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PubMed2005

The quantitative prediction of in vivo enzyme-induction caused by drug exposure from in vitro information on human hepatocytes.

There have been no reports of the quantitative prediction of induction for drug-metabolizing enzymes in humans. We have tried to predict such enzyme induction in humans from in vitro data obtained using human hepatocytes. The in vitro and in vivo data on enzyme induction by inducers, such as rifampicin, phenobarbital and omeprazole, were collected from the published literature. The degree of enzyme induction in humans was compared with that predicted from in vitro data on human hepatocytes. Using the in vivo data, we calculated the hepatic intrinsic clearance of typical CYP substrates, such as midazolam and caffeine, before and after inducer treatment and estimated the induction ratios of hepatic intrinsic clearance following treatment. In the in vitro studies, the amount of mRNA or enzyme and enzyme activity in human hepatocytes, with or without an inducer, were compared and the induction ratios were estimated. The unbound mean concentration was taken as an index of drug exposure and the induction ratios in the in vivo and in vitro studies were compared. The unbound mean concentrations of inducers used in the in vitro studies were higher than those in the in vivo studies. The maximum induction ratios by inducers in the in vitro studies were higher than those in the in vivo studies. The induction ratio for rifampicin, omeprazole, troglitazone, dexamethasone and phenobarbital increased as the unbound mean concentration increased to reach a constant value. The induction of CYP3A and 1A was analyzed by the Emax model. The maximum induction ratio (Emax) and the concentration at half maximum induction (EC50) for rifampicin, omeprazole, troglitazone, dexamethasone and phenobarbital were 12.3, 0.847 micromol/L, 2.36, 0.225 micromol/L, 6.86, 0.002 micromol/L, 8.30, 9.32 micromol/L, and 7.62, 58.4 micromol/L, respectively. The Emax and EC50 of omeprazole for CYP1A were 12.02 and 0.075 micromol/L, respectively. The predicted induction ratio of all those inducers, except for omeprazole, based on the Emax and EC50 values obtained from the in vitro data were similar to the observed values. On the whole, a good correlation between the observed and predicted induction ratio of omeprazole was observed (r=0.768, p<0.05), although the predicted induction ratio was higher than the observed value. In conclusion, the present study suggests that it is possible to predict quantitatively the CYP3A enzyme induction from hepatocyte data.

Area Under Curve↗
PubMed1998

Disruption of endogenous regulator homeostasis underlies the mechanism of rat CYP1A1 mRNA induction by metyrapone.

The transcriptional induction of the cytochrome P-450 1A1 (CYP1A1) gene by xenobiotics such as polyaromatic hydrocarbons is dependent on their interaction with the aryl hydrocarbon receptor. Administration of the structurally unrelated compounds metyrapone (a cytochrome P-450 inhibitor) or dexamethasone (a glucocorticoid) to male rats does not induce hepatic CYP1A1 mRNA. However, administration of both metyrapone and dexamethasone to male rats results in the induction of hepatic CYP1A1 mRNA expression. The induction response is mimicked in vitro in cultured rat hepatocytes by the addition of metyrapone and dexamethasone to a serum-free culture medium, suggesting that these compounds act directly on the liver in vivo to effect hepatic CYP1A1 mRNA induction. An examination of the characteristics of CYP1A1 induction by metyrapone and dexamethasone in combination in vitro indicate that at least 6 h of treatment is required for detectable levels of CYP1A1 mRNA to accumulate in hepatocytes. In contrast, beta-naphthoflavone, which is known to bind to the aryl hydrocarbon receptor to effect CYP1A1 gene expression, induces detectable levels of CYP1A1 mRNA within 2 h of treatment. CYP1A1 mRNA is also induced when hepatocytes are treated with metyrapone in combination with the protein synthesis inhibitor cycloheximide but not with dexamethasone in combination with cycloheximide, indicating that CYP1A1 mRNA induction is strictly dependent on the presence of metyrapone and suggesting that the metyrapone-associated induction of CYP1A1 mRNA is dependent on a loss of a constitutively expressed protein that functions to suppress CYP1A1 gene expression. The role of dexamethasone in metyrapone-associated induction of CYP1A1 is probably mediated through the glucocorticoid receptor since the glucocorticoid receptor antagonist RU486 reduces the levels of CYP1A1 mRNA induced by metyrapone and dexamethasone in combination. Increasing the levels of the photosensitizer riboflavin present in the culture medium 10-fold and exposure to light increases the levels of CYP1A1 mRNA induced by metyrapone and dexamethasone in combination in vitro, suggesting that photoactivation of inducing medium constituent(s) might be required for induction. Failure to induce CYP1A1 mRNA by co-administration of metyrapone and dexamethasone in hepatocytes cultured in a balanced salt solution with or without photoactivation indicates that induction is dependent on a photoactivated component of the culture medium and not on metyrapone or dexamethasone alone. The addition of tryptophan in the presence of riboflavin to the balanced salt solution restores CYP1A1 mRNA induction by metyrapone alone and induction is increased when medium is exposed to light, indicating that induction is dependent on tryptophan photoactivation in vitro. Metyrapone failed to compete with 2,3,7,8-tetrachlorodibenzo-p-dioxin for specific binding to the aryl hydrocarbon receptor in rat liver cytosolic fractions. These results suggest that CYP1A1 might be induced in rats by metyrapone through an indirect mechanism associated with an elevation in the level of an endogenously generated inducer such as photoactivated product(s) of tryptophan and not because of metyrapone's interacting with the aryl hydrocarbon receptor. The dependence of CYP1A1 induction on dexamethasone or cycloheximide suggests that derepression by a glucocorticoid receptor-modulated negative-acting factor of CYP1A1 gene expression might be critical to induction by metyrapone.

Animals↗
PubMed2000

Stripping/sweeping the membranes for inducing labour or preventing post-term pregnancy.

BACKGROUND: Stripping or sweeping of the membranes aims to initiate labour through a cascade of physiological events. These may reduce pregnancy duration or pre-empt formal induction of labour with either oxytocin, prostaglandins or amniotomy. OBJECTIVES: The objective of this review was to assess the effects of membrane sweeping to promote or induce labour on maternal and perinatal outcomes. SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group trials register and the Cochrane Controlled Trials Register (last searched April 1998). SELECTION CRITERIA: Adequately controlled trials of digital separation of the membranes from the lower uterine segment for inducing labour or for preventing post-term pregnancy, compared to either no vaginal examination or vaginal examination for cervical assessment only without the intention to detach the membranes. DATA COLLECTION AND ANALYSIS: Two reviewers assessed trial quality and extracted data. MAIN RESULTS: Fourteen trials were included. Sweeping of the membranes, performed as a general policy in women at term, was associated with reduced duration of pregnancy and the frequency of pregnancy continuing beyond 41 weeks (relative risk 0.42, 95% confidence interval 0.19 to 0.93, random effects model) and 42 weeks. After sweeping of the membranes, there was a 17% risk reduction (confidence interval 6 to 29%, random effects model) in the use of more formal methods for labour induction. There was no difference in the mode of delivery or in the risk of infection. Discomfort during vaginal examination and other adverse effects (bleeding, irregular contractions) were more frequently reported by women allocated to sweeping. REVIEWER'S CONCLUSIONS: Routine use of sweeping of membranes from 38 weeks of pregnancy onwards does not seem to produce clinically important benefits. When used as a means for induction of labour, the reduction in the use of more formal methods of induction needs to be balanced against women's discomfort and other adverse effects.

Extraembryonic Membranes↗
PubMed1977

Ontogeny of B-lymphocyte function. III. In vivo and in vitro studies on the ease of tolerance induction in B lymphocytes from fetal, neonatal, and adult mice.

The ease of tolerance induction in B lymphocytes from fetal, neonatal, and adult mice was studied in vivo, in a cell transfer system, and in vitro. Three different tolerogens were used: ultracentrifuged BGG, DNP(6)-D-GL, and ultracentrifuged DNP(22)-BGG. Irradiated thymectomized mice were reconstituted with B cells from fetal or neonatal liver or adult spleen or bone marrow. The mice were injected with tolerogen 1 day later. They were given normal thymus cells and challenged with either BGG or DNP(44)-BGG between 4 and 14 days after tolerance induction. With BGG no difference in ease of B-cell tolerance induction was observed in mice reconstituted with B cells from 17-day fetal liver, neonatal liver, 8- day-old spleen, adult spleen, or adult bone marrow. B cells from 14-day fetal donors are relatively resistant to tolerance induction. In contrast, with DNP(6)-D-GL and DNP(22)-BGG B cells from neonatal donors were clearly more susceptible to tolerance induction than were B cells from adult donors. Comparable results were obtained in studies on tolerance induction in vitro. Neonatal B cells were more susceptible than adult B cells to tolerance induction upon culture with DNP(6)-D-GL or DNP(22)-BGG. However, neonatal and adult B cells were identical with respect to ease of tolerance induction in vitro with deaggregated BGG. The results suggest that there are multiple mechanisms for B-cell tolerance induction. Immature B cells appear to be more susceptible to tolerance induction by some mechanisms but not by others. It is suggested that immature B cells are more susceptible to tolerance induction with moderately polyvalent antigens such as hapten-carrier conjugates. With antigens like BGG which do not haverepeated epitopes no difference between mature and fetal B cells in regard to ease of tolerance induction is observed. These observations raise questions about the importance of relative ease of tolerance induction in immature B cells as a mechanism controlling the normal induction of self tolerance.

Animals↗
PubMed2004

Shock on T versus direct current voltage for induction of ventricular fibrillation: a randomized prospective comparison.

VF is induced during ICD implantation to determine efficacy of therapy. Establishing the best clinical method of induction of VF would potentially be beneficial in reducing the number of induction attempts and reducing the frequency of inadvertent induction of VT. Commonly used methods to induce VF include shock in the T wave vulnerable period (T shock) and high frequency stimulation. This study compared the efficacy of T shock with a new induction method using a 9-V DC pulse. The study was a randomized, prospective, case crossover trial in patients receiving ICDs. VF was induced by T shock and DC in a randomized sequence during an ICD implant. VF was induced at least four times in each patient (two T shocks and two DC inductions) and with each induction; attempts were continued with modifications until successful. A paired evaluation between the T shock/DC induction was performed in 37 patients (28 men, age 64 +/- 12 years) with a left ventricular ejection fraction of 0.40 +/- 0.20. Arrhythmia indications were VT (n = 23), VF (n = 10), and VT/VF (n = 4). Drug therapy included amiodarone (n = 10), metoprolol (n = 6), digoxin (n = 1), and lidocaine (n = 1). The average T shock voltage was 207.0 +/- 16.1 V. The S1 cycle drive length was consistently 400 ms, and the mean S2 coupling interval was 317.8 +/- 19.6 ms. The length of time DC applied averaged 3.8 +/- 1.4 seconds. A total of 148 episodes of VF were included in the analysis. T shock induced VF with a cycle length of 213.5 +/- 35.1 ms, and DC induced VF with a cycle length of 214.6 +/- 34.5 ms (P = 0.86). Although VF was eventually induced for each randomization, the number of attempts required were dependent on the method of induction. The successful DC first attempt VF induction rate was 96%, with three patients requiring two attempts during one of the DC inductions. T shock had a 68% first attempt success rate with 21 patients requiring multiple T shocks to induce VF. All nine female patients had at least one unsuccessful first attempt T shock, which contributed to an overall unsuccessful first attempt induction rate significantly higher in women then men (36.1% vs 12.5%, P = 0.001). A constant DC voltage induction of VF may be more effective than T shock for induction of VF in a clinical setting because it reduces the number of attempts required to induce VF. By either method, VF appears to be more difficult to induce in women. DC induction has the advantage of simple programming of only duration of stimulation. These findings have implications particularly for ICD implantation with conscious sedation.

Amiodarone↗
PubMed2006

[Transvaginal ultrasound assessment of the cervix and digital examination before labor induction].

OBJECTIVE: To examine the relationship between sonographic measurement of cervical length and Bishop score with duration of labour induction. METHODS: A prospective, blinded, observational study was performed in 191 pregnant women undergoing labor induction. Ultrasound measurement of cervical length and determination of Bishop score were performed. Induction was based exclusively on the Bishop score according to Obstetric Unit protocol. The criteria for considering the cervix unripe were either Bishop score < 6 or a cervical length = 26 mm. Duration of induction is defined like the induction-to-delivery interval. The main outcomes assessed were the duration of induction, the delivery within 24 h of induction and type of delivery. RESULTS: The duration of induction was between 2 h 27 min and 61 h 30 min. We found an association between cervical length and Bishop score with duration of induction. The duration of induction was significantly increased in nulliparous (median 18 h 38 min vs. 9 h 18 min). There was no correlation of age or weight of pregnant women with the duration of induction. Comparison between Bishop score and cervical length in predicting delivery within the first 24 hours showed that the pregnant women with low Bishop score had a higher risk of deliver after 24 hours of induction (OR = 21.16), as the ones with cervical length longer than 26 mm (OR = 5.06). Analyzing the relation of these two parameters with type of delivery we realize that low Bishop score has a higher risk of cesarean section (OR = 2.67) and that there wasn't any relation between type of delivery and cervical length. DISCUSSION: In this study we verified a statistically significant relation between Bishop score, US cervical length and previous vaginal birth with induction duration. Pregnant woman's age and weight didn't have influence on the duration of induction. The study showed that both Bishop score and US cervical length are useful in predicting delivery within the first 24 hours. Bishop score was also related with type of delivery.

Adolescent↗
PubMed2000

A micromere induction signal is activated by beta-catenin and acts through notch to initiate specification of secondary mesenchyme cells in the sea urchin embryo.

At fourth cleavage of sea urchin embryos four micromeres at the vegetal pole separate from four macromeres just above them in an unequal cleavage. The micromeres have the capacity to induce a second axis if transplanted to the animal pole and the absence of micromeres at the vegetal pole results in the failure of macromere progeny to specify secondary mesenchyme cells (SMCs). This suggests that micromeres have the capacity to induce SMCs. We demonstrate that micromeres require nuclear beta-catenin to exhibit SMC induction activity. Transplantation studies show that much of the vegetal hemisphere is competent to receive the induction signal. The micromeres induce SMCs, most likely through direct contact with macromere progeny, or at most a cell diameter away. The induction is quantitative in that more SMCs are induced by four micromeres than by one. Temporal studies show that the induction signal is passed from the micromeres to macromere progeny between the eighth and tenth cleavage. If micromeres are removed from hosts at the fourth cleavage, SMC induction in hosts is rescued if they later receive transplanted micromeres between the eighth and tenth cleavage. After the tenth cleavage addition of induction-competent micromeres to micromereless embryos fails to specify SMCs. For macromere progeny to be competent to receive the micromere induction signal, beta-catenin must enter macromere nuclei. The macromere progeny receive the micromere induction signal through the Notch receptor. Signaling-competent micromeres fail to induce SMCs if macromeres express dominant-negative Notch. Expression of an activated Notch construct in macromeres rescues SMC specification in the absence of induction-competent micromeres. These data are consistent with a model whereby beta-catenin enters the nuclei of micromeres and, as a consequence, the micromeres produce an inductive ligand. Between the eighth and tenth cleavage micromeres induce SMCs through Notch. In order to be receptive to the micromere inductive signal the macromeres first must transport beta-catenin to their nuclei, and as one consequence the Notch pathway becomes competent to receive the micromere induction signal, and to transduce that signal. As Notch is maternally expressed in macromeres, additional components must be downstream of nuclear beta-catenin in macromeres for these cells to receive and transduce the micromere induction signal.

Animals↗
PubMed2000

The role of cardioplegia induction temperature and amino acid enrichment in neonatal myocardial protection.

BACKGROUND: Warm cardioplegic induction improves the ischemically "stressed" adult heart. However, it is rarely used in infants, despite the fact that many newborn hearts are stressed by other factors such as hypoxia. The need for amino acids as well as their mechanism of action has also not been studied. METHODS: We first assessed the role of cardioplegic induction temperature in 10 nonhypoxic neonatal piglets undergoing 70 minutes of multidose blood cardioplegic arrest. Five piglets (group 1) received a cold (4 degrees C) induction, and 5 (group 2) a warm (37 degrees C) induction. Twenty-six other piglets underwent ventilator hypoxia (fraction of inspired oxygen, 8% to 10%) for 60 minutes before cardiopulmonary bypass (stress). Six piglets (group 3) then underwent 70 minutes of cardiopulmonary bypass without ischemia (hypoxia controls), and 20 underwent 70 minutes of cardioplegic arrest. Five of these (group 4) received cold cardioplegic induction, and 15 received warm induction; in 5 of these (group 5), the warm cardioplegic solution contained amino acids, in 5 others (group 6), it was unsupplemented, and in the remaining 5 (group 7), nitroglycerin was added to determine the role of vasodilation. Myocardial function was assessed by pressure-volume loops (expressed as a percent of control), and coronary vascular resistance was measured with cardioplegic infusions. RESULTS: In nonhypoxic (normal) piglets, cold (group 1) and warm (group 2) induction completely preserved systolic function (end-systolic elastance, 100% versus 104%) and preload recruitable stroke work (100% versus 102%), with minimal increase in diastolic compliance (162% versus 156%). Hypoxia-reoxygenation alone (group 3) depressed systolic function (end-systolic elastance, 51%+/-2%) and preload recruitable stroke work (54%+/-3%), and raised diastolic stiffness (260%+/-15%). The detrimental effects of reoxygenation persisted (unchanged from reoxygenation alone) with cold induction (group 4) or warm induction without amino acids (groups 6 and 7). In contrast, warm induction with amino acids (group 5) restored systolic function (end-systolic elastance, 105%+/-3%; p < 0.001 versus groups 3, 4, 6, and 7) and preload recruitable stroke work (103%+/-2%; p < 0.001 versus groups 3, 4, 6, and 7), and decreased diastolic stiffness (154%+/-7%; p < 0.001 versus groups 3, 4, 6, and 7). However, there was no difference in myocardial oxygen consumption in hypoxic hearts receiving a warm induction (6.9 versus 6.5 versus 7.3 mL/g per 5 minutes) (groups 5, 6, 7), and coronary vascular resistance was lowest with nitroglycerin (group 7). CONCLUSIONS: Cardioplegic induction can be given either warm or cold in nonhypoxic neonatal hearts. In contrast, only warm induction with amino acids repairs the hypoxic injury, but the primary mechanism of action is not related to increased metabolic activity or vasodilation.

Adenosine↗
PubMed2001

Comparison of sevoflurane with isoflurane for rapid mask induction in midazolam and butorphanol-sedated dogs.

Rapid mask induction can be a useful induction technique for veterinary patients, although it is often accompanied by exaggerated excitement responses in unpremedicated animals (Mutoh et al.: Jpn. J. Vet. Anesth. Surg. 26, 109-116; J. Vet. Med. Sci. 57, 1007-1013; J. Vet. Med. Sci. 57, 1121-1124; 1995). The aim of this study was to compare sevoflurane with isoflurane for rapid mask induction in six dogs sedated by a combination of midazolam (0.1 mg/kg) and butorphanol (0.2 mg/kg). Induction with sevoflurane (5%, 2.4 minimum alveolar concentration [MAC]) in O2 resulted in shorter time to loss of the palpebral reflex, negative tail clamp response, and successful intubation than with isoflurane (3%, 2.4 MAC) in O2. There were no changes in heart rate or mean arterial blood pressure during induction with sevoflurane, whereas an increase in heart rate was observed in dogs induced with isoflurane. A decrease in respiratory rate compared with the pre-induction rate was observed during induction, and associated mild respiratory acidosis, characterized by an increase in arterial PCO2, was measured at the end of the induction period in both induction groups. None of the animals had episodes of induction-related complications. These results suggest that both sevoflurane and isoflurane produce a smooth onset of induction in midazolam and butorphanol-sedated dogs. Sevoflurane is a more suitable for rapid mask induction than isoflurane since it provides faster induction associated with a lower blood/gas partition coefficient.

Anesthesia, Inhalation↗
PubMed1985

Failed induction of labour.

Over a 15-month period 1,057 consecutive inductions of labour were performed representing a 10% induction rate; 174 (16.5%) of these patients were delivered by Caesarean section of which 74 (7.0%) were for failed induction of labour, 58 (5.5%) for fetal distress, 19 (1.8%) for cephalopelvic disproportion, 6 for malposition and 17 for other reasons. The mean cervical score at induction of labour was 5.7 and 5.5 for cephalopelvic disproportion (CPD) and malposition respectively but was 4.0 for failed induction. The mean cervical dilatation at the time of Caesarean section was 5.7 cm and 6.6 cm for CPD and malposition respectively whereas it was 3.5 cm for failed induction. Mean maximum dose of oxytocin was 19.2 milliunits per minute (mu/min) and 22.5 mu/min for CPD and malposition respectively whereas it was 24.7 mu/min for cases of failed induction. Nulliparas with a cervical score of 3 or less had a 65.4% Caesarean section rate of which more than two-thirds were for failed induction of labour. Analysis of indications for induction of labour revealed that a fair number of inductions had debatable obstetric indications. Tailoring induction of labour to the cervical score and indication might reduce the Caesarean section rate for failed induction of labour. Rational management to ensure an adequate dose of oxytocin and sufficient time in the first stage of labour is important. Failed induction of labour may be differentiated from failure of labour progress due to CPD or malposition.

Adult↗
PubMed1994

Elective and routine induction of labor. A retrospective analysis of 274 cases.

A retrospective analysis of elective induction of labor at term and routine induction after 42 completed weeks' gestation was conducted to assess neonatal and maternal outcome in a low-risk obstetric population at a tertiary care facility. In 1989, 639 labor inductions were performed at the Christ Hospital and Medical Center. Two hundred one inductions were performed between 37 and 41 6/7 weeks' (elective induction), while 73 were performed at 42 weeks' gestation and beyond (routine induction). Cervical status was ascertained on admission. Patients undergoing routine induction had a longer second stage of labor as compared to patients undergoing elective induction. Otherwise the duration of labor and membrane rupture did not significantly differ between the two groups. Nulliparous patients with an unfavorable cervix who were induced electively had a trend toward a higher cesarean section rate than nulliparas with an unfavorable cervix induced routinely. There was no difference between the elective and routine induction populations with respect to the incidence of fetal distress, neonatal outcome or maternal outcome. Respiratory distress syndrome was noted in three cases, all secondary to meconium aspiration and all from the elective induction group. The incidence of birth weight > or = 4,000 g was equal in the elective and routine induction groups, and no birth weights < or = 2,500 g were recorded. No cases of iatrogenic prematurity were noted, either. When compared to routine induction after 42 weeks' gestation, there is no advantage to elective induction, especially in nulliparous patients with unfavorable cervixes.

Adult↗
PubMedDate not supplied

Effects of ovulation induction on ovarian morphology: an animal study.

OBJECTIVE: The aim of this study was to investigate whether the ovulation induction has relation with postneoplastic lesions. MATERIALS AND METHODS: Seventy-eight female, 90-day-old rats were enrolled for the trial. They were divided into three groups. In the first group, 13 rats received one cycle of ovulation induction with Follitropin Beta and human chorionic gonadotropin. The second group of 13 rats received three cycles of ovulation induction, and the third study group consisted of 13 rats which received six cycles of ovulation induction. Each group had a control group consisting of same number of rats that had not received ovulation induction. At the 12th month after the ovulation induction protocols ended, rat ovaries were extirpated for histopathological examination. In histopathological examination, malignant lesions, ovarian cyst and cyst diameter, epithelial stratification, epithelial tufting, mitotic index, polymorphism of epithelial cells and nucleus, epithelial cell nuclear diameter, chromatin density nuclear atypia, and mitotic activity in ovarian cyst epithelium were evaluated. RESULTS: No malignant ovarian lesion was found in the three groups. Ovarian cyst development was most frequent in the rats that underwent six cycles of ovulation induction. Epithelial stratification and tufting were most frequent in the rats which underwent ovulation induction six times. Significant difference was found between induction and control groups in second and third groups for cellular and nuclear polymorphism, presence of nucleolus, and nuclear chromatin density. CONCLUSIONS: Although development of malignant lesion were not found in any of the rat ovaries after ovulation induction, increase in the prevalence of epithelial dysplasia especially with increase in the number of induction cycles shows that some ovarian pathologies can occur subsequent to ovulation induction.

Animals↗
PubMed1987

Metal induction of heme oxygenase.

The experimental data that have been reviewed support the following conclusions regarding metal induction of microsomal heme oxygenase activity: 1. Induction of heme oxygenase in liver, kidney, and other organs of rodents is a nonspecific, toxic response to parenteral administration of numerous metal compounds. 2. The Co2+ and Cd2+ ions are especially potent for induction of heme oxygenase in rat liver; Sn2+, Ni2+, and As3+ are especially potent for induction of the enzyme in rat kidney; Hg2+ is especially potent for induction of the enzyme in rat adrenal. 3. Rat spleen, testis, and brain are relatively refractory to metal induction of heme oxygenase activity; in testicular microsomes from Cd2+-treated rats, heme oxygenase activity is markedly inhibited. 4. Metal induction of heme oxygenase requires de novo synthesis of mRNA and protein, based on 1) experiments with metabolic inhibitors (actinomycin D, puromycin, and cycloheximide) and 2) translation assays of heme oxygenase mRNA. 5. Heme oxygenase induction by metals is generally suppressed by treatments with SH compounds (for example, cysteine and glutathione) and enhanced by agents that deplete tissue SH levels (for example, diethyl maleate), suggesting that the induction mechanism may involve binding of metal ions to SH-containing regulatory molecules. 6. Administration of DDC exerts a pronounced synergistic effect on Ni2+ induction of heme oxygenase activity in rat tissues, attributable in part to enhanced cellular uptake of nickel. 7. Induction of heme oxygenase is not sustained during repeated daily treatments of rats with NiCl2, pointing to an adaptive mechanism for tolerance to the enzyme inducer. Investigations of metal induction of heme oxygenase activity have commonly involved sc or ip administration of the test compounds to rats. The paucity of studies in other species and the dearth of experiments with oral or respiratory exposures hinder extrapolations of the animal data to human environmental or occupational exposures to metal compounds.

Animals↗
PubMed2000

Induction of drug metabolising enzymes: pharmacokinetic and toxicological consequences in humans.

Currently, 5 different main mechanisms of induction are distinguished for drug-metabolising enzymes. The ethanol type of induction is mediated by ligand stabilisation of the enzyme, but the others appear to be mediated by intracellular 'receptors'. These are the aryl hydrocarbon (Ah) receptor, the peroxisome proliferator activated receptor (PPAR), the constitutive androstane receptor (CAR, phenobarbital induction) and the pregnane X receptor [PXR, rifampicin (rifampin) induction]. Enzyme induction has the net effect of increasing protein levels. However, many inducers are also inhibitors of the enzymes they induce, and the inductive effects of a single drug may be mediated by more than one mechanism. Therefore, it appears that every inducer has its own pattern of induction; knowledge of the main mechanism is often not sufficient to predict the extent and time course of induction, but may serve to make the clinician aware of potential dangers. The possible pharmacokinetic consequences of enzyme induction depend on the localisation of the enzyme. They include decreased or absent bioavailability for orally administered drugs, increased hepatic clearance or accelerated formation of reactive metabolites, which is usually related to local toxicity. Although some severe drug-drug interactions are caused by enzyme induction, most of the effects of inducers are not detected in the background of nonspecific variation. For any potent inducer, however, its addition to, or withdrawal from, an existing drug regimen may cause pronounced concentration changes and should be done gradually and with appropriate monitoring of therapeutic efficacy and adverse events. The toxicological consequences of enzyme induction in humans are rare, and appear to be mainly limited to hepatoxicity in ethanol-type induction.

Animals↗
PubMedDate not supplied

The effect of 3-methylcholanthrene, Aroclor 1254, and phenobarbital induction on the metabolism of biphenyl by rat and mouse 9000g supernatant liver fractions.

The metabolism of biphenyl in vitro in 9000 g supernatant fractions from livers of noninduced rats and mice was compared with the metabolism in similar liver fractions of rats and mice induced with 3-methylcholanthrene (3-MC), Aroclor 1254 and phenobarbital (PB). Analyses were carried out by open-tubular capillary gas chromatography and by gas chromatography/mass spectrometry. The major metabolite of biphenyl in all instances was 4-hydroxybiphenyl, and only very small amounts of diols were observed before induction. After induction by 3-MC, an increase was observed in all monohydroxybiphenyls for rat liver 9000 g supernatant fractions, and the 2,5- and 3,4-diols were present in greater amount. The effect of Aroclor 1254 induction resembled that observed for 3 MC induction. Induction of PB showed very little effect. For the mouse, induction with 3-MC resulted in an increase in all monohydroxybiphenyls and an increase in 2,5- and 3,4-diols. Induction with Aroclor 1254 resulted in an increase in 2-hydroxybiphenyl formation, but not in 4-hydroxylation. Thus the effects of 3-MC and Aroclor 1254 induction on biphenyl metabolism are similar in the rat but not in the mouse. Very little change was observed after PB induction. The effect of 3-MC induction (rat and mouse) on hydroxylation of monohydroxybiphenyls was to increase ortho- and para-hydroxylation in the hydroxy-substituted ring. Single-stage oxidations can be studied in vitro, but in vivo experiments are more informative when two or more stages of oxidation are involved. Although 2-hydroxylation of biphenyl is not a specific effect of cytochrome P1-r50 induction, biphenyl can be used as a test substance in animals to recognize this type of induction.

Animals↗
PubMed2001

Intravenous oxytocin alone for cervical ripening and induction of labour.

BACKGROUND: Oxytocin is the commonest induction agent used worldwide. It has been used alone, in combination with amniotomy or following cervical ripening with other pharmacological or non-pharmacological methods. Prior to the introduction of prostaglandin agents oxytocin was used as a cervical ripening agent as well. In developed countries oxytocin alone is more commonly used in the presence of ruptured membranes whether spontaneous or artificial. In developing countries where the incidence of HIV is high, delaying amniotomy in labour reduces vertical transmission rates and hence the use of oxytocin with intact membranes warrants further investigation. This review will address the use of oxytocin alone for induction of labour. Amniotomy alone or oxytocin with amniotomy for induction of labour has been reviewed elsewhere in the Cochrane Library. Trials which consider concomitant administration of oxytocin and amniotomy will not be considered. This is one of a series of reviews of methods of cervical ripening and labour induction using a standardised methodology. OBJECTIVES: To determine the effects of oxytocin alone for third trimester cervical ripening or induction of labour in comparison with other methods of induction of labour or placebo/no treatment. SEARCH STRATEGY: The Cochrane Pregnancy and Childbirth Group Trials Register, the Cochrane Controlled Trials Register and bibliographies of relevant papers. Last searched: May 2001. SELECTION CRITERIA: The criteria for inclusion included the following: (1) clinical trials comparing vaginal prostaglandins used for third trimester cervical ripening or labour induction with placebo/no treatment or other methods listed above it on a predefined list of labour induction methods; (2) random allocation to the treatment or control group; (3) adequate allocation concealment; (4) violations of allocated management not sufficient to materially affect conclusions; (5) clinically meaningful outcome measures reported; (6) data available for analysis according to the random allocation; (7) missing data insufficient to materially affect the conclusions. DATA COLLECTION AND ANALYSIS: A strategy was developed to deal with the large volume and complexity of trial data relating to labour induction. This involved a two-stage method of data extraction. The initial data extraction was done centrally, and incorporated into a series of primary reviews arranged by methods of induction of labour, following a standardised methodology. The data is to be extracted from the primary reviews into a series of secondary reviews, arranged by category of woman. MAIN RESULTS: In total, 110 trials were considered; 52 have been excluded and 58 included examining a total of 11,129 women. Comparing oxytocin alone with expectant management: Oxytocin alone reduced the rate of unsuccessful vaginal delivery within 24 hours when compared with expectant management (8.3% versus 54%, relative risk (RR) 0.16, 95% confidence interval (CI) 0.10,0.25) but the caesarean section rate was increased (10.4% versus 8.9%, RR 1.17, 95% CI 1.01,1.36). This increase in caesarean section rate was not apparent in the subgroup analyses. Women were less likely to be unsatisfied with induction rather than expectant management, in the one trial reporting this outcome (5.5% versus 13.7%, RR 0.43, 95% CI 0.33, 0.56). Comparing oxytocin alone with vaginal prostaglandins: Oxytocin alone was associated with an increase in unsuccessful vaginal delivery within 24 hours (52% versus 28%, RR 1.85, 95% CI 1.41, 2.43), irrespective of membrane status, but there was no difference in caesarean section rates (11.4% versus 10%, RR 1.12, 95% CI 0.95, 1.33). Comparing oxytocin alone with intracervical prostaglandins: Oxytocin alone was associated with an increase in unsuccessful vaginal delivery within 24 hours when compared with intracervical PGE2 (51% versus 35%, RR 1.49, 95% CI 1.12,1.99). For all women with an unfavourable cervix regardless of membrane status, the caesarean section rates were increased (19.0% versus 13.1%, RR 1.42, 95% CI 1.11, 1.82). REVIEWER'S CONCLUSIONS: Overall, comparison of oxytocin alone with either intravaginal or intracervical PGE2 reveals that the prostaglandin agents probably overall have more benefits than oxytocin alone. The amount of information relating to specific clinical subgroups is limited, especially with respect to women with intact membranes. Comparison of oxytocin alone to vaginal PGE2 in women with ruptured membranes reveals that both interventions are probably equally efficacious with each having some advantages and disadvantages over the others. With respect to current practice in women with ruptured membranes induction can be recommended by either method and in women with intact membranes there is insufficient information to make firm recommendations.

Cervical Ripening↗
PubMed1983

Effects of antimutagens on prophage induction in E coli lysogenic for lambda.

The effects of caffeine, acriflavine, spermine, quinacrine, and adenosine on spontaneous and UV-induced prophage induction in repair-proficient and -deficient strains of lysogenic Escherichia coli were examined. Caffeine caused a coinducing effect on UV induction in KMBL 160 (repair proficient) and KMBL 163 (uvrA), an anti-inducing effect in KMBL 161 (uvrE), and had no detectable effect in KMBL 164 (uvrC). Acriflavine increased UV induction in KMBL 160 and decreased it in all three repair-deficient mutant strains. Spontaneous induction was reduced by acriflavine in all four strains. Spermine caused a decrease in UV induction in KMBL 160 and KMBL 164, while it had limited effect in KMBL 161 and KMBL 163. For spontaneous induction spermine caused an increase in KMBL 160 and KMBL 163, a decrease in KMBL 164 and no detectable effect in KMBL 161. Quinacrine had no significant effect on spontaneous induction in KMBL 160 and KMBL 164, but caused a decrease in spontaneous induction in KMBL 161 and KMBL 163. Quinacrine produced no effect on UV induction in KMBL 160; however, it decreased UV induction in the three repair-deficient strains to some extent. A significant increase in spontaneous induction in KMBL 160 was caused by adenosine, while it had little effect in the repair-deficient strains. UV induction was not affected by adenosine.

Acriflavine↗
PubMed2004

The value of ultrasound in the prediction of successful induction of labor.

OBJECTIVES: To examine the value of pre-induction sonographic assessment of cervical length, posterior cervical angle and occipital position in the prediction of the induction-to-delivery interval within 24 h, the likelihood of vaginal delivery within 24 h, the likelihood of Cesarean section and to compare sonographic assessment with the Bishop score. METHODS: In 604 singleton pregnancies, induction of labor was carried out at 35-42 weeks of gestation. Immediately before induction, transvaginal sonography was performed for measurement of cervical length and posterior cervical angle and a transabdominal scan was carried out to determine the position of the fetal occiput. The value of occipital position, posterior cervical angle, cervical length, parity, gestational age, maternal age, and body mass index (BMI) on the induction-to-delivery interval within 24 h, the likelihood of vaginal delivery within 24 h and the likelihood of Cesarean section were investigated by Cox proportional hazard model or logistic regression analysis. RESULTS: Vaginal delivery occurred in 484 (80.1%) women and this was within 24 h of induction in 388 (64.2%). Cesarean section was performed in 120 (19.9%). Occiput-anterior (OA) and transverse (OT) positions were analyzed as one group as the odds ratios (OR) and the HR were similar and different from occiput-posterior (OP), which was analyzed as another group. Prediction of the induction-to-delivery interval was provided by the occipital position, pre-induction cervical length, parity and posterior cervical angle. Prediction of the likelihood of vaginal delivery within 24 h was provided by the occipital position, cervical length, posterior cervical angle and BMI. Prediction of the likelihood of Cesarean section was provided by the occipital position, cervical length, parity, maternal age and BMI. In the prediction of vaginal delivery within 24 h, for a specificity of 75%, the sensitivity for ultrasound findings was 89% and for the Bishop score it was 65%. The respective sensitivities for Cesarean section were 78% and 53%. CONCLUSION: In women undergoing induction of labor, significant independent prediction of the induction-to-delivery interval within 24 h, the likelihood of vaginal delivery within 24 h and the likelihood of Cesarean section are provided by pre-induction cervical length, occipital position, posterior cervical angle and maternal characteristics. Sonographic parameters were superior to the Bishop score in the prediction of the outcome of induction.

Body Mass Index↗