Search

Persistent pulmonary hypertension of the newborn (PPHN) is a complication of term birth, characterized by persistent hypoxemia secondary to failure of normal postnatal reduction in pulmonary vascular resistance, with potential for short- and long-term morbidity and mortality. The primary pharmacologic goal for this condition is reduction of the neonate's elevated pulmonary vascular resistance with inhaled nitric oxide, the only approved treatment option. Various adjunctive, unapproved therapeutics have been trialed with mixed results, likely related to challenges with recruiting the full, intended patient population into clinical studies. Recently, real-world data and subsequent derived evidence have been utilized to improve the efficiency of various pediatric clinical trials. We aim to provide recent perspectives regarding the use of real-world data in the planning and execution of pediatric clinical trials and how this may facilitate more streamlined assessment of future therapeutics for the treatment of PPHN and other neonatal conditions., Competing Interests: Declaration of competing interest The authors do not have any conflicts to declare., (Copyright © 2022. Published by Elsevier Ltd.)

Cervical cancer are generally caused by a persistent infection with the oncogenic virus, HPV. Patients with HPV integration are more prone to develop cervical cancer than patients without integration. In this proof-of-concept study, we aimed to develop a sensitive method based on targeted amplicon based NGS for early and precise detection of high-risk HPV-genotypes that are highly associated with the development of cervical cancer. Furthermore, we aimed to investigate if amplicon based NGS allowed for HPV genotyping in cervical lesions and whether it could detect HPV integration. The cohort included a group of CIN3 + biopsies (n = 64), CIN2 samples that progressed (n = 5), CIN2 samples that regressed (n = 3), healthy controls (n = 10), and plasma samples (n = 10) from cervical cancer patients. Sequencing was performed using a custom targeted NGS panel designed to detect all 25 high-risk and probably high-risk and two low-risk HPV genotypes. The method was validated by the SPF 10 PCR-DEIA-LiPA 25 assay. In the cohort, the following HPV genotypes were identified: HPV-16, 18, 31, 33, 35, 45, 51, 52, 56, 58, and 59. When comparing the results from the SPF 10 PCR-DEIA-LiPA 25 analyses with the NGS analyses, there was close to a perfect agreement (K = 0.92) among the genotyped HPV types, while in the two cases with complete disagreement, a third assay was applied, and here the results of the NGS analyses were confirmed. Whereas multiple HPV types were detected by the SPF 10 PCR-DEIA-LiPA 25 assay, the NGS analysis clearly suggest that there is one predomentant HPV type. The NGS assay was capable of detecting HPV-16 in a previous false-negative sample classified by the INNO-LiPA assay, emphasizing the importance of including multiple regions of the HPV genome when genotyping. For the 10 plasma samples, our NGS analyses showed full agreement with the digital droplet PCR (ddPCR) analyses of HPV positive as well as negative plasma samples. Lastly, the custom panel was capable of detecting the integration of HPV-16 in the SiHa cell line. The HPV panel provides a highly cost-effective method for HPV detection and genotyping, as exemplified by a list price of around 75 € per sample. In conclusion, the current study demonstrates that targeted NGS is capable of detecting and genotyping HPV in both FFPE biopsies and plasma samples. This method provides for early diagnosis and prognosis of cervical cancer disease progression, thereby optimizing the potential of recovery and survival for these patients., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The physiological absorption model presented in part I of this work is now extended to account for dosage-form-dependent gastrointestinal (GI) transit as well as disintegration and dissolution processes of various immediate-release and modified-release dosage forms. Empirical functions of the Weibull type were fitted to experimental in vitro dissolution profiles of solid dosage forms for eight test compounds (aciclovir, caffeine, cimetidine, diclofenac, furosemide, paracetamol, phenobarbital, and theophylline). The Weibull functions were then implemented into the model to predict mean plasma concentration-time profiles of the various dosage forms. On the basis of these dissolution functions, pharmacokinetics (PK) of six model drugs was predicted well. In the case of diclofenac, deviations between predicted and observed plasma concentrations were attributable to the large variability in gastric emptying time of the enteric-coated tablets. Likewise, oral PK of furosemide was found to be predominantly governed by the gastric emptying patterns. It is concluded that the revised model for GI transit and absorption was successfully integrated with dissolution functions of the Weibull type, enabling prediction of in vivo PK profiles from in vitro dissolution data. It facilitates a comparative analysis of the parameters contributing to oral drug absorption and is thus a powerful tool for formulation design., (Copyright © 2011 Wiley Periodicals, Inc.)

To enable more precise prediction of oral drug absorption, an existing physiologically based absorption model was revised. The revised model reflects detailed knowledge of human gastrointestinal (GI) physiology including fluid secretion and absorption, and comprises an elaborate representation of the intestinal mucosa. The alimentary canal from the stomach to the rectum was divided into 12 compartments. A mucosal compartment was added to each luminal segment of the intestine. A training set of 111 passively absorbed drugs with reported fractions of dose absorbed was used to optimize the semiempirical equation, which calculates intestinal permeability coefficients. The model was subsequently integrated into an established physiologically based pharmacokinetic software and validated by prediction of plasma concentration-time profiles of eight test compounds with diverse physicochemical properties. A good correlation between the simulated and experimental fractions of dose absorbed was established for the 111 compounds in the training set. Subsequently, the concentration-time profiles of six out of eight test compounds were predicted with high accuracy. The detailed model for GI transit and absorption presented in this study can help to understand the complex processes of oral absorption better and will be useful during the drug development process., (Copyright © 2011 Wiley-Liss, Inc.)

Delayed absorption of nifedipine when administered as a 20 mg immediate release soft gelatin capsule to fasted volunteers has been reported. Physiologically based pharmacokinetic (PBPK) modeling and in vitro dissolution data were used to explore our hypothesis that at high doses of nifedipine it precipitates in the stomach. Plasma concentration-time profiles following different doses of nifedipine were simulated using commercial PBPK software and compared to in vivo data. In vitro dissolution tests were performed with Adalat 10 mg capsules in different volumes of fasted state simulated gastric fluid (FaSSGF). The discrepancy in plasma concentration-time profiles between the different nifedipine doses could be well simulated, assuming protracted dissolution for the 20 mg dose. Nifedipine release from one Adalat 10 capsule in 250 or 500 mL FaSSGF was completed within 15 min whereas when release from two capsules, corresponding to 20 mg nifedipine, was studied in 250 mL FaSSGF, a maximum of about 75% drug dissolved was observed after 15 min followed by a decline in the % dissolved to a final value of approximately 40%. Based on the in silico and in vitro results it can be concluded that the observed prolongation in nifedipine absorption following the 20 mg dose was likely caused by nifedipine precipitation in human stomach., ((c) 2009 Wiley-Liss, Inc. and the American Pharmacists Association)

A novel pressure-balanced injection valve was evaluated for use with ultrahigh pressure liquid chromatography (UHPLC) at pressures up to 120 MPa (1,200 bar). Fused-silica capillaries (30-33 cm x 100 microm I.D.) packed with nonporous 1.5 microm isohexylsilane-modified (C6) silica particles were employed to study maximum pressure, injection reproducibility, injection time, and sample amount consumed for an injection. The new valve was more reproducible, convenient, and required much less sample than previously used injection systems. The effect of column diameter on efficiency and sensitivity was studied. The 100 microm I.D. columns demonstrated approximately 40% lower efficiency but 10-fold higher sensitivity than the 29 microm I.D. columns. Columns packed with nonporous C6 particles produced higher efficiencies than columns packed with a 1.5 microm porous octadecylsilane-modified (C18) material.

Background: Calcium antagonists such as nitrendipine reduce the effects of cyclosporin on renal haemodynamics, however, their long-term efficacy has not been established. We did a randomised trial to investigate the effects of nitrendipine on renal function in renal-transplant patients treated with cyclosporin., Methods: 253 renal-transplant patients were recruited: 52 normotensive patients (diastolic blood pressure <90 mm Hg) were assigned placebo and 57 nitrendipine 5 mg twice daily; 71 hypertensive patients (diastolic blood pressure >90 to <115 mm Hg) were assigned placebo and 73 nitrendipine 10 mg twice daily. Nitrendipine was increased to 20 mg twice daily if the target diastolic blood pressure (<90 mm Hg) was not achieved. The patients were seen once a month for 24 months; blood pressure and serum creatinine concentration were recorded at each visit. Analysis was by intention to treat., Findings: 63 patients were withdrawn (35 nitrendipine, 28 placebo). The mean serum creatinine concentration at baseline was slightly higher in the nitrendipine group (146.7 micromol/L [SE 4.42]) than in the placebo group (137.0 micromol/L [3.54]. At the 24-month endpoint or at dropout, serum creatinine concentration was significantly higher in the 123 patients in the placebo group than the 130 patients in the nitrendipine group (160.8 [7.1] vs 148.5 [5.3], p for effect of treatment=0.025, analysis of covariance in a two-way classification; 95% CI for difference -1.77 to -22.98). At study entry, the blood pressures of the placebo and the nitrendipine groups were almost identical. At 24 months, blood pressure was higher in the normotensive patients given a placebo than in those patients given nitrendipine. By contrast, blood-pressure values were similar in those hypertensive patients given a placebo and those given nitrendipine at the end of treatment., Interpretation: The calcium antagonist nitrendipine has no adverse effects on kidney function in renal-transplant patients with cyclosporin. The drug has a small but significant nephroprotective effect, that is independent of the drug's antihypertensive action.

The role of cytomegalovirus infection in allograft injury is controversial. A subgroup of renal graft recipients who had histologically proven late-acute rejection did not respond to conventional anti-rejection therapy (80% graft loss within 1 year). These patients showed an expansion of memory-type CD8 peripheral-blood T cells that expressed interferon-gamma mRNA and an association with clinically symptomless cytomegalovirus infection (82% PCR positive, 42% antigenaemia). Antiviral therapy with ganciclovir resulted in stable improved graft function in 17 of 21 treated patients with cytomegalovirus-associated late-acute rejection. The results underline the clinical relevance of cytomegalovirus-related graft injury and offer a novel therapeutic approach.