% lower (90% CI = 0.61‐1.11) in the male compared with the female group. These small differences are not considered clinically relevant, and dose adjustments based on age or gender are not anticipated. Rosuvastatin was well tolerated in all volunteers.
Effect of Phosphate Binders on Supplemental Iron Absorption in Healthy Subjects
Authors: Pruchnicki Maria C. , Coyle James D. , Hoshaw‐Woodard Stacy , Bay William H.
Published: September 2022

A single‐dose, prospective, randomized, four‐treatment, four‐period crossover study was conducted to determine the acute effect of therapeutically equivalent doses of three commonly used phosphate binders on oral iron absorption. Twenty‐three healthy subjects received 65 mg of elemental iron alone and with each phosphate binder (calcium carbonate 3000 mg, calcium acetate 2668 mg, or sevelamer HCl 2821 mg). Area under the change in plasma iron concentration‐time curve over 6 hours postdosing was measured. ANOVA was used to assess the statistical significance of differences in iron absorption among the treatments. The relative bioavailability of iron administered with each phosphate binder compared to iron administered alone was estimated. The relative iron bioavailabilities (95% confidence intervals) for the calcium carbonate, calcium acetate, and sevelamer HCl treatments were 0.81 (0.70, 0.94), 0.73 (0.63, 0.85), and 0.90 (0.78, 1.05), respectively. Thus, single doses of both calcium‐based phosphate binders significantly reduced single‐dose iron absorption, while sevelamer HCl did not.
Interaction Trial between Artemether‐Lumefantrine (Riamet®) and Quinine in Healthy Subjects
Authors: Lefèvre Gilbert , Carpenter Polly , Souppart Claire , Schmidli Heinz , Martin John M. , Lane Andrew , Ward Chris , Amakye Dereck
Published: September 2022

Forty‐two healthy Caucasian subjects were randomized in a double‐blind, parallel three‐group study (14 subjects per group) to investigate potential electrocardiographic and pharmacokinetic interactions between the antimalarials artemether‐lumefantrine (six‐dose regimen of Riamet® over3 days) and quinine (2‐h intravenous infusion of 10 mg/kg body weight, not exceeding 600 mg in total, 2 h after the last dose of Riamet®). The study medications were all safe and well tolerated after all treatments. Neither the pharmacokinetics of lumefantrine nor the pharmacokinetics of quinine was influenced by the presence of the other drug. Plasma levels of artemether and dihydroartemisinin appeared to be lower following the combined treatment Riamet® + quinine, but this was not considered to be clinically relevant. Riamet® alone had no effect on QTc interval. Infusion of quinine alone caused a transient prolongation of QTc interval, which was consistent with the known cardiotoxicity of quinine, with this effect being slightly but significantly greater when quinine was infused after Riamet®. It would thus appear that the inherent risk of QTc prolongation of IV quinine was enhanced by prior administration of Riamet®. However, these occasional QTc prolongations, which were small in magnitude and not correlated with plasma concentrations of any of the compounds, were not considered to be of clinical importance. In conclusion, overlapping therapy with artemether‐lumefantrine and IV quinine in the treatment of patients with complicated or multidrug‐resistant Plasmodium falciparum malaria may result in a modest increased risk of QTc prolongation, but this is far outweighed by the potential therapeutic benefit.
The Influence of Diltiazem Versus Cimetidine on Propranolol Metabolism
Authors: Tateishi Tomonori , Ohashi Kyoichi , Fujimura Akio , Ebihara Akio
Published: September 2022

The present study was undertaken to examine whether the inhibitory effect of diltiazem on the metabolism of propranolol differs from that of cimetidine. Six healthy male volunteers received a single oral dose of 20 mg propranolol with pretreatment with placebo, 60 mg diltiazem, or 400 mg cimetidine three times daily for 4 days. Diltiazem and cimetidine increased the area under the concentration (AUC) of propranolol and its glucuronide. Cimetidine also increased the urinary excretion of propranolol glucuronide. There were no significant differences in the AUC of 4‐hydroxypropranolol (4OHPPL) and its conjugates or the urinary excretion of conjugated 4OHPPL. Diltiazem increased the AUC of naphthoxylactic acid (NLA) and the urinary excretion to NLA. After cimetidine pretreatment, there was the trend toward a decrease in the partial metabolic clearance to 4OHPPL and a significant decrease in that of NLA. These results suggest that diltiazem and cimetidine inhibit the oxidation pathways of propranolol in different manners. Cimetidine might inhibit both oxidative pathways to 4OHPPL and NLA, whereas diltiazem might not inhibit the pathway to NLA.