Epidemiology of hypertension during pregnancy.

Hypertension during pregnancy, defined as a diastolic blood pressure of at least 90 mm Hg, occurs in about 7% of Western countries. Primiparity and familial factors are the most important risk factors. Fifty percent of women experienced blood pressure elevation as late as the last month of pregnancy.

Plasma-free amino acid concentrations during ketamine anesthesia in the rhesus monkey: a short methodological study.

The effect of ketamine anesthesia on the pattern of free amino acids in plasma was investigated in four healthy non-pregnant rhesus monkeys. Blood samples were collected at intervals during a period of 150 min both with and without anesthesia. Repeated measures analysis of variance, with time and ketamine/control as trial factors, was used. In only four amino acids were any changes with time or with ketamine treatment observed, the rest remaining unchanged. Ketamine anesthesia seemed to reduce the concentrations of several amino acids, but the findings were not conclusive.

The rhesus monkey as a model for studies of pregnancy induced changes in metoprolol metabolism.

Five pregnant Rhesus monkeys were catheterized in the hepatic and femoral veins. They were simultaneously given 168 or 176 micrograms of 3H-metoprolol intravenously, and 9 mg of metoprolol per kg body weight orally. The same procedure was repeated a few months after delivery. Analyses of the unlabelled drug in blood were made by gas-chromatography and of the 3H-labelled metoprolol, by liquid scintillation. The apparent volume of distribution as well as the terminal half-lives of metoprolol were in the same range during pregnancy and in non-pregnancy. The oral bioavailability of metoprolol was lower (6-22%) during pregnancy than in non-pregnancy (9-49%). The apparent oral clearance and the intrinsic hepatic clearance were in a similar range although there was a greater variation in the intrinsic clearance values. The former clearance estimate was lower in the non-pregnant state only for three of the five animals. The systemic clearance varied very little and was in the same range during pregnancy and in non-pregnancy. The changes in apparent oral clearance and in oral bioavailability of metoprolol between the pregnant and non-pregnant Rhesus monkey are similar to the changes observed in pregnant women, although the absolute values are different.

Amino acid transport across the placenta measured by positron emission tomography and analyzed by compartment modelling.

The materno-fetal transfer of methionine in the Rhesus monkey was investigated using positron emission tomography, a non-invasive in vivo tracer technique based on short-lived radionuclides. A bolus dose of [11CH3]-l-methionine was administered intravenously and the radioactivity concentrations in the placenta, the fetus and the maternal arterial blood were measured as functions of time and fitted to an equation derived from a four compartment model of the feto-placental complex. Rate constants were calculated describing maternal placental blood flow, the transfer of [11CH3]-l-methionine to the placental tissue and the fetus. The transfer rate of methionine to the fetus was estimated as 0.8-1.5 nmol/min/g placenta and was similar to the transfer to the placental tissue. An approximate blood flow through the intervillous space of 128 ml/min was found. The correlation between placental transfer to the fetus and the maternal blood flow in the intervillous space was low.

Regional distribution of the opioid receptor agonist N-(methyl-11C)pethidine in the brain of the rhesus monkey studied with positron emission tomography.

The regional distribution and kinetics in the brain of Rhesus monkeys of N-(methyl-11C)-pethidine have been studied by positron emission tomography, PET. 11C-Pethidine reached the brain with peak radioactivities appearing within 6-10 min. after administration. Highest radioactivities were measured in areas corresponding to the thalamus, the striatal area and also the lowest transection of the temporal lobes, with an uptake of 2.7-3.1 times the homogenous dilution of the radioactive dose. Low radioactivities were seen in the cerebellum and the occipital lobes. This distribution corresponds to the regional density of opioid receptors using in vitro binding techniques. The 11C-pethidine derived radioactivity left the brain with an initial half-life of 40-60 min., followed by an elimination which paralleled the plasma elimination of unlabelled pethidine. After pretreatment of the monkey with a small dose of naloxone, the radioactivities decreased about 40% in areas corresponding to the thalamus, striatum and lowest section of the temporal lobes, indicating competition for the same binding sites. By the use of a three-compartment model, it was possible to get an estimate of 11C-pethidine receptor binding characteristics in the brain. The ratio of Kon/Koff, equal to Bmax./Kd, was 0.06-0.1. This indicates that pethidine is bound with low affinity to the opioid receptors and is a poor ligand for studies of opioid receptor function with PET. Brain kinetics of 11C-pethidine is mainly determined by its blood kinetics.

Distribution of 11C-labelled morphine and pethidine after spinal administration to Rhesus monkey.

The kinetics of 11C-labelled morphine and pethidine were studied by positron emission tomography (PET) at different levels of the spinal canal (C4, T4, T5, T6, L1 and L6). Studies were performed in the Rhesus monkey after intrathecal and extradural administration of the drugs at the lumbar level (L3-L4 or L4-L5, seven experiments). Radioactivity 100-300 times higher than with even distribution in the body was measured initially near the site of injection for both morphine and pethidine, irrespective of the route of administration. After injection of pethidine, high activity was observed at the L6 and L1 levels, whilst the radioactive uptake was lower at T6 (10-20% of those at lumbar level). Morphine-derived 11C-radioactivity showed more constant levels along the spinal canal, except at C4 where radioactivity was low. In CSF taken from the cervical level the peaks of radioactivity of the two drugs appeared 80-170 min after injection. The importance of different distribution routes was quantified in a pharmacokinetic compartment model, using the above results. The systemic distribution was extensive, irrespective of drug or route of administration. From the site of injection the systemic distribution was at least 60 times larger than the rostral distribution within the spinal canal.

Positron emission tomography in studies on fetomaternal disposition of opioids.

The noninvasive radiotracer technique, positron emission tomography, has been applied in studies on the transfer of drugs from mother to fetus in Rhesus monkeys. 11C-labelled morphine or heroin was administered intravenously to pregnant monkey and the radioactivities with time were measured in the placenta, fetal liver and maternal blood. The information from the 11C-morphine experiment was supplemented with data from the simultaneous administration of 14C-morphine followed by the analysis of unchanged drug and metabolites in maternal blood and also in one sample from fetal blood. In placenta, 11C-morphine and 11C-heroin rapidly reached high radioactivities already within the first few minutes after administration. The transfer of 11C-morphine-derived radioactivity to the fetus was also rapid, although there was a lag-time in relation to the placental uptake. The elimination rate of the radioactivity was fast from the blood, placenta and the fetal liver and in plasma there was a rapid appearance of conjugated morphine metabolites. The fetal plasma concentration of morphine was twice that in maternal plasma 100 min after injection. The transfer of 11C-heroin-derived radioactivity to the fetus was even faster than was the elimination of radioactivity. The plasma kinetics of morphine in the mother and fetus was simulated in a compartment flow model and simulated concentrations agreed well with measured values.

Urinary excretion of a glucose-containing tetrasaccharide. A parameter for increased degradation of glycogen.

The urinary excretion of a glucose-containing oligosaccharide, Glc alpha[1-6Glc alpha[1-4Glc alpha[1-4Glc, (Glc4) has been measured in various physiological and pathological conditions. The Glc4 content of 24 h samples from the same individual was relatively constant, whereas 2 h samples showed up to 4-fold variations in Glc4 concentration. This variation is associated mainly with increased excretion of Glc4 after meals. A carbohydrate-rich diet, starvation or a protein-rich diet, and intense physical activity all affected the urinary excretion of Glc4. Both oral and intravenous administration of glycogen in a Rhesus monkey resulted in increased excretion of Glc4. When Glc4 itself was injected intravenously in small amounts renal clearance was rapid and complete. In contrast, injection of a larger amount resulted in incomplete (approximately 10%) renal clearance, probably due to uptake and metabolism of the oligosaccharide. In patients with glycogen storage diseases, certain malignancies, and pancreatitis, 24 h urinary Glc4 excretion exceeded the normal range. The diagnostic implications of these observations deserve evaluation. The results presented suggest a need for standardization of nutritional status and physical activity when monitoring urinary Glc4 excretion for diagnostic purposes.

Influence of monoamine oxidase inhibitors and a dopamine uptake blocker on the distribution of 11C-N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, 11C-MPTP, in the head of the rhesus monkey.

N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, MPTP, is a neurotoxic substance known to induce a parkinsonian syndrome in primates. The distribution of intravenously injected 11C-labelled MPTP (11C-MPTP) in the head of Rhesus monkeys was studied by means of positron emission tomography, PET. The influence of pretreatment with two monoamine oxidase (MAO) inhibitors, namely pargyline and clorgyline, and a dopamine uptake blocker, nomifensine, on the distribution was also evaluated. The 11C-radioactivity was taken up in all brain regions and maximum radioactivities were found 3-8 min after intravenous administration of MPTP. The 11C-MPTP-derived radioactivity showed a constant value throughout the study period in areas corresponding to the striatum and mesencephalon in monkeys not pretreated and in monkeys pretreated with clorgyline and with nomifensine. Pargyline pretreatment, however, resulted in consecutive elimination of 11C-MPTP-derived radioactivity from the different brain regions with half-lives of 40-60 min. The total radioactivity in blood was also higher after pargyline pretreatment indicating successful inhibition of metabolism. The eyes and temporal muscle each showed radioactivity values of the same order in all monkeys irrespective of pretreatment. The results support findings by other authors that MPTP was rapidly converted in the brain to a reactive metabolite which concentration remained constant in the brain during the PET study. Pargyline in the dosage used is known to be a non-selective MAO inhibitor and it prevented the metabolism of 11C-MPTP to the products retained in the brain.(ABSTRACT TRUNCATED AT 250 WORDS)

The risk of endometrial neoplasia and treatment with estrogens and estrogen-progestogen combinations. First results of a cohort study after one to four completed years of observation.

This prescription-based cohort investigation was undertaken in order to study whether climacteric estrogen treatment of women in a Swedish population might be associated with an increased risk of endometrial cancer, and whether added progestogens can afford any protection from developing estrogen-related endometrial neoplasia. Some 23 000 women who had been prescribed estrogens were followed up regarding the outcome of neoplastic lesions of the endometrium. The results are based on an observation period of one to four completed years, corresponding to 89 000 person-years. Among those cohort members exposed to estrogens alone, regardless of the duration, the relative risk of endometrial cancer was 1.3 (95% confidence interval 0.9 to 1.7). The inclusion of premalignant endometrial changes resulted in a significantly increased relative risk of 1.6 (1.2-2.1). The relative risk estimates in association with estrogen-progestogen combinations were 0.6 (0.2-1.4) for endometrial cancer and 0.8 (0.4-1.5) when including premalignant lesions. These data indicated a possible protective effect of progestogens against the development of endometrial neoplasia. It was concluded that estrogens were - within an observation period of 4 years - associated with an increased risk of premalignant endometrial lesions.

A prospective controlled trial of metoprolol-hydralazine treatment in hypertension during pregnancy.

In an open, controlled trial, treatment with a combination of metoprolol and hydralazine was compared with non-pharmacological management of mild and moderate hypertension in pregnancy. One hundred and sixty-one women participated in the study. The drug-treated group showed significantly better blood pressure control than the group not given antihypertensives. Induction of labor before term, because of maternal or fetal complications, was somewhat more frequent in the control group. Nine women in the treatment group and 5 in the control group developed albuminuria. Three infants in the drug-treated group died perinatally, and one in the control group. The outcome for the newborns was similar in both groups concerning birth weight, head circumference and Apgar score and in the frequencies of respiratory distress, bradycardia and hypoglycemia. The better blood pressure control achieved with these drugs makes it possible to treat the patient at home and reduce the risk of emergency delivery, but treatment does not seem to be mandatory for a good outcome of the pregnancy in cases of mild and moderate hypertension during pregnancy.

Positron emission tomography in experimental perinatology.

Positron emission tomography (PET) is a new tracer technique by which short-lived radionuclides, such as 11C are used for labeling drugs, amino acids and other compounds. The concentration in the various organs is determined non-invasively after I.V. injection. Positrons, emitted by 11C attract an electron, and the two masses are annihilated by emitting photons. These can be registered by external detectors. Measurement of the radioactivity per volume of tissue as a function of time is accomplished by computerized processing of the data. The PET technique may be used for studies of the kinetics of the injected compound in different organs of the body. However, PET registers only the total radioactivity meaning that the measured 11C-radioactivity represents the sum of the parent compound and the radiolabelled metabolites. Chemical and radiochemical analyses in various body fluids may then help to interpret the PET images.

Fetal blood sampling through ultrasound-guided puncture of the umbilical vein in rhesus monkeys.

Fetal blood was obtained through puncture of the umbilical vein in Rhesus monkeys. The puncture needle was introduced during direct visual control through ultrasound. This method offers a possibility to obtain fetal blood without opening the uterine cavity. Injection into the fetal circulation is also possible.

11C-methionine kinetics in pregnant rhesus monkeys studied by positron emission tomography: a new approach to feto-maternal metabolism.

By use of Positron Emission Tomography (PET), dynamic studies of the metabolism within the feto-maternal unit can be performed using various tracers. Many compounds like amino acids, carbohydrates, fatty acids and drugs can be performed using various tracers. Many compounds like amino acids, carbohydrates, fatty acids and drugs can be labelled with 11C and used as tracers. 11C-labelled L- or D-methionine was injected intravenously into pregnant Rhesus monkeys. The distribution of the radioactivity in maternal muscles, aorta, placenta and the liver of the fetus was quantitatively estimated as a function of time. Simultaneously blood, urine and amniotic fluid samples were analyzed for 11C-activity. The distribution of 11C between the high and the low molecular fraction of plasma (MW greater than 5000) was studied after gel filtration. Both when 11C-L- and D-methionine were given, the radioactivity rapidly crossed the placenta and was accumulated in the fetal liver. In the 11C-L-methionine experiments, about 70 per cent of the radioactivity in plasma was found in the high molecular fraction one hour after injection. A greater part of 11C-D-compared to 11C-L-activity was excreted in the urine.