A Semi-mechanistic Gastric Emptying Model for the Population Pharmacokinetic Analysis of Orally Administered Acetaminophen in Critically Ill Patients

Purpose  

To develop a semi-mechanistic population pharmacokinetic model based on gastric emptying function for acetaminophen plasma concentration in critically ill patients tolerant and intolerant to enteral nutrition before and after prokinetic therapy.     

The population pharmacokinetics of R- and S-warfarin: effect of genetic and clinical factors

BACKGROUND

Warfarin is a drug with a narrow therapeutic index and large interindividual variability in daily dosing requirements. Patients commencing warfarin treatment are at risk of bleeding due to excessive anticoagulation caused by overdosing. The interindividual variability in dose requirements is influenced by a number of factors, including polymorphisms in genes mediating warfarin pharmacology, co-medication, age, sex, body size and diet.

AIMS

To develop population pharmacokinetic models of both R- and S-warfarin using clinical and genetic factors and to identify the covariates which influence the interindividual variability in the pharmacokinetic parameters of clearance and volume of distribution in patients on long-term warfarin therapy.

METHODS

Patients commencing warfarin therapy were followed up for 26 weeks. Plasma warfarin enantiomer concentrations were determined in 306 patients for S-warfarin and in 309 patients for R-warfarin at 1, 8 and 26 weeks. Patients were also genotyped for CYP2C9 variants (CYP2C9*1,*2 and *3), two single-nucleotide polymorphisms (SNPs) in CYP1A2, one SNP in CYP3A4 and six SNPs in CYP2C19. A base pharmacokinetic model was developed using NONMEM software to determine the warfarin clearance and volume of distribution. The model was extended to include covariates that influenced the between-subject variability.

RESULTS

Bodyweight, age, sex and CYP2C9 genotype significantly influenced S-warfarin clearance. The S-warfarin clearance was estimated to be 0.144 l h⁻¹ (95% confidence interval 0.131, 0.157) in a 70 kg woman aged 69.8 years with the wild-type CYP2C9 genotype, and the volume of distribution was 16.6 l (95% confidence interval 13.5, 19.7). Bodyweight and age, along with the SNPs rs3814637 (in CYP2C19) and rs2242480 (in CYP3A4), significantly influenced R-warfarin clearance. The R-warfarin clearance was estimated to be 0.125 l h⁻¹ (95% confidence interval 0.115, 0.135) in a 70 kg individual aged 69.8 years with the wild-type CYP2C19 and CYP3A4 genotypes, and the volume of distribution was 10.9 l (95% confidence interval 8.63, 13.2).

CONCLUSIONS

Our analysis, based on exposure rather than dose, provides quantitative estimates of the clinical and genetic factors impacting on the clearance of both the S- and R-enantiomers of warfarin, which can be used in developing improved dosing algorithms.     

EUS spectrum analysis for in vivo characterization of pancreatic and lymph node tissue: a pilot study

BACKGROUND: EUS is limited by variability in the examiner's subjective interpretation of B-scan images to differentiate among normal, inflammatory, and malignant tissue. By using information otherwise discarded by conventional EUS systems, quantitative spectral analysis of the raw radiofrequency (RF) signals underlying EUS images enables tissue to be characterized more objectively. OBJECTIVE: Our purpose was to determine the feasibility of using spectral analysis of EUS data for characterization of pancreatic tissue and lymph nodes. DESIGN AND SETTING: A pilot study of eligible patients was conducted to analyze the RF data obtained during EUS by using spectral parameters. PATIENTS: Twenty-one subjects who underwent EUS of the esophagus, stomach, pancreas, and surrounding intra-abdominal and mediastinal lymph nodes. MAIN OUTCOME MEASUREMENTS: Linear regression parameters of calibrated power spectra of the RF signals were tested to differentiate normal pancreas from chronic pancreatitis and from pancreatic cancer as well as benign from malignant-appearing lymph nodes. RESULTS: The mean intercept, slope, and midband fit of the spectra differed significantly among normal pancreas, adenocarcinoma, and chronic pancreatitis when all were compared with each other (P < .01). On direct comparison, mean midband fit for adenocarcinoma differed significantly from that for chronic pancreatitis (P < .05). For lymph nodes, mean midband fit and intercept differed significantly between benign- and malignant-appearing lymph nodes (P < .01 and P < .05, respectively). LIMITATIONS: Small sample population and spatial averaging inherent to this technique. CONCLUSIONS: Mean spectral parameters in EUS imaging can provide a noninvasive method to discriminate normal from diseased pancreas and lymph nodes.     

Nonshaved cranial surgery in black Africans: a short-term prospective preliminary study

BACKGROUND: Many studies on white populations have shown the absence of any scientific, or even beneficial, basis for the traditional preoperative ritual of shaving the operative field. We were not able to lay our hands on any document regarding this subject on any black African population. METHODS: We prospectively performed 17 cranial procedures in nonshaved fields in 15 selected black Africans in the Lagos State University Teaching Hospital, Ikeja, Nigeria. RESULTS: There was no serious complication recorded over a short-term follow-up of 2 to 6 months. The short, curly, crimpy, and densely knotted black African scalp hairs however did pose some unique perioperative challenges to us. CONCLUSIONS: Nonshaved cranial surgery, as in whites/Asians, can also be safely carried out in black Africans. This however demands some attention to details in the perioperative care of the incision sites. We found this caveat to be particularly more imperative in black Africans because of their unique anthropological scalp hair characteristics.     

Clinicopathology of childhood-onset renal systemic lupus erythematosus

AIMS: To determine the clinicolaboratory renal manifestations; glomerular, extra-glomerular histopathologic lesions; renal tubular dysfunction (RTD) frequency and outcome of a short-term renal follow up in Nigerian children with systemic lupus erythematosus (SLE). METHODS: A non-randomized prospective study of consecutive cases of childhood-onset SLE with nephropathy was conducted. Baseline/follow-up clinicolaboratory data were collected. Each patient was followed up for 12 months. RESULTS: Seven of the 11 children studied were girls. The median age at diagnosis was 11.0 years. Median diagnosis time interval (1.9 years) and median time of renal disease onset (1.0 year) were similar. Hypertension, nephrotic syndrome and acute renal failure (ARF) occurred in 45.5%, 54.5% and 63.7% of the patients, respectively. The glomerular lesions were non-proliferative lupus nephritis (LN) in 9.0% (class II LN); focal (class III LN) and diffuse (class IV LN) proliferative LN (PLN) in 27.0% and 64.0%, respectively. Tubulointerstitial nephritis (TIN, 91.0%) and RTD (64.0%) were common. ARF (P = 0.033) and RTD (P = 0.015) were significantly associated with severe TIN. Complete renal remission rate at end-point was 71.4%. Relapse and renal survival rates were 14.3% and 86.0%, respectively. RTD was persistent in 43.0%. CONCLUSION: Renal function disorders, diffuse PLN and extra-glomerular lesions were frequent. Significant association of ARF and RTD with severe TIN in this series suggests the need for early renal tubular function (RTF) assessment in our SLE patients. Deranged RTF may be marker of severe TIN in SLE warranting early confirmatory renal biopsy and aggressive interventional treatment.     

Neo‐adjuvant Capecitabine Chemotherapy in Women with Newly Diagnosed Locally Advanced Breast Cancer in a Resource‐poor Setting (Nigeria): Efficacy and Safety in a Phase II Feasibility Study

The majority of clinical trials of neo‐adjuvant therapy for breast cancer have been conducted in resource‐rich countries. We chose Nigeria, a resource‐poor country, as the major site for a phase II feasibility open‐label multicenter clinical trial designed to evaluate the efficacy, safety, and tolerability of neo‐adjuvant capecitabine in locally advanced breast cancer (LABC). Planned treatment consisted of 24 weeks of capecitabine at a dose of 1,000 mg/m² twice daily (2,000 mg/m² total per day). The primary endpoints were overall, partial, complete clinical response rate (OCR, PCR, CCR) and complete pathologic response (cPR). A total of 16 patients were recruited from August 2007 to April 2010. The study was terminated early as a result of slow accrual. After the first three cycles of therapy, PCR were seen in five of 16 patients (31%; 95% CI 11–59%). Of the remaining 11 patients, eight had no response (NR) or stable disease (SD), and three had progressive disease (PD). Seven patients proceeded with further therapy of which had SD. OCR at the end of eight cycles was 44% (95% CI 20–70%). Clinical response and radiologic response by ultrasonomammography were highly concordant (spearman correlation 0.70). The most common adverse effect was Grade 1 hand–foot syndrome, which was seen in 75% of patients. Despite several limitations, we successfully carried out this phase II feasibility study of neo‐adjuvant capecitabine for LABC in Nigeria. Capecitabine monotherapy showed good overall response rates with minimal toxicity and further studies are warranted.     

Staphylococcus sciuri gene erm(33), encoding inducible resistance to macrolides,lincosamides, and streptogramin B antibiotics,is a product of recombination between erm(C) and erm(A)

A gene which mediates inducible resistance to macrolides, lincosamides, and streptogramin B antibiotics, designated erm(33), was detected on the Staphylococcus sciuri plasmid pSCFS1. Analysis of the erm(33) reading frame suggested that this gene was the product of a recombination between an erm(C) gene and an erm(A) gene. Such a recombination event is a novel observation for erm genes.