Pharmacokinetics and dosage adjustment in patients with renal dysfunction

Introduction  Chronic kidney disease is a common, progressive illness that is becoming a global public health problem. In patients with kidney dysfunction, the renal excretion of parent drug and/or its metabolites will be impaired, leading to their excessive accumulation in the body. In addition, the plasma protein binding of drugs may be significantly reduced, which in turn could influence the pharmacokinetic processes of distribution and elimination. The activity of several drug-metabolizing enzymes and drug transporters has been shown to be impaired in chronic renal failure. In patients with end-stage renal disease, dialysis techniques such as hemodialysis and continuous ambulatory peritoneal dialysis may remove drugs from the body, necessitating dosage adjustment. Methods  Inappropriate dosing in patients with renal dysfunction can cause toxicity or ineffective therapy. Therefore, the normal dosage regimen of a drug may have to be adjusted in a patient with renal dysfunction. Dosage adjustment is based on the remaining kidney function, most often estimated on the basis of the patient's glomerular filtration rate (GFR) estimated by the Cockroft–Gault formula. Net renal excretion of drug is a combination of three processes: glomerular filtration, tubular secretion and tubular reabsorption. Therefore, dosage adjustment based on GFR may not always be appropriate and a re-evaluation of markers of renal function may be required. Discussion  According to EMEA and FDA guidelines, a pharmacokinetic study should be carried out during the development phase of a new drug that is likely to be used in patients with renal dysfunction and whose pharmacokinetics are likely to be significantly altered in these patients. This study should be carried out in carefully selected subjects with varying degrees of renal dysfunction. In addition to this two-stage pharmacokinetic approach, a population PK/PD study in patients participating in phase II/phase III clinical trials can also be used to assess the impact of renal dysfunction on the drug's pharmacokinetics and pharmacodynamics. Conclusion  In conclusion, renal dysfunction affects more that just the renal handling of drugs and/or active drug metabolites. Even when the dosage adjustment recommended for patients with renal dysfunction are carefully followed, adverse drug reactions remain common.     

Molecular Basis of Autosomal Recessive Chronic Granulomatous Disease in Iran

Introduction  

Chronic granulomatous disease (CGD) is a rare inherited condition resulting from mutations in the genes that encode the proteins of the NADPH oxidase enzyme in phagocytes, rendering these cells incapable of killing invading pathogens.     

N<Superscript>pro</Superscript> His49 and E<Superscript>rns</Superscript> Lys412 mutations in pig bovine viral diarrhea virus type 2 synergistically enhance the cellular antiviral response

Type I interferons are major components of the innate immune response of hosts, and accordingly, many viruses have evolved mechanisms to modulate the host response during infection. Bovine viral diarrhea virus (BVDV) nonstructural protein N^pro and structural protein E^rns play important roles in inhibiting type I interferon. The aim of this study was to explore the epistatic effects of amino acid mutations in N^pro and E^rns in porcine ST cells to characterize the immune response induced by BVDV-2. Plasmids with mutant amino acids His49 (H49), Glu22 (E22) in N^pro, and His300 (H300), Lys412 (K412) in E^rns which had been changed to Alanine (A) had similar effects on type I interferon production in MDBK and ST cells, but resulted in much greater ISG15, OAS, and Mx production in ST cells. The rescued vASH/N^proH49E^rnsK412 virus showed the best efficiency with respect to modulating antiviral cytokines, indicating that the amino acids N^pro H49 and E^rns K412 had highly synergistic effects in abolishing the ability to inhibit type I interferon. These findings have importance practical implications owing to the increasing prevalence of BVDV infections, including persistent infections, in domestic pigs.     

Suboptimal therapy controls clinically apparent disease but not subclinical progression of Vogt-Koyanagi-Harada disease

Purpose To evaluate clinical and angiographic differences in patients with Vogt-Koyanagi-Harada (VKH) disease during the early 4-month treatment phase with high- or medium-dose systemic corticosteroid therapy. Methods VKH patients treated at the Centre for Ophthalmic Specialized Care, Lausanne, Switzerland (n = 4), or the Department of Ophthalmology, Tokyo Medical and Dental University, Tokyo, Japan (n = 5), underwent a pre-treatment indocyanine green angiography (ICGA) and a follow-up ICGA four months after treatment began. Lausanne patients received high-dose, systemic corticosteroid therapy, with or without immunosuppressive therapy. Tokyo patients received medium-dose systemic corticosteroid therapy that included 3 days of intravenous pulse methylprednisolone. ICGA signs including choroidal stromal vessel hyperfluorescence and leakage, hypofluorescent dark dots (HDD), fuzzy vascular pattern of large stromal vessels and disc hyperfluorescence were retrospectively compared. Results The pre-treatment ICGA demonstrated that each of the nine patients had choroidal inflammatory foci, as indicated by HDD. At 4-month follow-up, clinical and fluorescein findings had improved almost equally in both groups. HDD had resolved in the Lausanne group but persisted in the Tokyo group. Sunset glow fundus occurred in three of the Tokyo patients and none of the Lausanne patients. Conclusions Submaximal doses of inflammation suppressive therapy are sufficient to suppress clinically apparent disease but not the underlying lesion process. This explains the propensity for sunset glow fundus in seemingly controlled disease.     

Prevalence of benign prostatic hyperplasia in a population-based study in Iranian men 40 years old or older

Epidemiology of benign prostatic hyperplasia (BPH) is incompletely understood. The following study was done to estimate the prevalence of BPH according to obstructive and irritative symptoms of prostate obstruction determined by uroflowmetry and prostate size. In a cross-sectional study a total of 8,466 men aged 40 or older were interviewed by 74 general practitioners and answered the International Prostate Symptom Score (I-PSS) questionnaire. The subjects were randomly identified from 30 counties of Iran. They were invited to have a digital rectal examination (DRE), serum total prostate-specific antigen (tPSA) assay, abdominal ultrasonography to measure prostate size and measurement of maximum urinary flow rate (Qmax). Data on medical history, toxic habits, and current use of medications were obtained. Of the men interviewed, the prevalence of BPH, defined as I-PSS greater than 7, maximum flow less than 15 ml/s and prostate size greater than 30 gm, was 23.8%. The prevalence increased with age, from 1.2% in men 40–49 to 36% in those >70 years (tested for trend, P = 0.001). A positive association was found between BPH and body mass index (BMI) (P = 0.04), height (P = 0.03), diabetes mellitus (P = 0.04), increased total energy intake (P = 0.02), age-adjusted levels of total PSA (P = 0.02), heart disease (P = 0.03), and marital status (P = 0.01). The prevalence of BPH is relatively high in Iran. The provided bothersome due to BPH did not correlate to symptom severity and should be considered independently in clinical decision-making.     

Outcome of Microscopic Incomplete Resection (R1) of Colorectal Liver Metastases in the Era of Neoadjuvant Chemotherapy

Background  

Data from patients with colorectal liver metastases (CRLM) who received neoadjuvant chemotherapy before resection were reviewed and evaluated to see whether neoadjuvant chemotherapy influences the predictive outcome of R1 resections (margin is 0 mm) in patients with CRLM.     

Vitamin D and prostate cancer prognosis: a Mendelian randomization study

Purpose

Decreased vitamin D levels have been associated with prostate cancer, but it is unclear whether this association is causal. A functional single-nucleotide polymorphism (SNP) in the group-specific component (GC) gene (T > G, rs2282679) has been associated with 25-hydroxy (25-OH) vitamin D and 1.25 dihydroxy (1.25-OH2) vitamin D levels.

Methods

To examine the hypothesized inverse relationship between vitamin D status and prostate cancer, we studied the association between this SNP and prostate cancer outcome in the prospective PROCAGENE study comprising 702 prostate cancer patients with a median follow-up of 82 months.

Results

GC rs2282679 genotypes were not associated with biochemical recurrence [hazard ratios (HR) 0.91, 95 % confidence interval (CI) 0.73–1.12; p = 0.36], development of metastases (HR 1.20, 95 % CI 0.88–1.63; p = 0.25) or overall survival (HR 1.10; 95 % CI 0.84–1.43; p = 0.50).

Conclusions

A causal role of vitamin D status, as reflected by GC rs2282679 genotype, in disease progression and mortality in prostate cancer patients is unlikely.

     

Psychometric evaluation of a radio electric auricular treatment for stress related disorders: a double-blinded,placebo-controlled controlled pilot study

Background  

The aim of this double-blind randomized study is to test the efficacy of a radio electric stimulator device using an auricular reflex therapy protocol for stress-related symptoms.     

Measurement properties of the benign prostatic hyperplasia impact index in tadalafil studies

Background  

To assess the measurement properties of the Benign Prostatic Hyperplasia Impact Index (BII) for use in men with Lower Urinary Tract Symptoms (LUTS) secondary to Benign Prostatic Hyperplasia (BPH) treated with tadalafil.     

Characterization of pollution transport into Texas using OMI and TES satellite,GIS and in situ data,and HYSPLIT back trajectory analyses: implications for TCEQ State Implementation Plans

Transport of pollution from remote sources into the state of Texas has been shown by modeling techniques, satellite, and in situ data. Attaining a better understanding of the impact (i.e., temporally) of remote pollution sources will provide a more robust/quantifiable basis for State Implementation Plans (SIPs) that govern air quality. Utilizing Tropospheric Emission Spectrometer (TES) and Ozone Monitoring Instrument (OMI) and in situ data for ozone (O₃) and nitrogen dioxide (NO₂) and Hybrid Single-Particle Lagrangian Integrated Trajectory Model (HYSPLIT), we assess whether high-pollution events in Texas are primarily sourced locally (i.e., within Texas) or remotely. We focus on TES and OMI dates that exemplify high O₃ and NO₂, over Texas’s lower troposphere from August 5, 2006, to June 21, 2009. For all dates and altitudes, 4-day back trajectory analyses, exemplified by high TES O₃, show that remotely sourced from the Gulf of Mexico, Southeast USA, Midwest USA, Northeast USA, the Atlantic Ocean, Pacific Ocean, Mexico to Texas. The only exception is air at 1 km on July 22, 2006, which shows that air at this altitude is sourced within Texas. Throughout half of the eastern portion of Texas, TES shows O₃ enhancements in the boundary layer and OMI shows O₃ and NO₂ enhancements via tropospheric column profiles (O₃ between 75 and 90 ppbv; NO₂ ≥5.5 molecules cm^?2). These enhancements complement the HYSPLIT 4-day trajectory analyses, which gives further indication that they are influenced by transport from remote sources. Dates with co-located satellite and in situ data (e.g., August 2, 2005) further exemplify the need to consider satellite and in situ data and modeling data/forecasts when creating SIPs for compliance with Environmental Protection Agency and the Texas Commission on Environmental Quality air quality standards. Despite the fact that quantifying local versus remote sources is in its early stages, Texas has become increasingly compliant with Environmental Protection Agency (EPA) regulations. Environmental Systems Research Institute’s ArcGIS exemplifies the noticeable decrease in the number of days that locales in Texas exceed EPA’s limit for O₃. From 2005 to 2009, population standard deviation and standard error of the mean, and true sample deviation of the sample mean for O₃ and NO₂, at all 16 monitoring sites distributed throughout Texas, are temporally consistent and small—reinforcing the reliability of in situ data as they are consistent throughout. This investigation has global implications for regions within countries that enforce air quality mandates. Such governing bodies should consider utilizing data assimilation (of in situ data) for air quality prediction as a part of the governmental process that produces such laws. This could potentially keep regions more accountable for emissions both locally and far from high source points.