ABSTRACT:The antidiabetic agent glyburide (glibenclamide) is frequently used for the treatment of type II diabetes and is increasingly being used for the treatment of gestational diabetes. Evidence suggests that breast cancer resistance protein/ATP-binding cassette, subfamily
Prescription and over-the-counter drug use during pregnancy is necessary for many women today. A study of US and Canadian women found that, on average, 2.3 drugs were used during pregnancy; however, 28% reported using more than 4. For some women, this is because they become pregnant with preexisting conditions that require ongoing or intermittent pharmacotherapy. For others, this is because pregnancy itself can give rise to new medical conditions such as gestational diabetes and preeclampsia. The principal concern of prescribing physicians is whether or not agents will harm the fetus (i.e., have teratogenic effects). This concern rose to prominence primarily as a result of the thalidomide disaster. Marketed for use in morning sickness, thalidomide was found to be a potent teratogen capable of producing a variety of birth defects relating to development. Consequently, determining the teratogenicity of new drugs currently dominates the objectives of pregnancy-relevant experiments conducted throughout drug development. This often comes at the expense of valuable pharmacokinetic (PK) studies, which are seldom performed pre-market. Sex differences in PK parameters have been demonstrated in animals and humans since the 1930s. It is, therefore, not surprising that differences also arise in pregnancy. A wide array of physiological and hormonal changes occur during pregnancy; most begin early in the first trimester and increase linearly until parturition. Physicians lacking adequate PK information typically prescribe the standard adult dose in pregnancy, and this can be either inadequate or excessive depending on a variety of factors. The purpose of this report is to highlight this issue and illustrate how current methods used to obtain PK data in pregnancy are insufficient. The steps that are being taken to address this issue will also be discussed.
Purpose
The authors report a seven-year-old male, designated FR, with severe sensorineural hearing loss. Features include round face, hypertelorism, epicanthal folds, and flat nasal root. Although there were early developmental concerns, all but his speech delay resolved when he was placed in an educational program that accommodated his hearing loss. To investigate genetic causes for his hearing loss, genetic studies were performed.
Methods
History, physical examination, audiologic assessment, and imaging were performed according to usual practice. FMR1, GJB2, GJB6, and POU3F4 genes were sequenced. Chromosomal studies consisted of karyotyping and breakpoint analysis by fluorescence in situ hybridization (FISH).
Results
Results from FMR1, GJB2, GJB6, and POU3F4 sequencing and echocardiography, ECG, and abdominal ultrasound were normal. CT revealed a large fundus of the internal auditory canals and absence of the bony partition between the fundus and the adjacent cochlear turns with a widened modiolus bilaterally. CT findings are consistent with those described in persons with DFNX2 hereditary deafness. His karyotype was 46,inv(X)(q13q24),Y.ish inv(X)(XIST+)mat. FISH refined the breakpoints to inv(X)(q21.1q22.3). The Xq21.1 breakpoint was narrowed to a 25 kb region 450 kb centromeric to the DFNX2 gene, POU3F4. There are rare case reports of DFNX2 patients with chromosomal rearrangements positioned centromeric to POU3F4 and no mutations within the gene.
Conclusions
We hypothesize that FR's hearing loss is caused by dysregulation of POU3F4 due to separation from regulatory elements affected by the inversion.
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