Sigurd Vitols

Lamotrigine in Pregnancy: Pharmacokinetics During Delivery, in the Neonate, and During Lactation

Summary: Purpose: To investigate the pharmacokinetics of lamotrigine (LTG) during delivery, during the neonatal period, and lactation.

HYPOCHOLESTEROLAEMIA IN MALIGNANCY DUE TO ELEVATED LOW-DENSITY-LIPOPROTEIN-RECEPTOR ACTIVITY IN TUMOUR CELLS: EVIDENCE FROM STUDIES IN PATIENTS WITH LEUKAEMIA

59 patients with acute leukaemia were examined to see if hypocholesterolaemia, which is commonly found in acute leukaemia, was due to the high low-density-lipoprotein (LDL)-receptor activity of leukaemic cells. LDL-receptor activity was found to be inversely correlated with plasma-cholesterol concentration. Patients with both a high LDL-receptor activity per cell and a high white-blood-cell count had the lowest cholesterol concentrations. During chemotherapy, cholesterol levels rose concomitantly with the disappearance from the peripheral blood of leukaemic cells. Hypocholesterolaemia in leukaemia and other neoplastic disorders may be due to increased LDL-receptor activity in the malignant cells. This high uptake and degradation of LDL by malignant cells could be utilised to target neoplastic cells with LDL-bound chemotherapeutic agents.

Lamotrigine in Pregnancy and Lactation: A case Report

Summary: Purpose: We investigated the effect of pregnancy on the kinetics of lamotrigine (LTG), passage of LTG over the placenta and the excretion of the drug in breast milk.

Influence of age on the metabolism of plasma low density lipoproteins in healthy males.

The plasma concentration of the atherogenic low density lipoproteins (LDL) increases with age. To clarify the mechanism of this change, we studied the kinetics of autologous 125I-LDL apolipoprotein B (apo B) in 41 normolipidemic, nonobese healthy males. For comparison, they were divided into three age groups: young, 21-39 yr (n = 18), middle-aged, 40-59 yr (n = 11), and old, 60-80 yr (n = 12). The levels of plasma LDL cholesterol and LDL apo B increased from respectively 3.4 +/- 0.1 (SEM) mmol/liter and 86 +/- 2 mg/dl in the young to 4.1 +/- 0.1 mmol/liter and 95 +/- 3 mg/dl in the old (P less than 0.01), and this increase was linked to a progressively decreased (r = -0.38, P less than 0.02) fractional catabolic rate of LDL apo B (0.348 +/- 0.010 pools per day in the young vs. 0.296 +/- 0.009 pools per day in the old, P less than 0.01). The production rate of LDL apo B did not differ significantly between the groups. The reduced fractional catabolic rate of LDL apo B in the old was not associated with a decrease in binding affinity of the LDL particle to its receptor, as judged from its ability to compete for 125I-LDL fibroblast binding. When hepatic LDL receptor expression was stimulated by cholestyramine treatment in six old males, their LDL apo B fractional catabolic rate increased to the levels observed in the young subjects. We conclude that the increase in LDL which normally occurs with age is explained by a reduced capacity for its removal, and hypothesize that this is mediated via a reduced hepatic LDL receptor expression.

Topiramate kinetics during delivery, lactation, and in the neonate : Preliminary observations

Summary:  Purpose: To study the pharmacokinetics of topiramate (TPM) during delivery, lactation, and in the neonate.

Pharmacokinetics of Gabapentin during Delivery, in the Neonatal Period, and Lactation: Does a Fetal Accumulation Occur during Pregnancy?

Summary:  Purpose: To study the pharmacokinetics of gabapentin (GBP) during delivery, lactation, and in the neonatal period.

Plasma concentrations of lamotrigine and its 2-N-glucuronide metabolite during pregnancy in women with epilepsy

Objective: To further characterize pregnancy‐induced alterations in the pharmacokinetics of lamotrigine (LTG).

Elevated uptake of low density lipoprotein by drug resistant human leukemic cell lines

Overexpression of a 170kD membrane glycoprotein, P-glycoprotein (Pgp), which acts as an energy dependent efflux pump for cytotoxic drugs is believed to be one of the factors that is responsible for clinical drug resistance. Recent studies suggest that Pgp is also responsible for the intracellular transport of cholesterol from the plasma membrane to the endoplasmic reticulum. Leukemic cells from patients with acute myelogenous leukemia have an elevated uptake of low density lipoprotein (LDL) when compared with white blood cells from healthy individuals. Since elevated LDL receptor expression and multidrug resistance are both common events in leukemic cells, we investigated LDL receptor expression in sensitive and drug resistant human leukemic cell lines. We found a 2- to 10-fold higher uptake of LDL in five out of five drug resistant K562 cell lines. All three drug resistant HL60 cell lines studied also had higher uptake than the parental cells. The LDL receptor expression in vincristine resistant Pgp positive K562 cells was less sensitive to downregulation by sterols than in parental cells. There was no selective effect of the Pgp inhibitor PSC-833 or other Pgp modulators on LDL receptor activity in Pgp positive cells. Since also resistant Pgp, multidrug resistance protein 1, and breast cancer resistance protein negative cells exhibited an elevated LDL receptor activity, we conclude that overexpression of these proteins is not the mechanism behind the elevated LDL uptake in the drug resistant leukemic cell lines. The findings are of interest for the concept of using lipoproteins as carriers of cytotoxic drugs in cancer treatment.

Simvastatin impairs mitogen-induced proliferation of malignant B-lymphocytes from humans--in vitro and in vivo studies.

Chronic lymphocytic leukemia (CLL) cells express lower low density lipoprotein (LDL) receptor activity and higher 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase activity than normal mononuclear blood cells indicating that CLL cells may depend on cholesterol synthesis for their proliferation. We studied the effects of competitive inhibitors of HMG-CoA reductase on malignant lymphocyte proliferation in vitro and in vivo. Tumor B-cells from 13 patients with CLL, hairy cell leukemia, or immunoblastic B-cell lymphoma were cultured for 4 d in the presence of B-cell mitogens and cholesterol synthesis inhibitors. Simvastatin and lovastatin suppressed, in a concentration-dependent manner, the mitogen-induced cellular thymidin uptake in medium with 10% human AB-serum or lipoprotein-deficient serum. Pravastatin was active only in medium with lipoprotein-deficient serum. Ten previously untrated patients with CLL received simvastatin orally, 40 mg daily for 12 wk. Mean reductions in total plasma and LDL cholesterol were 30% (range 9–46%) and 37% (range 16–63%), respectively. Cells from four patients showed moderate to minor increases in the degradation rate of 125I-LDL suggesting that the need for exogenous cholesterol had increased, three patients showed an increase in HMG-CoA reductase activity, and the cells from one patient showed both. There was no significant change in the clinical disease status during medication. However, four of the ten patients developed a therapy-demanding progressive disease during the subsequent year. Further clinical studies with cholesterol synthesis inhibitors in leukemia are warranted.

Metabolism of lipoprotein remnants in humans. Studies during intestinal infusion of fat and cholesterol in subjects with varying expression of the low density lipoprotein receptor.

To study the possible importance of the low density lipoprotein (LDL) receptor in regulating the degree of postprandial lipemia, a cholesterol-rich fat emulsion was infused into the duodenum of subjects who were divided into four groups based on the expected variation in the expression of the LDL receptor: young men (n = 11), elderly men (n = 7), male patients on estrogen therapy (n = 5), and patients with familial hypercholesterolemia (n = 9). In familial hypercholesterolemia, fasting plasma levels of lipoproteins of d less than 1.006 g/ml, intermediate density lipoproteins, and LDLs were increased. During the fat infusion, the cholesterol and triglyceride contents in the d less than 1.006 g/ml fraction increased to a similar extent in all groups, whereas a concomitant reduction of LDL cholesterol levels was observed. The degree of the decrease in LDL cholesterol was positively correlated with the observed increase in triglycerides in the d less than 1.006 g/ml fraction. There were no signs of accumulation of intermediate density lipoproteins during infusion in any of the groups studied. The results indicate that the capacity for clearance of chylomicrons and chylomicron remnants is not affected by variation in LDL receptor expression.