Action mechanisms of cell-division-arresting benzimidazoles and of sterol biosynthesis-inhibiting imidazoles, 1,2,4-triazoles, and pyrimidines.
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Benzimidazoles↗
Biomedical subjects
D Berg
Publications and source records attributed to D Berg.
Measurement of myocardial fatty acid metabolism: kinetics of iodine-123 heptadecanoic acid in normal dog hearts.
To define the potential of iodine-123 heptadecanoic acid (IHA) for the noninvasive assessment of myocardial fatty acid metabolism with gamma camera imaging, the influence of myocardial oxygen consumption (MVO2) and blood flow (MBF) on extraction and half-times of IHA were investigated in dogs. Following IHA injection into the left circumflex coronary artery, extraction fraction and half-times were derived from the peak and slope of the IHA time activity curve, which consisted of a vascular, early, and late phase. Single-pass extraction fraction of IHA averaged 0.53 +/- 0.11 s.d. at control and was not influenced by MVO2 and MBF. The half-time of the early phase (T = 9.3 min +/- 2.8 s.d. in controls) as well as the ratio between the size of the early and late phase increased with MVO2 (r = 0.82, r = 0.87, respectively). Thus, early phase intracellular turnover of IHA increased, yet clearance of 123I activity was slowed by augmented cardiac work. Preliminary data of HPLC and electrophoretic analysis of myocardial arterial and venous blood samples over time indicate that the early phase is characterized by a decreasing washout of IHA and a relative increase of radioiodine washout. The half-time of the late phase (T = 245 min +/- 156 s.d. at control) was not related to MVO2 and MBF. In conclusion, myocardial fatty acid metabolism cannot be measured from the half-time of the early phase but might be analyzed from the ratio between the size of the early and late phase when using IHA.
Animals↗
[Perioperative infection prevention with cefotaxime].
In a study comprising 172 patients who had been abdominally or vaginally hysterectomised, the effectivity of short-term prophylaxis with cefotaxim on various infection parameters was examined. The 100 patients of the prophylaxis group showed a significant reduction (p less than 0.01) of postoperative fever and of pelvic infections after vaginal hysterectomies. With abdominal hysterectomies, wound infections and pelvic infections were not reduced so strikingly. Infections of the urinary tract were seen less frequently in the prophylaxis group. Perioperative short-term prophylaxis is meaningful in vaginal hysterectomies, whereas in abdominal hysterectomies such prophylaxis will be useful only in cases with enhanced risk of infection.
Adult↗
[Hyperprolactinemic ovarian insufficiency].
About 20% of all menstrual cycle disorders are due to a hyperprolactinemia. Although changes in the bony area of the sella indicating intrasellar space-requiring processes have been found in only 30% of these women presenting hyperprolactinemic ovarian insufficiency, an adenoma of the pituitary gland is probably also responsible for the hyperprolactinemia observed in the rest of the cases. Treatment is however not strictly necessary, as long as there are no other endocrine dysfunctions, and a pregnancy is not desired. Side-effects of a therapy of dopamine agonists can be diminished by a gradually increasing dosage.
Adenoma↗
[Selective removal of one twin with trisomy 21 by sectio parva in the 23rd week of pregnancy and later spontaneous birth of the healthy twin].
In a 41-year old tertipara with twin pregnancy, foetal chromosome analysis showed a boy without abnormal findings, 46, XY, and a boy with free trisomy 21. Abortion of the abnormal twin was performed in the 23rd week of pregnancy via sectio parva. Despite preoperative onset of tocolysis and ultimately performed circular suture of the cervix, premature rupture of the membranes occurred in the 28th pregnancy week, followed by spontaneous birth of the second twin weighing 1010 g. Raising of the premature baby did not present any special problems.
Adult↗
[Placental villous stem vessel occlusions. Studies of a twin placenta retained in utero following selective sectio parva].
During a twin pregnancy of a 41-year old woman, a selective sectio parva was performed, without removing the placenta, in the 23rd week of gestation. An amniotic fluid examination after routine amniocentesis showed a free trisomy 21 in only one of the twins. The twin with normal caryotype was delivered in the 28th week. His placenta was well developed, whereas the placenta of the other child showed severe obliterations of the stem arteries with partial avascularity of the villi. The histological aspect was that of a so-called "endarteritis obliterans". Since the twin delivered via sectio parva showed no signs of dystrophy, we presume that at the time of delivery his placenta had developed regularly. The changes of the placenta, demonstrated by histological examinations, seemed to be caused by the stopping of the foetal blood circulation. We suggest that the intrauterine death is not caused by "endarteritis obliterans" only as often described previously. Obviously, the morphological picture of endarteritis obliterans can be the result of cessation of foetal blood circulation. Obliteration of stem arteries might be the main reason for the stillbirth with significant signs of dystrophy. The similar histological picture in placentae of normally developed stillbirths is obviously caused by discontinuation of foetal blood circulation.
Adult↗
[Treatment of anovulatory patients by pulsatile administration of gonadotropin releasing hormone].
83 anovulatory patients refractory to clomiphene were treated with gonadotropin releasing hormone (GnRH) in pulsatile form (Zyklomat). 146 of 172 treated cycles were ovulatory. A total of 37 pregnancies occurred. The patients were classified into three groups according to the degree of severity of their cyclic disturbance and according to the results of testosterone determinations. In amenorrhoic women with normal testosterone values (group I) the authors found the highest incidence of ovulation and pregnancies. In the patients of group II the ovulation rates were high, whereas the incidence of pregnancies was low (this group comprised anovulatory oligomenorrhoea and normal testosterone values). It was found that about 30% of the anovulatory women with elevated testosterone levels (group III) were refractory to therapy, the proliferation phases being mostly considerably prolonged during the ovulatory cycles. It is concluded from the results of this study that in women with normoandrogenemic amenorrhoea the treatment of first choice should be pulsatile application of GnRH. In many hyperandrogenemic, anovulatory patients treatment with gonadotrophins should be considered as the presently more suitable method.
Adult↗
Reduction of the in vivo virulence of Candida albicans by pretreatment with subinhibitory azole concentrations in vitro.
Cells of Candida albicans exposed to subinhibitory concentrations of clotrimazole or bifonazole in shake cultures were found to have a reduced capacity to divide normally or produce germ tubes and mycelia under appropriate conditions, although treated cultures produced a cell mass equivalent to that of the untreated controls. The long-term morphological effects are considered to be due to azole-caused disturbances in ergosterol biosynthesis. When cells, pretreated with subinhibitory concentrations of the azole compounds, were injected intravenously in mice, the resultant infections were of reduced severity in comparison to controls, as measured by mortalities and colony forming units in kidneys.
Animals↗
Bifonazole and clotrimazole. Their mode of action and the possible reason for the fungicidal behaviour of bifonazole.
Bifonazole (Bay h 4502, Mycospor) and clotrimazole (Bay b 5097, Canesten) are potent inhibitors of ergosterol synthesis in yeasts and dermatophytes. Inhibition of demethylation of 4,4',14-trimethylsterols is accepted as primary mode of action responsible for their fungistatic efficacy. In Candida albicans, Microsporum canis, Trichophyton mentagrophytes as well as in Epidermophyton floccosum the ergosterol precursor 24-methylendihydrolanosterol accumulates, whereas in Torulopsis glabrata lanosterol accumulation occurs, due to the fact that in this organism side chain alkylation proceeds after demethylation reactions. Bifonazole additionally leads to a generally decreased rate of sterol biosynthesis as compared to clotrimazole, due to a direct inhibition of microsomal HMG-CoA-reductase. The additional fungicidal effects of bifonazole are considered to originate from a sequential action by inhibition of HMG-CoA-reductase and of cytochrome P450.
Antifungal Agents↗
Bifonazole, a biochemist's view.
Bifonazole, a new broad-spectrum antimycotic, interferes with sterol biosynthesis. Compared to clotrimazole, the primary mode of action of these two antimycotics is accepted to represent inhibition of the cytochrome P450-dependent hydroxylation at the sterol-C14-methyl group, which is the first step in C14-demethylation reaction. At least in dermatophytes bifonazole additionally inhibits directly HMG-CoA-reductase, the starting and regulatory enzyme in terpenoid biosynthesis, whereas after application of clotrimazole the activity of HMG-CoA-reductase is only decreased by feed-back control, resulting from accumulation of dihydrolanosterol. The inhibition of HMG-CoA-reductase obviously is pathogen specific as the mammalian enzyme is not affected. By this, in contrast to clotrimazole, bifonazole possesses a sequential mode of action, namely inhibition of cytochrome P450-dependent C14-demethylation of sterols and direct inhibition of HMG-CoA-reductase. In vitro bifonazole shows a strongly pH-dependent efficacy. The uptake kinetics of bifonazole have been measured with different pathogens. With respect to budding cells of Candida albicans it can be shown that the pH dependence of efficacy is due to a parallel pH dependence of the intracellular concentration of active ingredient. Even sublethal concentrations of bifonazole cause prior damages of young cells of C. albicans. These effects might explain the loss of infectivity of C. albicans after incubation with sublethal concentrations of bifonazole.
Animals↗
Ovulation and pregnancy after pulsatile administration of gonadotropin releasing hormone.
Twenty-seven patients with primary or secondary amenorrhea were treated with gonadotropin releasing hormone (GnRH). They were given 20 micrograms of GnRH in 50 microliter solution i.v. every 90 min by means of a peristaltic pump (Zyklomat, Ferring GmbH, Kiel). Two days after a rise in basal body temperature and when a ferning test on cervical mucus was negative the Zyklomat was removed and injections of hCG (2,500 IU) were given on alternate days until three injections had been administered. Ovulation occurred in 32 out of 40 treatment cycles and 11 patients conceived. Three of them miscarried at 6, 8, and 15 weeks of gestation. There were no severe complications of treatment and we did not encounter ovarian hyperstimulation and multiple pregnancy.
Adult↗
[Pulsatile GnRH substitution in Kallmann's syndrome in women].
Anosmia and primary amenorrhoea are guiding symptoms of Kallmann's syndrome (olfacto-genital syndrome) in which agenesis of the olfactory lobe is associated with congenital defects in the mediobasal region of the hypothalamus, thus preventing a sufficient GnRH synthesis. In three patients with Kallmann's syndrome, the secretion of gonadotropins on bolus injection of 25 micrograms GnRH was comparable with prepubertal reaction. In one patient, the hypophyseal function was normalized, and ovulatory cycles were induced by pulsatile GnRH substitution via a portable computerized pump (Zyklomat). Pregnancy occurred. The duration of treatment required to induce ovulation was identical during two subsequent treatment cycles, contrary to observations in functional hypothalamic amenorrhoeas. The marked ovarian reaction shows that even if there is no endogenous GnRH secretion, a pulsatile dose of less than 20 micrograms seems to be sufficient.
Amenorrhea↗
[Treatment of hyperprolactinemic amenorrhea by pulsatile administration of gonadotropin-releasing hormone].
Two patients with hyperprolactinemic secondary amenorrhoea were treated with gonadotropin releasing hormone (GnRH). Both desired children and had an incompatibility to treatment with Dopamin agonists (Zyklomat). Both patients ovulated and had regular follicular maturation in spite of rising prolactin levels. The pregnancies occurred in the first treatment cycles. The pulsatile intravenous administration of GnRH is apparently a viable alternative plan of management in patients with a moderate hyperprolactinemia and incompatibility to Dopamine agonists to the treatment with gonadotropins which was in use up to now.
Adult↗
[Results of sling surgery using Tutoplast dura].
From 1976-1979 127 patients were treated with a tutoplast dura sling operation. Either an open or a closed sling was used. Between one and four and one half years later 117 patients were re-examined and 65 patients had urodynamic tests. The late results of tutoplast dura sling operations are good and compare favorably to the upper data indicated in the literature. The best results are obtained in cases of prolapse. The closed sling has higher success rates but also higher complication rates than the open sling. Primary operations have better results than operations for recurrence. A severe stress incontinence should be subjected to specific primary treatment.
Dura Mater↗
[Determination of concentration of an antibiotic (Cefotaxim) in the vaginal mucosa after preoperative intravenous administration].
In 11 patients in whom an antibiotic (Cefotaxim) had been applied preoperatively, the tissue concentration was determined in the vaginal mucosa where postoperative infections after gynaecological operations are most common. The tissue concentration is compared with the minimum inhibition concentration of the pathogens identified directly before the operation in the cervicovaginal flora. In the case of the aerobic pathogens--with the exception of Pseudomonas aeruginosa--the concentration is far in excess of the necessary MIC, whereas with the anaerobic pathogens the concentration is only partly greater than the MIC. Resistance exists against Bacteroides fragilis.
Cefotaxime↗
Concentrations of 2-methoxyoestrogens in human serum measured by a heterologous immunoassay with an 125I-labelled ligand.
A radioimmunoassay has been developed for the measurement of 2-methoxyoestrogens in samples of human serum without chromatography after solvent extraction. Antibodies raised against 2-methoxyoestradiol-17 beta-hemi-succinyl-BSA served as binding protein and 2-methoxyoestrone-17-cmo-[125I]iodohistamine served as 125I-labelled ligand. A specific (little or no cross-reactivities to other oestrogens), sensitive (2.4 +/- 0.9 pg/tube) and precise (6.5% intra-assay; 9.1% inter-assay) assay was obtained by employing the heterologous bridge system. The following concentrations were found in serum samples of healthy subjects (median, range in parentheses): men (19-58 years): less than 10.3 (less than 10.3-35.5) pg/ml (n = 22); women follicular phase: 46 (18-63) pg/ml (n = 8); luteal phase: 70 (31-138) pg/ml (n = 8); post-menopausal women: 33 (21-76) pg/ml (n = 10); pregnant women 11th-16th week: 674 (216-1678) pg/ml (n = 46); 37th-40th week: 3768 (2035-10691) pg/ml (n = 34); newborn cord serum 1608 (575-3095) pg/ml (n = 41).
Adult↗
Synthesis of immunogenic C-6 derivatives of 2-methoxyestrone and 2-methoxyestradiol-17 beta and characterization of the corresponding antisera.
The synthesis, purification and structural confirmation of the 6-(carboxymethoxyimino) derivatives of 2-methoxyestrone and 2-methoxyestradiol-17 beta are described. These derivatives were coupled to bovine serum albumin by the mixed anhydride method, and rabbits were immunized with the product. The resulting antisera showed high affinity and specificity for 2-methoxyestrone and 2-methoxyestradiol-17 beta, respectively, with low cross reactivities to structurally related estrogens.
2-Methoxyestradiol↗
Concentrations of 2-hydroxyoestrogens in human sera measured by a heterologous immunoassay with an 125I-labelled ligand.
A heterologous immunoassay for 2-hydroxyoestrogens has been established in which antibodies raised against 2-hydroxyoestradiol-17-succinyl-BSA serve as binding protein and 2-hydroxyoestrone-17-cmo-[125I]iodohistamine as radioligand. Lipophilic serum components competing for binding sites in this system were defined as total 2-hydroxyoestrogens'. The underlying assumption of specificity was supported by the pattern of cross-reactivity evaluated with structural related steroids and o-diphenols and by the fact, that an additional chromatography of the serum extracts preceding the competing reaction had little if any effect. Sensitivity: 2.8 +/- 1 pg/tube; accuracy: Y = 0.91x + 2.2; r = 0.989; precision: 5.8% intra-assay; 6.5% inter-assay. The following concentrations (+/- standard deviation) were found in the sera of healthy subjects. Young men: 29 +/- 5 pg/ml (n = 11); women follicular phase: 32 +/- 8 pg/ml (n = 25); luteal phase: 53 +/- 13 pg/ml (n = 23); postmenopausal women: 13 +/- 4 pg/ml (n = 10); pregnant women 11th--20th week: 70 +/- 16 mg/ml (n = 64); 36th--40th week: 240 +/- 23 pg/ml (n = 40); newborn cord blood: 604 +/- 43 pg/ml (n = 48).
Adult↗