Lopinavir protein binding in HIV‐1‐infected pregnant women

Background

Pregnancy may alter protein binding (PB) of highly bound protease inhibitors due to changes in plasma concentrations of albumin and α‐1 acid glycoprotein (AAG). Small changes in PB can greatly impact the fraction of drug unbound (FU) exerting pharmacological effect. We report lopinavir (LPV) PB during third trimester (antepartum, AP) compared to ≥1.7 weeks postpartum (PP) to determine if FU changes compensate for reduced total concentrations reported previously.

Methods

P1026s enrolled women receiving LPV/ritonavir, soft gel capsules 400/100 mg or 533/133 mg twice daily. LPV FU, albumin and AAG were determined AP and PP.

Results

AP/PP samples were available from 29/25 women respectively with all but one woman receiving the same dose AP/PP. LPV FU was increased 18% AP vs. PP (mean 0.96±0.16% AP vs. 0.82±0.21% PP, P=0.001). Mean protein concentrations were reduced AP (AAG=477 mg/L; albumin=3.28 mg/dL) vs. PP (AAG=1007 mg/L; albumin=3.85 mg/dL) (P<0.0001 for each comparison). AAG concentration correlated with LPV binding. Total LPV concentration did not correlate with LPV FU AP or PP. However, higher LPV concentration PP was associated with reduced PB and higher FU after adjustment for AAG.

Conclusions

LPV FU was higher and AAG lower AP vs. PP. The 18% increase in LPV FU AP is smaller than the reduction in total LPV concentration reported previously and is not of sufficient magnitude to eliminate the need for an increased dose during pregnancy.

     

Homozygous cystinuria and the oculo-cerebro-renal dystrophy of Lowe in same family

The mother and daughter in a family had homozygous cystinuria and were also heterozygous carriers of the oculo-cerebro-renal dystrophy of Lowe. The daughter was also epileptic. The son had Lowe's syndrome and the father an increased urinary excretion of cystine and lysine. This evidence together with other case reports suggests that the defect in cystinuria and that of Lowe's syndrome may be connected.     

Urinalysis and the plain abdominal radiograph in the diagnosis of ureteric colic

Objectives : 1. To investigate the diagnostic accuracy of urinalysis and the plain abdominal radiograph in predicting positive intravenous pyelography for patients with a history and examination suggestive of ureteric colic. 2. To examine the disposition of patients presenting to the emergency department with ureteric colic. Methods : A retrospective cohort study set in a tertiary referral hospital emergency department over a 12‐month period was conducted. Three hundred and eighteen patients who presented with a provisional diagnosis of ureteric colic and had intravenous pyelography were identified from radiology department logs and emergency department discharge International Classification of Disease‐9 codes. Results : Three hundred and eighteen patients were identified. Sixty‐nine per cent had positive intravenous pyelography. Sensitivity and specificity of: urinalysis were 93% and 41%; abdominal X‐ray, 57% and 83%; and urinalysis plus abdominal X‐ray, 99% and 36%, respectively. Seventy‐seven per cent were admitted to the emergency department observation ward. Twenty‐seven per cent were subsequently admitted under the hospital’s urology service. Conclusions : Sex, haematuria and the presence of a calculus on abdominal X‐ray were all significant predictors of positive intravenous pyelography. Haematuria was sensitive but not specific for positive intravenous pyelography. The addition of the abdominal X‐ray marginally improves the diagnostic accuracy.     

Mutations in RPSA and NKX2‐3 link development of the spleen and intestinal vasculature

Idiopathic intestinal varicosis is a developmental disorder defined by dilated and convoluted submucosal veins in the colon or small bowel. A limited number of families with idiopathic intestinal varices has been reported, but the genetic cause has not yet been identified. We performed whole‐exome and targeted Sanger sequencing of candidate genes in five intestinal varicosis families. In four families, mutations in the RPSA gene were found, a gene previously linked to congenital asplenia. Individuals in these pedigrees had intestinal varicose veins and angiodysplasia, often in combination with asplenia. In a further four‐generation pedigree that only showed intestinal varicosities, the RPSA gene was normal. Instead, a nonsense mutation in the homeobox gene NKX2‐3 was detected which cosegregated with the disease in this large family with a LOD (logarithm of the odds) score of 3.3. NKX2‐3 is a component of a molecular pathway underlying spleen and gut vasculature development in mice. Our results provide a molecular basis for familial idiopathic intestinal varices. We provide evidence for a relationship between the molecular pathways underlying the development of the spleen and intestinal mucosal vasculature that is conserved between humans and mice. We propose that clinical management of intestinal varices, should include assessment of a functional spleen.