Peripartum Pharmacotherapy: A Pharmacist’s Guide Barnes, Kylie N.; Leader, Lauren D.; Cieri-Hutcherson, Nicole E. ...
Journal of Pharmacy Practice,
04/2024, Volume:
37, Issue:
2
Book Review, Journal Article
Peer reviewed
Complications throughout the peripartum period may be caused by preexisting conditions or pregnancy-induced conditions and may alter pharmacotherapy management. Pharmacotherapy management during late ...pregnancy and delivery requires careful consideration due to changing hormones, hemodynamic status, and pharmacokinetics, and concerns for potential maternal and/or fetal morbidity. Increased maternal and fetal monitoring are often required and may lead to therapy changes. Pharmacists, as key members of the interprofessional team, can contribute essential perspective to the management of postpartum pharmacotherapy through assessment and recommendation of appropriate and judicious use of medications.
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NUK, OILJ, SAZU, UKNU, UL, UM, UPUK, VSZLJ
Aim(s)
The current investigation aims to provide new insights into fetal exposure to tacrolimus in utero by evaluating maternal and umbilical cord blood (venous and arterial), plasma and unbound ...concentrations at delivery. This study also presents a case report of tacrolimus excretion via breast milk.
Methods
Maternal and umbilical cord (venous and arterial) samples were obtained at delivery from eight solid organ allograft recipients to measure tacrolimus and metabolite bound and unbound concentrations in blood and plasma. Tacrolimus pharmacokinetics in breast milk were assessed in one subject.
Results
Mean (±SD) tacrolimus concentrations at the time of delivery in umbilical cord venous blood (6.6 ± 1.8 ng ml−1) were 71 ± 18% (range 45–99%) of maternal concentrations (9.0 ± 3.4 ng ml−1). The mean umbilical cord venous plasma (0.09 ± 0.04 ng ml−1) and unbound drug concentrations (0.003 ± 0.001 ng ml−1) were approximately one fifth of the respective maternal concentrations. Arterial umbilical cord blood concentrations of tacrolimus were 100 ± 12% of umbilical venous concentrations. In addition, infant exposure to tacrolimus through the breast milk was less than 0.3% of the mother's weight‐adjusted dose.
Conclusions
Differences between maternal and umbilical cord tacrolimus concentrations may be explained in part by placental P‐gp function, greater red blood cell partitioning and higher haematocrit levels in venous cord blood. The neonatal drug exposure to tacrolimus via breast milk is very low and likely does not represent a health risk to the breastfeeding infant.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
A Survey on Ear Biometrics ABAZA, Ayman; ROSS, Arun; HEBERT, Christina ...
ACM computing surveys,
02/2013, Volume:
45, Issue:
2
Journal Article
Peer reviewed
Recognizing people by their ear has recently received significant attention in the literature. Several reasons account for this trend: first, ear recognition does not suffer from some problems ...associated with other non-contact biometrics, such as face recognition; second, it is the most promising candidate for combination with the face in the context of multi-pose face recognition; and third, the ear can be used for human recognition in surveillance videos where the face may be occluded completely or in part. Further, the ear appears to degrade little with age. Even though current ear detection and recognition systems have reached a certain level of maturity, their success is limited to controlled indoor conditions. In addition to variation in illumination, other open research problems include hair occlusion, earprint forensics, ear symmetry, ear classification, and ear individuality. This article provides a detailed survey of research conducted in ear detection and recognition. It provides an up-to-date review of the existing literature revealing the current state-of-art for not only those who are working in this area but also for those who might exploit this new approach. Furthermore, it offers insights into some unsolved ear recognition problems as well as ear databases available for researchers.
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IZUM, KILJ, NUK, PILJ, SAZU, UL, UM, UPUK
In gestational diabetes mellitus (GDM), women are unable to compensate for the increased insulin resistance during pregnancy. Data are limited regarding the pharmacodynamic effects of metformin and ...glyburide during pregnancy. This study characterized insulin sensitivity (SI), β‐cell responsivity, and disposition index (DI) in women with GDM utilizing a mixed‐meal tolerance test (MMTT) before and during treatment with glyburide monotherapy (GLY, n = 38), metformin monotherapy (MET, n = 34), or GLY and MET combination therapy (COMBO; n = 36). GLY significantly decreased dynamic β‐cell responsivity (31%). MET and COMBO significantly increased SI (121% and 83%, respectively). Whereas GLY, MET, and COMBO improved DI, metformin (MET and COMBO) demonstrated a larger increase in DI (P = 0.05) and a larger decrease in MMTT peak glucose concentrations (P = 0.03) than subjects taking only GLY. Maximizing SI with MET followed by increasing β‐cell responsivity with GLY or supplementing with insulin might be a more optimal strategy for GDM management than monotherapy.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Purpose
The purpose of this report is to describe, for the first time, the pharmacokinetics of dacarbazine (DTIC) and its metabolites 5-3-methyl-triazen-1-yl-imidazole-4-carboxamide (MTIC), ...5-3-hydroxymethyl-3-methyl-triazen-1-yl-imidazole-4-carboxamide (HMMTIC) and 5-aminoimidazole-4-carboxamide (AIC) during pregnancy (
n
= 2) and postpartum (
n
= 1).
Methods
Non-compartmental DTIC, MTIC, HMMTIC, and AIC pharmacokinetics (PK) were estimated in one case at 29 week gestation and 18 day postpartum and a second case at 32 week gestation, in women receiving DTIC in combination with doxorubicin, bleomycin, and vinblastine for treatment of Hodgkin’s lymphoma. Drug concentrations were measured by HPLC.
Results
In the subject who completed both pregnancy and postpartum study days, DTIC area under the concentration–time curve (AUC) was 27% higher and metabolite AUCs were lower by 27% for HMMTIC, 38% for MTIC, and 83% of AIC during pregnancy compared to postpartum. At 7 and 9 year follow-up, both subjects were in remission of their Hodgkin’s lymphoma.
Conclusions
Based on these two case reports, pregnancy appears to decrease the metabolism of the pro-drug dacarbazine, likely through inhibition of CYP1A2 activity. Lower concentrations of active metabolites and decreased efficacy may result, although both these subjects experienced long-term remission of their Hodgkin’s lymphoma.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The objectives of this study were to characterize and compare the metabolic profile of cyclosporine A (CsA) catalyzed by CYP3A4, CYP3A5 and human kidney and liver microsomes, and to evaluate the ...impact of the CYP3A5 polymorphism on product formation from parent drug and its primary metabolites. Three primary CsA metabolites (AM1, AM9 and AM4N) were produced by heterologously expressed CYP3A4. In contrast, only AM9 was formed by CYP3A5. Substrate inhibition was observed for the formation of AM1 and AM9 by CYP3A4, and for the formation of AM9 by CYP3A5. Microsomes isolated from human kidney produced only AM9 and the rate of product formation (2 and 20
μM CsA) was positively associated with the detection of CYP3A5 protein and presence of the
CYP3A5*1 allele in 4 of the 20 kidneys tested. A kinetic experiment with the most active
CYP3A5*1-positive renal microsomal preparation yielded an apparent
K
m (15.5
μM) similar to that of CYP3A5 (11.3
μM). Ketoconazole (200
nM) inhibited renal AM9 formation by 22–55% over a CsA concentration range of 2–45
μM. Using liver microsomes paired with similar CYP3A4 content and different CYP3A5 genotypes, the formation of AM9 was two-fold higher in
CYP3A5*1/*3 livers, compared to
CYP3A5*3/*3 livers. AM19 and AM1c9, two of the major secondary metabolites of CsA, were produced by CsA, AM1 and AM1c when incubated with CYP3A4, CYP3A5, kidney microsomes from
CYP3A5*1/*3 donors and all liver microsomes. Also, the formation of AM19 and AM1c9 was higher from incubations with liver and kidney microsomes with a
CYP3A5*1/*3 genotype, compared to those with a
CYP3A5*3/*3 genotype. Together, the data demonstrate that CYP3A5 may contribute to the formation of primary and secondary metabolites of CsA, particularly in kidneys carrying the wild-type
CYP3A5*1 allele.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Gestational diabetes mellitus is a condition similar to type 2 diabetes mellitus (T2DM) in that patients are unable to compensate for the degree of insulin resistance, and both conditions are often ...treated with metformin. The comparative pharmacodynamic response to metformin in these 2 populations has not been studied. This study characterized insulin sensitivity, β‐cell responsivity, and disposition index following a mixed‐meal tolerance test utilizing a minimal model of glucose, insulin, and C‐peptide kinetics before and during treatment with metformin. The study included women with gestational diabetes mellitus (n = 34), T2DM (n = 14), and healthy pregnant women (n = 30). Before treatment, the gestational diabetes mellitus group had significantly higher baseline (45%), dynamic (68%), static (71%), and total β‐cell responsivity (71%) than the T2DM group. Metformin significantly increased insulin sensitivity (51%) as well as disposition index (97%) and decreased mixed‐meal tolerance test peak glucose concentrations (8%) in women with gestational diabetes mellitus after adjustment for gestational age–dependent effects; however, in women with T2DM metformin only significantly affected peak glucose concentrations (22%) and had no significant effect on any other parameters. Metformin had a greater effect on the change in disposition index (Δ disposition index) in women with gestational diabetes mellitus than in those with T2DM (P = .01). In conclusion, response to metformin in women with gestational diabetes mellitus is significantly different from that in women with T2DM, which is likely related to the differences in disease severity.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
To characterize the pharmacokinetics and pharmacogenetics of nifedipine in pregnancy.
Pregnant women receiving oral nifedipine underwent steady-state pharmacokinetic testing over one dosing interval. ...DNA was obtained and genotyped for cytochrome P450 (CYP) 3A5 and CYP3A4*1B. Nifedipine and oxidized nifedipine concentrations were measured in plasma, and pharmacokinetic parameters were compared between those women who expressed a CYP3A5*1 allele and those who expressed only variant CYP3A5 alleles (*3,*6, or *7).
Fourteen women had complete data to analyze. Four women (29%) expressed variant CYP3A5; three of these women were also CYP3A4*1B allele carriers. The mean half-life of nifedipine was 1.68 ± 1.56 hours. The area under the curve from 0 to 6 hours for the women receiving nifedipine every 6 hours was 207 ± 138 µg·h /L. Oral clearance was different between high expressers and low expressers (232.0 ± 37.8 µg/mL versus 85.6 ± 45.0 µg/mL, respectively; p = 0.007).
CYP3A5 genotype influences the oral clearance of nifedipine in pregnant women.
Studies in rodents indicate that the disruption of P-glycoprotein (P-gp) function increases drug distribution into the developing fetus and organs such as the brain. To simultaneously and serially ...evaluate the effect of P-gp activity and inhibition on the tissue distribution of drugs in a more representative animal model, we tested the feasibility of conducting whole-body PET of the pregnant nonhuman primate (Macaca nemestrina). We used (11)C-verapamil as the prototypic P-gp substrate and cyclosporine A (CsA) as the prototypic inhibitor.
Four pregnant macaques (gestational age, 145-159 d; gestational term, 172 d) were imaged after the intravenous administration of (11)C-verapamil (30-72 MBq/kg) before and during intravenous infusion of CsA (12 or 24 mg/kg/h, n = 2 each). The content of verapamil and its metabolites in plasma samples was determined using a rapid solid-phase extraction method. The plasma and tissue time-radioactivity concentration curves of (11)C were integrated over 0-9 min after each verapamil injection. The tissue or arterial plasma area under the time-concentration curve (AUC(tissue)/AUC(plasma)) served as a measure of the tissue distribution of (11)C radioactivity. CsA effect on (11)C radioactivity distribution was interpreted as P-gp inhibition. The change in the fetal liver AUC ratio served as a reporter of placental P-gp inhibition.
CsA effect on tissue distribution of (11)C radioactivity (AUC ratios) did not increase with the mean blood concentration of CsA, indicating a near-maximal P-gp inhibition. CsA increased maternal brain and fetal liver distribution of (11)C radioactivity by 276% +/- 88% (P < 0.05) and 122% +/- 75% (P < 0.05), respectively. Changes in other measured tissues were not statistically significant.
These data demonstrate for the first time, to our knowledge, the feasibility of simultaneous, serial, noninvasive imaging of P-gp activity and inhibition in multiple maternal organs and the placenta in the nonhuman primate. Our findings, consistent with previous data in rodents, indicate that the activity of P-gp in the placenta and the blood-brain barrier is high and that the inhibition of P-gp facilitates drug distribution across these barriers.
Clonidine is a centrally acting, alpha-2 adrenergic agonist used for the treatment of hypertension during pregnancy. The metabolic pathways of clonidine are poorly understood, and the quantitative ...contribution of specific human cytochrome P450 (P450) isoforms has not been systematically assessed. In this study, 17 cDNA-expressed P450 enzymes, in addition to pooled human liver microsomes, were evaluated for clonidine 4-hydroxylation activity in vitro. Five P450 enzymes-CYP2D6, 1A2, 3A4, 1A1, and 3A5-catalyzed measurable formation of 4-hydroxyclonidine. Selective inhibition studies in human liver microsomes confirmed that these isoforms are jointly responsible for 4-hydroxylation of clonidine in vitro, and CYP2D6 accounted for approximately two-thirds of the activity. The major role of CYP2D6 in clonidine metabolism might explain the increase in its nonrenal clearance during pregnancy.
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