Population pharmacokinetic analysis of oseltamivir and oseltamivir carboxylate following intravenous and oral administration to patients with and without renal impairment

This work characterizes the pharmacokinetics (PK) of oseltamivir phosphate (OP) and its active metabolite, oseltamivir carboxylate (OC), and investigates oseltamivir i.v. dosing regimens for treatment of influenza in patients with normal renal function and with various degrees of renal impairment. Initially, data collected from 149 subjects with normal renal function and mild to severe renal impairment who were administered 40–200 mg oseltamivir i.v. were described by a four-compartment model. Two compartments described OP, one compartment described OC and one compartment described OP to OC metabolism. Then, data of 128 subjects administered 20–1,000 mg oseltamivir orally were added. The absorption model included three first-order processes with direct (via first-pass) input in the OC compartment and two (direct and delayed) inputs in the OP compartment. Simulations and PK bridging were used to recommend i.v. dosing regimens. The analysis demonstrated that renal function had a major effect on OC clearance (CL _M ) and exposure. CL _M for subjects with mild, moderate and severe renal impairment was 18, 50, and 84 % lower than for subjects with normal renal function. Simulations were used to select i.v. dosing regimens that provide OC C_min coverage and exposures comparable to those achieved in subjects with normal renal function administered 75 mg b.i.d. orally. The oseltamivir dose depended on the degree of renal impairment and was independent of route of administration. Specifically, 75 mg b.i.d. is recommended for subjects with normal renal function or mild renal impairment, 30 mg b.i.d. for subjects with moderate renal impairment, and 30 mg q.d. for subjects with severe renal impairment. Recommended i.v. doses were the same as those recommended for oral administration in corresponding renal impairment groups.     

Peroral Endoscopic Myotomy Is a Safe and Feasible Option in Management of Esophageal Diverticula: Systematic Review and Meta-Analysis

Digestive Diseases and Sciences - Esophageal diverticula can cause significant symptoms and affect the quality of life. There has been recent interest in the use of peroral endoscopic myotomy in...     

Type II Achalasia Is Increasing in Prevalence

Background

Three manometric subtypes of achalasia were defined in the Chicago Classification approximately 10 years ago: type I (aperistalsis), type II (pan-pressurization), and type III (spastic). Since the widespread use of this classification scheme, the evolving prevalence of these subtypes has not been elucidated. We aim to determine the prevalence of each subtype a decade after the adoption of the Chicago Classification.

Methods

This is a retrospective cohort analysis of patients diagnosed with achalasia on high-resolution manometry (HRM) at two major academic medical centers between 2015 and 2018. Patients were excluded if they had a diagnosis of another esophageal motility disorder, previously treated achalasia, or foregut surgery. Demographic data, manometric subtype, and esophageal dilatation grade on endoscopy were obtained. Prevalence of achalasia subtypes was compared with a published historical control population (2004–2007). Fischer’s exact and t tests were used for analysis.

Results

Of 147 patients in the contemporary cohort and 99 in the historical control cohort, the prevalence of type I achalasia was 8% versus 21%, type II 63% versus 50%, and type III 29% versus 29%, respectively (p?=?0.01). The mean age in our population was 58 years compared to 57 years in the historical control, and the proportion of men 48% versus 47%, respectively (p?=?0.78). Mean endoscopic dilatation grade in the contemporary cohort was 1.5 for type I patients, 0.9 for type II, and 0.4 for type III, compared with 1.5, 0.6, and 0.4, respectively. Overall mean dilatation grade was 0.8 in our cohort versus 0.7 in the historical control (p?=?0.58).

Conclusion

The prevalence of type II achalasia was significantly greater and prevalence of type I significantly less in our patient population compared to our predefined historical control. Other characteristics such as age and sex did not appear to contribute to these differences. Histopathological evidence has suggested that type II achalasia may be an earlier form of type I; thus, the increased prevalence of type II achalasia may be related to earlier detection of the disease. The adoption of HRM, widespread use of the Chicago Classification, and increased disease awareness in the past decade may be contributing to these changes in epidemiology.

     

Neurological monitoring and sedation protocols in the Liver Intensive Care Unit

Metabolic Brain Disease - Patients with liver disease often have alteration of neurological status which requires admission to an intensive care unit. Patients with acute liver failure (ALF),...     

Effect of different fixative solutions on eyes with experimental proliferative vitreoretinopathy

The aim of this study was to evaluate the use of different fixatives on the reliability of histopathological changes in a rabbit model of proliferative vitreoretinopathy (PVR). Twenty eyes from 10 rabbits were divided into four groups. The right eyes were used in two experimental groups (each n = 5), and the left, in two control groups (each n = 5). Using a newly developed scleral incision marker, an oblique scleral incision was standardized in the experimental groups, followed by intravitreal injection of 0.4 ml autologous blood and the left for wound repair for four weeks. Eyes were enucleated at four weeks. The groups differed in the type of used fixative solution (formaldehyde 4% vs. 1% buffered formaldehyde and 1.25% glutaraldehyde). The eyes were evaluated for the development of fibrosis, retinal detachment (RD), and processed for histopathology. Fibrous ingrowth of a variable degree was present in the experimental groups originating from the trauma site. Experimental eyes fixed with formaldehyde 4% had RD extension that was greater than that fixed in formaldehyde/glutaraldehyde mixture; however, the difference did not reach statistical significance (P = 0.15). This difference was not fully explained by the fibrosis which developed. In addition, in control groups, formaldehyde 4% induced a fixative-dependent retinal separation that was absent in eyes fixed with formaldehyde/glutaraldehyde mixture (P = 0.03). In conclusion, a mixture of buffered formaldehyde 1% and glutaraldehyde 1.25% combined with standardized scleral incision resulted in consistent pathological changes. A reliable PVR model is a condition sine qua non to evaluate antifibrotic treatment strategies.     

Proteomics applied to the clinical follow-up of patients after allogeneic hematopoietic stem cell transplantation

A phase 1 diagnostic study was performed to evaluate a novel technology for clinical proteomic research based on capillary electrophoresis and mass spectrometry. Urine from 40 patients after hematopoietic stem cell transplantation (HSCT; 35 allogeneic, 5 autologous) and 5 patients with sepsis was collected for a period of 100 days and analyzed. More than 1000 different polypeptides could be detected in individual samples. Polypeptide patterns excreted in the urine of patients were significantly different from those of healthy volunteers. No significant differences were detected comparing different conditioning regimens. The aim of this study was to identify polypeptide patterns functioning as early indicators of graft-versus-host disease (GVHD). Eighteen patients developed GVHD after allogeneic HSCT. Sixteen differentially excreted polypeptides formed a pattern of early GVHD markers, allowing discrimination of GVHD from patients without complications with 82% specificity and 100% sensitivity, cross-validated. Inclusion of 13 sepsis-specific polypeptides allowed us to distinguish sepsis from GVHD with a specificity of 97% and a sensitivity of 100%. Sequencing 2 prominent GVHD-indicative polypeptides led to the identification of a peptide from leukotriene A4 hydrolase and a peptide from serum albumin. The data reveal that capillary electrophoresis and mass spectrometry allow identification of biomarkers for a variety of diseases or related complications.     

Influence of a strictly perioperative antibiotic prophylaxis vs a prolonged postoperative prophylaxis on surgical site infections in maxillofacial surgery

Purpose

The adequate perioperative antibiotic prophylaxis in maxillofacial surgery is still under discussion due to the wide range of hard and soft tissue procedures as well as contaminated, semi-contaminated and clean surgical sides. Perioperative antibiosis is an easy applicable tool that can be used to decrease nosocomial morbidity and mortality by reducing the rate of infections. We compared strictly perioperative antibiosis with an extended postoperative prophylactic antibiosis.

Materials and methods

In this study, 901 consecutive patients, from a tertiary care maxillofacial surgery department were included and distributed into two groups: The first group received peri- and postoperative antibiotic prophylaxis (PP; n = 365) from the day of operation until the fifth day postoperatively. The second group was treated with single shot prophylaxis with intraoperative repetition as needed (SSP; n = 536) only. Furthermore, the patients were grouped according to their main diagnosis and surgical procedure. For comparison, general anamnestic data, cultured bacteria and resistances, number of surgical site infections and duration of hospitalization were compared.

Results

There were no statistically significant differences in general diseases or extent of surgery between the groups. There was no statistical difference in the surgical site infections between the groups regardless of their diagnosis. There were significant correlations between tracheotomised patients (p < 0.001) as well as patients with a higher BMI (p = 0.009) and the incidence of surgical site infections. Most common cultured bacteria were staphylococci.

Conclusion

Based on the findings of the study, we believe that a perioperative antibiosis delivers a sufficient prophylaxis for patients undergoing maxillofacial surgery procedures.

     

Bone tissue engineering in oral peri‐implant defects in preclinical in vivo research: A systematic review and meta‐analysis

The regeneration and establishment of osseointegration within oral peri‐implant bone defects remains a clinical challenge. Bone tissue engineering (BTE) is emerging as a promising alternative to autogenous and/or biomaterial‐based bone grafting. The objective of this systematic review was to answer the focused question: in animal models, do cell‐based BTE strategies enhance bone regeneration and/or implant osseointegration in experimental peri‐implant defects, compared with grafting with autogenous bone or only biomaterial scaffolds? Electronic databases were searched for controlled animal studies reporting on peri‐implant defects and implantation of mesenchymal stem cells (MSC) or other cells seeded on biomaterial scaffolds, following Preferred Reporting Items for Systematic reviews and Meta‐Analyses (PRISMA) guidelines. Random effects meta‐analyses were performed for the outcomes histomorphometric bone area fraction (BA) and bone‐to‐implant contact (BIC). Nineteen studies reporting on large animal models (dogs and sheep) were included. Experimental defects were created surgically (16 studies) or via ligature‐induced peri‐implantitis (LIPI, three studies). In general, studies presented with an unclear to high risk of bias. In most studies, MSC were used in combination with alloplastic mineral phase or polymer scaffolds; no study directly compared cell‐loaded scaffolds vs. autogenous bone. In three studies, cells were also modified by ex vivo gene transfer of osteoinductive factors. The meta‐analyses indicated statistically significant benefits in favour of: (a) cell‐loaded vs. cell‐free scaffolds [weighted mean differences (WMD) of 10.73–12.30% BA and 11.77–15.15% BIC] in canine surgical defect and LIPI models; and (b) gene‐modified vs. unmodified cells (WMD of 29.44% BA and 16.50% BIC) in canine LIPI models. Overall, heterogeneity in the meta‐analyses was high (I² 70–88%); considerable variation was observed among studies regarding the nature of cells and scaffolds used. In summary, bone regeneration and osseointegration in peri‐implant defects are enhanced by the addition of osteogenic cells to biomaterial scaffolds. Although the direction of treatment outcome is clearly in favour of BTE strategies, due to the limited magnitude of treatment effect observed, no conclusive statements regarding the clinical benefit of such procedures for oral indications can yet be made. Copyright © 2017 John Wiley & Sons, Ltd.