Drug dosing during pregnancy—opportunities for physiologically based pharmacokinetic models

Drugs can have harmful effects on the embryo or the fetus at any point during pregnancy. Not all the damaging effects of intrauterine exposure to drugs are obvious at birth, some may only manifest later in life. Thus, drugs should be prescribed in pregnancy only if the expected benefit to the mother is thought to be greater than the risk to the fetus. Dosing of drugs during pregnancy is often empirically determined and based upon evidence from studies of non-pregnant subjects, which may lead to suboptimal dosing, particularly during the third trimester. This review collates examples of drugs with known recommendations for dose adjustment during pregnancy, in addition to providing an example of the potential use of PBPK models in dose adjustment recommendation during pregnancy within the context of drug-drug interactions. For many drugs, such as antidepressants and antiretroviral drugs, dose adjustment has been recommended based on pharmacokinetic studies demonstrating a reduction in drug concentrations. However, there is relatively limited (and sometimes inconsistent) information regarding the clinical impact of these pharmacokinetic changes during pregnancy and the effect of subsequent dose adjustments. Examples of using pregnancy PBPK models to predict feto-maternal drug exposures and their applications to facilitate and guide dose assessment throughout gestation are discussed

Early arm swelling after breast surgery: changes on both sides

Lymphedema is a common complication of treatment for breast cancer. However, little information is available describing changes in upper limb volumes in the early stages following surgery.Retrospective audit.Women who underwent unilateral mastectomy or axillary node removal for breast cancer at the Princess Alexandra Hospital, Brisbane, Australia.Circumferential measurements taken at 10 cm intervals from the ulnar styloid on each arm were converted to segmental volumes using the frustum approach.Pre-surgery baseline measures were taken by a physiotherapist at Preadmission Clinic at the Princess Alexandra Hospital. Follow-up measures were taken 6 weeks after surgery by Domiciliary Allied Health Acute Care and Rehabilitation Service physiotherapists in patients' homes.Limb segment volumes increased in the proximal upper limb segments at follow-up. The proportion of patients with a 10% or greater increase in volume in one or more segments of their upper limb were similar for ipsilateral (35%) and contralateral (32%) sides (to side of surgery), respectively. No significant interaction between time and arm (ipsilateral versus contralateral) was identified.These findings demonstrate that limb segment volume changes affect a greater proportion of patients during the first 6 weeks following surgery than previously recorded. They also indicate that flow of lymph from the side of surgery to the contralateral side may disperse lymph between sides during this early post-operative period. This has implications for how swelling is measured during this period and strategies to prevent onset of lymphedema

Fatores de risco para linfedema após câncer de mama: uma revisão da literatura Risk factors of arm lymphedema after breast cancer: a literature review

O linfedema representa uma das principais seqüelas do câncer de mama. Esta revisão da literatura visou discutir os principais fatores associados ao linfedema após o tratamento do câncer de mama. Foram selecionados 26 artigos publicados entre janeiro de 2000 e março de 2008 nas bases Medline e Lilacs, utilizando os descritores breast neoplasms, lymphedema, upper extremity, arm e risk factors. Sua revisão permitiu discutir os fatores relacionados ao linfedema, quanto a: clínica e paciente (tabagismo, escolaridade, etnia, comorbidades, hipertensão arterial, diabetes melito, menopausa, idade, peso corporal, índice de massa corporal, atividade física, membro dominante, restrição articular, infecção, seroma e trauma no membro superior); tratamento do câncer de mama (cirurgia, reconstrução mamária, número de linfonodos retirados, nível da linfadenectomia axilar, radioterapia, quimioterapia, hormonioterapia e tempo transcorrido após o tratamento); tumor (tamanho, grau, localização, comprometimento dos linfonodos axilares e estadiamento). A revisão feita indica que a linfadenectomia axilar, a radioterapia em cadeias de drenagem e a obesidade são fatores preponderantes do risco para desenvolvimento do linfedema.<br>Arm lymphedema is one of the most frequent sequelae of breast cancer treatment. The purpose of this literature review was to discuss main risk factors of lymphedema after breast cancer treatment. The search in Medline and Lilacs databases, by means of key words breast neoplasms, lymphedema, upper extremity, arm, and risk factors, allowed selecting 26 studies published between January, 2000, and March, 2008. This review discusses factors linked to: clinic and the patient (smoking, education level, race/ethnicity, comorbidity, hypertension, diabetes, menopause, age, weight, body mass index, physical activity, handedness, impaired range of motion, infection, seroma and arm injuries); breast cancer treatment (type of surgery, breast reconstruction, number of axillary lymph nodes removed, level of axillary surgery, radiotherapy, chemotherapy, tamoxifen treatment, and time-span after axillary lymph node dissection); tumour (size, grade, location, node status, number of positive nodes and stage of the tumour). This review shows that the axillary surgery, axillary radiotherapy and obesity are important risk factors of lymphedema