Consequences of renal insufficiency on the hepatic clearance of some drugs

There have been numerous investigations into the effect of kidney or liver diseases on the renal or hepatic elimination of drugs, but little is known about the possible consequences of renal insufficiency on the hepatic clearance of medicinal agents. The first reports of diminished presystemic elimination of drugs in renal failure were presented by Bianchetti in 1976 for propranolol and by Levy in 1979 for dextropropoxyphene. We confirmed the fact that the hepatic presystemic elimination of drugs might be diminished by kidney diseases. We studied this phenomenon with the beta-blocking agents tolamolol, bufuralol and oxprenolol. Tolamolol is eliminated from the body mainly by aromatic hydroxylation and, for bufuralol, aliphatic hydroxylation also plays an important role, whereas, for oxprenolol, glucuroconjugation of the unchanged compound is an important route of elimination. After oral administration, the areas under the plasma/blood concentration curves were markedly increased in patients with renal insufficiency as compared to healthy subjects. The clearance approach of Rowland and Tozer led to the conclusion that decrease of the presystemic hepatic elimination might be the main reason for this finding. Cefoperazone is a cephalosporin eliminated to 75% by the biliary route under normal conditions. In a study in which the drug was intravenously infused to both healthy volunteers and patients with renal insufficiency, we found that in some patients the extrarenal clearance was markedly reduced. It is probable that in this situation the patients also suffered from a slight hepatic insufficiency, as sometimes observed in the case of kidney disease associated with a poor physical condition. It is well-known that in patients with terminal liver failure, the kidney may also be involved, producing a condition known as the "hepato-renal" syndrome. We feel that there is evidence to support the hypothesis that renal failure can disturb the pharmacokinetics of drugs by processes other than merely reducing their renal excretion. The precise causes of the decreased hepatic elimination found in renal patients remains, however, to be determined.     

Behaviour of glibenclamide on repeated administration to diabetic patients

Summary Six maturity onset diabetic patients took glibenclamide 5 mg by mouth, every morning 10 min before a standard breakfast. Serum levels of immunoreactive glibenclamide, glucose and immunoreactive insulin were measured repeatedly on the first and 15th days of treatment. Measured glibenclamide blood levels were in close agreement with an analogue computer simulation of data obtained from healthy volunteers: there was no accumulation of drug in the blood, but there was strong evidence for the existence of a slowly equilibrating deep compartment. Considerable insulin release and correction of the breakfast-induced hyperglycaemia were observed immediately after administration of the drug, as well as 5 h later, at lunch time. The clinical significance of blood levels of glibenclamide, as well as the correlation of pharmacokinetics with pharmacodynamics, are discussed in the light of these results.Glossary of symbols IR- immuno-reactive - GLI glibenclamide - IRI immuno-reactive insulin - GLU glucose - AK 1 values obtained with patient AK on the first day of treatment - AK 15 values obtained with patient AK on the 15th day of treatment - b serum level - b_max maximal serum level - t time after dose - t_max time of maximal serum level - G gastro-intestinal system - B central compartment (blood) - T peripheral compartment (tissue) - E excreta - M,N coefficients of the equation of a bi-exponential decay curve - µ, v exponents of the equation of a bi-exponential decay curve - e base of natural logarithms - K_BG K_EB K_TB K_BT first order rate constants (e. g. K_BG means: into B, from G) - K_BG first order rate constants - etc. not corrected for the volume of distribution     

Proliferative lesions of oviduct and uterus in CD-1 mice exposed prenatally to tamoxifen

Tamoxifen (TAM) is widely used as adjuvant breast cancer therapy after surgery and as a chemopreventive agent in women of child-bearing age. However, TAM therapy has been shown to result in an increased incidence of endometrial carcinoma in women. The present study was designed to investigate the effects of TAM (5 mg/kg and 7.5 mg/kg body wt) given i.g. to pregnant CD-1 mice (1x/day, days 12 through 18 of gestation) on their female offspring. Progressive proliferative hyperplasia of the oviduct was frequently seen in TAM-exposed offspring, reaching 100% incidence by 52 weeks in both treatment groups. These females also developed progressive proliferative uterine lesions, including moderate/severe cystic endometrial hyperplasia (34-50%) and polypoid adenomas (27-30%) between 53 and 78 weeks. Deciduomas (15%) occurred at young ages (12 and 24 weeks) while leiomyomas (14%), a malignant leiomyosarcoma, and ovarian granulosa cell tumors (14%), were found between 72 and 78 weeks. Our findings thus suggest a strong association between transplacental TAM and reproductive tract abnormalities in female CD-1 mice.      

Hypoglycémie hyperinsulinémique persistante du nouveau-né et du nourrisson

Persistent hyperinsulinemic hypoglycaemia of infancy (PHHI) is the most frequent cause of hypoglycaemia in infancy. Clinical presentation is heterogeneous, with variable onset of hypoglycaemia and response to diazoxide, and presence of sporadic or familial forms. Underlying histopathological lesions can be focal or diffuse. Focal lesions are characterised by focal hyperplasia of pancreatic islet-like cells, whereas diffuse lesions implicate the whole pancreas. The distinction between the two forms is important because surgical treatment and genetic counselling are radically different. Focal lesions correspond to somatic defects which are totally cured by limited pancreatic resection, whereas diffuse lesions require a subtotal pancreatectomy exposing to high risk of diabetes mellitus. Diffuse lesions are due to functional abnormalities involving several genes and different transmission forms. Recessively inherited PHHI have been attributed to homozygote mutations for the beta-cell sulfonylurea receptor (SUR1) or the inward-rectifying potassium-channel (Kir6.2) genes. Dominantly inherited PHHI can implicate the glucokinase gene, particularly when PHHI is associated with diabetes, the glutamate dehydrogenase gene when hyperammonaemia is associated, or another locus.     

Actuarial survival in the premature infant less than 30 weeks' gestation

OBJECTIVE: Because survival from admission to discharge does not provide parents and physicians information about future life expectancy in the premature neonate, we characterized the actuarial survival, defined as the future life expectancy from a given postnatal age, in a large inborn population of premature infants < 30 weeks' gestation. STUDY DESIGN: We determined daily actuarial survival of 1925 inborn infants (23 to 29 weeks' gestation) admitted to the Baylor Affiliated Nurseries from July 1986 through December 1994, stratified by 100-g birth weight and by 1-week gestational-age intervals. RESULTS: In the 501- to 600-g birth weight stratum, actuarial survival improved from 31% at birth, to 61% on day of life 7, and then to 75% on day of life 28; in the 901- to 1000-g birth weight stratum, actuarial survival improved from 88%, to 94%, and then to 98% throughout the same times, respectively. Similar trends were obtained when data were stratified by gestational age. CONCLUSIONS: Survival in the smallest infants improves dramatically during the first few days of life, but there is a significant risk for late death in the smallest of these infants.     

The efficacy of the ketogenic diet-1998: a prospective evaluation of intervention in 150 children

OBJECTIVE: The ketogenic diet is a high-fat, low-protein, low-carbohydrate diet developed in the 1920s for the treatment of children with difficult to control seizures. Despite advances in both the pharmacotherapy and the surgery of epilepsy, many children continue to have difficult-to-control seizures. This prospective study sought to determine the ketogenic diet's effectiveness and tolerability in children refractory to today's medications. METHODS: One hundred fifty consecutive children, ages 1 to 16 years, virtually all of whom continued to have more than two seizures per week despite adequate therapy with at least two anticonvulsant medications, were prospectively enrolled in this study, treated with the ketogenic diet, and followed for a minimum of 1 year. Seizure frequency was tabulated from patients' daily seizure calendars and seizure reduction calculated as percentage of baseline frequency. Adverse events and reasons for diet discontinuation were recorded. RESULTS: The children (mean age, 5.3 years), averaged 410 seizures per month before the diet, despite an exposure to a mean of 6.2 antiepileptic medications. Three months after diet initiation, 83% of those starting remained on the diet and 34% had >90% decrease in seizures. At 6 months, 71% still remained on the diet and 32% had a >90% decrease in seizures. At 1 year, 55% remained on the diet and 27% had a >90% decrease in seizure frequency. Most of those discontinuing the diet did so because it was either insufficiently effective or too restrictive. Seven percent stopped because of intercurrent illness. CONCLUSIONS: The ketogenic diet should be considered as alternative therapy for children with difficult-to-control seizures. It is more effective than many of the new anticonvulsant medications and is well tolerated by children and families when it is effective.     

Inhibition of cigarette smoke-related lipophilic DNA adducts in rat tissues by dietary oltipraz

The present study investigated the effects of dietary oltipraz on cigarette smoke-related lipophilic DNA adduct formation. Female Sprague- Dawley rats were exposed daily to sidestream cigarette smoke in a whole- body exposure chamber 6 h/day for 4 consecutive weeks. One group of rats was maintained on control diet while another group received the same diet supplemented with either a low (167 p.p.m.) or high (500 p.p.m.) dose of oltipraz, starting 1 week prior to initiation of smoke exposure until the end of the experiment. Analysis of lipophilic DNA adducts by the nuclease P1-mediated 32P-post-labeling showed up to five smoke-related adducts. Adduct no. 5 predominated in both the lung and the heart while adduct nos 3 and 2 predominated in the trachea and bladder, respectively. Quantitative analysis revealed that the total adduct level was the highest in lungs (270+/-68 adducts/10(10) nucleotides), followed by trachea (196+/-48 adducts/10(10) nucleotides), heart (141+/-22 adducts/10(10) nucleotides) and bladder (85+/-16 adducts/10(10) nucleotides). High dose oltipraz treatment reduced the adduct levels in lungs and bladder by >60%, while the reduction in lungs in the low-dose group was approximately 35%. In trachea, the effect of low and high dietary oltipraz on smoke DNA adduction was equivocal, while smoke-related DNA adducts in the heart were minimally inhibited by high-dose oltipraz. In a repeat experiment that employed a 3-fold lower dose of cigarette smoke, oltipraz (500 p.p.m.) was found to inhibit the formation of DNA adducts in rat lungs and trachea by 80 and 65%, respectively. These data clearly demonstrate a high efficacy of oltipraz in inhibiting the formation of cigarette smoke-induced DNA adducts in the target tissues.      

Effects of dietary fat and a vegetable-fruit mixture on the development of intestinal neoplasia in the ApcMin mouse

The variation in colorectal cancer (CRC) incidence worldwide strongly suggests a role for dietary influences. Based on epidemiological data, protective effects of vegetables and fruit intake on CRC are widely claimed, while other data indicate a possible increased CRC risk from (higher) dietary fat intake. Therefore, we have investigated single and interactive effects of dietary fat and a vegetable-fruit mixture (VFM) in the ApcMin mouse, a mouse model for multiple intestinal neoplasia. In this study, four different diets (A-D) were compared, which were either low in fat (20% energy diets A/B) or high in fat (40% energy diets C/D). In addition, 19.5% (wt/wt) of the carbohydrates in diets B and D were replaced by a freeze-dried VFM. The diets were balanced so that they only differed among each other in fat/carbohydrate content and the presence of specific plant-constituents. Because the initiation of intestinal tumors in ApcMin mice occurs relatively early in life, exposure to the diets was started in utero. Without the addition of VFM, mice maintained at a high-fat diet did not develop significantly higher numbers of small or large intestinal adenomas than mice maintained at a low-fat diet. VFM added to a low-fat diet significantly lowered multiplicity of small intestinal polyps (from 16.2 to 10.2/mouse, 15 animals/group), but not of colon tumors in male ApcMin mice only. Strikingly, addition of VFM to female mice maintained on a low-fat diet and to both sexes maintained on a high-fat diet significantly enhanced intestinal polyp multiplicity (from 16.5 to 26.7 polyps/mouse). In conclusion, our results indicate that neither a lower fat intake nor consumption of VFM included in a high-fat diet decreases the development of polyps in mice genetically predisposed to intestinal tumor development.