Alteration of cytochrome P-450 by prolonged administration of imipramine and/or lithium to rats

Summary The aim of this study was to investigate imipramine-induced alterations of cytochrome P-450 and to determine whether prolonged concomitant administration of imipramine and lithium results in a pharmacokinetic interaction.Male Wistar rats received imipramine (10 mg/kg i. p.) at 12 h intervals or lithium chloride (100 mg/kg in drinking water) or they were treated with the combination of these drugs for 2 weeks. The long term treatment with imipramine produced a very complex alteration of cytochrome P-450: imipramine increased the level of the cytochrome, but it decreased the rate of its own aromatic hydroxylation in position 2. The rate of N-demethylation in the side chain was not changed. Consequently, in the case of both hydroxylation and demethylation, calculated molecular activities were decreased to 48% and 70% respectively. This differential change in activities corresponded well to the observed decrease of absorption in difference spectra (type I) produced in microsomes by imipramine. Carbamazepine-induced type I difference spectra were also decreased by imipramine pretreatment, but to a lesser extent. In contrast, hexobarbital type I binding was increased by imipramine treatment while type II difference spectra produced by metyrapone were not affected. The preliminary SDS-PAGE analysis of cytochrome P-450 isoenzymes of control and imipramine treated rats showed that the investigated antidepressant markedly intensified a protein band at 50.11 kD while bands at 51.28 kD, 56.20 kD and 56.88 kD were less intensive. These results indicate that the alteration of cytochrome P-450 by imipramine treatment is not only of quantitative but also of qualitative character. Lithium alone given to rats affected neither the concentration of cytochrome P-450 in microsomal protein nor the rate of imipramine metabolism in vitro. Lithium given jointly with imipramine reduced imipramine-induced elevation of cytochrome P-450. This, however, did not cause any change in the rate of imipramine metabolism in vitro and accordingly in imipramine pharmacokinetics in vivo. The concentration of lithium in the blood plasma tended to increase by concurrent administration of imipramine.Send offprint requests to K. J. Netter at the above address     

Microalbuminuria in diabetes: relationships between urinary albumin excretion and diabetes-related variables

A single observer reviewed 842 of the 917 known diabetic patients registered with 40 GPs in the Poole area. Fifty-nine per cent (493) of those reviewed submitted a timed overnight urine collection to measure albumin excretion rate (AER) and overnight albumin/creatinine ratio (ON-Alb/Creat); 43 samples were excluded because of urinary tract infection and/or proteinuria. A random urine sample was obtained in 607 diabetic patients to measure the random albumin/creatinine ratio (R-Alb/Creat); 68 specimens were excluded because of infection and/or proteinuria, and in a further 10 samples urinary creatinine was not measured. Stepwise multiple regression analyses found significant associations with the following variables: for AER, blood glucose (p = 0.001), smoking category (p = 0.002), sex (p = 0.034), and systolic blood pressure (p = 0.035); for R-Alb/Creat, blood glucose (p = 0.001), retinopathy (p = 0.004), systolic blood pressure (p = 0.004), diastolic blood pressure (p = 0.015), coronary artery disease (p = 0.02), sex (p = 0.034), and vibration sense (p = 0.038). Interestingly, glycosylated haemoglobin was not a significant determinant of albuminuria in either analysis.     

Lens alpha-neoproteins

The formation of lens alpha-neoprotein molecules which are built by the association of A and B subunit chains of alpha-crystallin but have a different quaternary structure than the native protein is a posttranslational process that progresses through the life span. Alpha-neoproteins occur regularly in all mature mammalian lenses tested. The mechanisms that have been identified for the formation of alpha neoproteins are imbalance in the biosynthesis of A- to B-chains, which leads to a ratio of less than 2A-chains to 1B-chain, and derivation of the chains after their initial association into native alpha-crystallin. In terms of quantity of neoproteins, no significant differences have been found between lenses with developing cataracts and normal control lenses of corresponding age. The possibility that there are structural differences between alpha-neoproteins in normal and cataractous lenses of the same age, as well as potential differences among alpha-neoproteins isolated from normal lenses of different ages, are presently under investigation.     

Autogeny in Culex salinarius from Texas, Florida and New Jersey

Autogeny was studied in Culex salinarius from College Station, Texas; Vero Beach, Florida; and Edison and Dennisville, New Jersey. Autogenous egg development varied from 14% in the Florida colony to 23 and 27%, respectively, in colonies from Texas and New Jersey. The mean number of eggs per autogenous female ranged from 13.5 to 23.7. As in other autogenous mosquitoes, the expression of autogeny was dependent on larval and adult diets. Mating did not influence autogeny as it does in some mosquitoes. Autogeny in Cx. salinarius was obligate at warm temperatures, but females denied a bloodmeal appeared to undergo facultative autogeny at colder temperatures.     

Clinicopathologic correlation of pigmented epiretinal membranes

We performed clinicopathologic correlation on ten surgically removed pigmented epiretinal membranes causing macular pucker. All cases occurred in eyes with existing retinal holes or tears, including eight cases of macular pucker after previous retinal detachment. These cases probably represented a limited form of proliferative vitreoretinopathy. All membranes contained pigment epithelial cells with polarity, basement membrane, and melanosomes. Cytoplasmic melanin granules accounted for the clinical feature of pigmentation in these eyes.     

Influence of site of obstetric care and delivery on pregnancy management and outcome

A retrospective cohort study of 863 pregnancies cared for by family physicians at three sites--rural-rural (RR), rural-urban (RU), and urban-urban (UU)--was designed to test the hypothesis that ready on-site access to perinatal subspecialists would improve pregnancy outcome. No differences in delivery type, length of gestation, birth weight, or nursery care were found. An Apgar score of less than 7 at 1 minute or less than 8 at 5 minutes was 2.17 and 2.31 times more likely at RU and 2.48 and 2.60 times more likely at UU, respectively, than at RR. The overall Cesarean section rate was 9.6 percent, forceps rate was 7.2 percent, and nonroutine nursery care rate was 7.9 percent. Neonatal and perinatal mortality rates were 3.5 and 4.6 per 1,000 live births. There is no evidence that on-site perinatal subspecialists improve perinatal outcome when care is provided by board-certified family physicians. Small obstetric centers provide quality perinatal care with outcome dependent on physician's skill rather than on technology.     

Body fat in normal adults estimated by oxygen-18- and deuterium-dilution and by anthropometry: a comparison

We estimated body fat in 20 normal adults (10 males and 10 females) from 18O- and 2H-dilution spaces and from the equations of Durnin & Womersley and Pollock, Schmidt & Jackson based on skinfold thickness measurements. Differences between methods for body fat estimation were found to be sex-dependent: subsequent analyses indicated significant differences between methods within each sex. Regardless of sex, the highest fat estimates were obtained with the 18O-dilution method, followed by those obtained with the 2H-dilution method or the Durnin & Womersley equation. The lowest fat estimates were obtained using the Pollock, Schmidt & Jackson equation. The 18O-dilution method and the Durnin & Wormersley anthropometric method are both suitable and appropriate for body fat estimation in adults studied under field conditions.     

To image or not to image

An 8-year-old girl was first seen at the age of 4 with nystagmus and hypoplastic discs. Subsequent follow-up demonstrated poor visual acuity and optic atrophy. A CT scan showed a chiasmal or perichiasmal mass. The presumptive diagnosis of an optic chiasmal glioma is being considered. The use of neuroimaging in chiasmal or perichiasmal lesions and the natural history and treatment of optic nerve and chiasmal gliomas are discussed.     

Effect of buffering on pharmacokinetics of ketoprofen enantiomers in man

Aims Concomitant administration of magnesium hydroxide may affect the rate or extent of absorption of non-steroidal anti-inflammatory drugs. In order to find out whether or not buffering modifies the pharmacokinetics of ketoprofen, plasma concentration-time courses resulting from oral administration of unbuffered formulations were compared with those of buffered formulations.
Methods Two groups of 12 healthy and young male subjects were included in two randomized cross-over studies and received single oral doses of ketoprofen 12.5 or 25  mg, respectively, given as tablets which were either unbuffered or buffered with magnesium hydroxide/citrate. Ketoprofen enantiomers in plasma were determined by h.p.l.c. up to 24  h post-dose.
Results Maximum plasma concentrations ( C _max ) of both the (R)- and (S)-enantiomer, observed after administration of the buffered formulations (12.5 and 25  mg), were higher compared with the unbuffered tablets by about 50–80%. The area under concentration-time data (AUC) was unaffected, and, hence, C _max/AUC was increased by buffering. Time to C _max ( t _max ) and mean residence time (MRT) tended to be or was shortened by buffering.
Conclusions It is concluded that buffering of two ketoprofen formulations with magnesium hydroxide/citrate enhanced the concentration maximum by increasing the rate of absorption and leaving AUC unaffected.