Orally active central dopamine and serotonin receptor ligands: 5-, 6-, 7-, and 8-[[trifluoromethyl)sulfonyl]oxy]-2-(di-n-propylamino)tetralins and the formation of active metabolites in vivo.

The racemic triflate derivatives 5-8 of the 5-, 6-, 7-, and 8-hydroxylated 2-(di-n-propylamino)-teralins 1-4 were shown to possess similar pharmacological profiles to their phenolic counterparts in in vitro binding and in vivo biochemical and behavioral assays in rats. Consequently, subcutaneous administration of the 5-, 6-, and 7-triflates displayed essentially dopaminergic agonist properties, while the 8-triflate was shown to be a selective 5-HT1A receptor agonist. With respect to their agonist activities, the triflates were less potent than their phenolic analogs. The absolute oral bioavailability of compound 8 (8-triflate) was 4-5 times greater than the corresponding hydroxylated compound. Interestingly, in the in vivo biochemical assay compound 8 was found to be more potent after oral than after subcutaneous administration, indicating formation of one or more active metabolites. Following a study of the metabolism of compound 8 in rat hepatocytes, the monopropyl analog 9 was identified as the major metabolite and was surprisingly found to be more potent than compound 8. Oral administration of compound 5 (5-triflate) resulted in behavioral and biochemical effects indicative of mixed DA/5-HT1A agonist properties not seen after subcutaneous administration. These results may also be indicative of the formation of active metabolites.

Synthesis and evaluation of pharmacological and pharmacokinetic properties of monopropyl analogs of 5-, 7-, and 8-[[(trifluoromethyl)sulfonyl]oxy]-2-aminotetralins: central dopamine and serotonin receptor activity.

In order to explore further the structure-activity relationships of serotonergic and dopaminergic ligands, a series of enantiopure 5-, 7-, or 8-triflate (-OTf)-substituted 2-(monopropylamino)-tetralins have been synthesized and evaluated in in vitro binding and in vivo biochemical and behavioral assays in rats. Consequently, the 8-OTf-substituted compound R-(+)-6 was found to be a potent and selective 5-HT1A (5-hydroxytryptamine) receptor agonist inducing a full-blown 5-HT syndrome in normal rats, while the corresponding 5-OTf-substituted compound S-(-)-12 was found to be a preferential dopamine (DA) autoreceptor agonist. A partial 5-HT syndrome was also observed for S-(-)-12, while the corresponding R-(+)-12 was found to be inactive at the DA and 5-HT receptors both in vitro and in vivo. Compounds 6 and 12 were found to be major urinary metabolites following oral administration of their dipropyl analogs (2 and 13, respectively). Thus 6 was proposed to be the metabolite responsible for the full-blown 5-HT syndrome seen after oral (but not subcutaneous) administration of 2. Similarly, 12 was proposed to be the metabolite responsible for the partial 5-HT syndrome seen after oral (but not subcutaneous) administration of 13. The bioavailability of R-(+)-6 (7.6 +/- 1.1%) appeared to be slightly lower than that of 2 (11.2 +/- 5.2%), although the in vitro metabolism of R-(+)-6 appeared to be slower than that of 2. Therefore first-pass metabolism was not thought to be the reason for the lower bioavailability of R-(+)-6, as compared to 2.

Synthesis and biological activities of (R)-5,6-dihydro-N,N-dimethyl-4H-imidazo[4,5,1-ij]quinolin-5-amine and its metabolites.

The imidazoquinoline (R)-5,6-Dihydro-N,N-dimethyl-4H-imidazo[4,5,1-ij]quinolin-5-amine [(R)-3] is a potent dopamine agonist when tested in animals but surprisingly shows very low affinity in in vitro binding assays. When incubated with mouse or monkey liver S9 microsomes, (R)-3 is metabolized by N-demethylation and oxidation to (R)-5,6-dihydro-5-(methylamino)-4H-imidazo[4,5,1-ij]quinolin-2(1H) -one [(R)-6], intermediate metabolites, where N-demethylation to the imidazoquinoline (R)-4 and where oxidation to the imidazoquinolinone (R)-5 has taken place, are also observed in these incubates. A cross-species study on the metabolism of (R)-3 in vitro has shown large variations in the extent of metabolism from species to species. Imidazoquinolinones (R)-5 and (R)-6 have comparable activity to (R)-3 in animals and also show good dopaminergic (D2) and serotonergic (5HT1A) activities in binding assays. It is probable that these metabolites account at least in part for the in vivo activity found for (R)-3. Efficient syntheses for compounds 3-6 as single enantiomers from quinoline are presented together with information on the biological activities and metabolic stabilities of these compounds.

Improvement of respiratory function in chronic asthmatic patients with autogenic therapy.

Stress, unpleasant emotions and autonomic imbalance may play a main role in precipitating asthmatic attacks. In this study two homogeneous groups of asthmatic patients (N = 24) are treated over an eight-month period. The experimental group was treated with autogenic therapy and the control group with supportive group psychotherapy. Respiratory function parameters measured were Forced Vital Capacity (FVC), Forced Expiratory Volume in the first sec (FEV1), Forced Expiratory Flow between 25% and 75% of the FVC (FEF25-75%), and Mesoexpiratory Flow (MEF50%). The group under Autogenic Therapy obtained a relevant clinical improvement (> 15% of pretreatment values) in respiratory function. No significant changes were observed in the control group. These results suggest that autogenic therapy could be an effective adjunctive treatment in bronchial asthma.

[Treatment of life threatening asthma with isoflurane]. / Tratamiento del "Life threatening asthma" con isofluorane.

Three patients, one adult, one adolescent and one child, with previous history of asthma difficult to treat and frequent acute crisis, were hospitalized with clinical signs of Life Threatening Asthma (LTA) refractory to intensive treatment, including intubation and mechanical ventilation, being treated with and inhaled anesthetic: Isoflurane. All patients responded satisfactorily to such treatment at a concentration varying from 0.5 to 1.5% and none of them suffered adverse reactions to the medication. The immediate therapeutic effect and the absence of intensive care are factors that indicate the use of Isoflurane.

Bochdalek hernia with hemorrhage in an adult.

Life-threatening herniation of intra-abdominal viscera through a patent Bochdalek foramen is well recognized in neonates. Persistent foramina, leading to clinical problems in adult life, are very rare. In the case of the 17-year-old girl described in this paper, two-thirds of the stomach had inverted and passed into the left side of the chest as had the splenic flexure of the colon and most of the greater omentum. There was 500 mL of blood free in the peritoneal cavity and 1200 mL in the left pleural cavity, with no hernial sac. The defect measured 5 cm in diameter. It was repaired primarily after reduction of the viscera. Prompt operative intervention is recommended in such cases to prevent strangulation and bleeding from engorged viscera.

Interindividual variation in the isomerization of 4-hydroxytamoxifen by human liver microsomes: involvement of cytochromes P450.

Tamoxifen and its metabolite 4-hydroxytamoxifen can both exist as geometrical isomers. Trans-tamoxifen is an oestrogen receptor antagonist and is used for the treatment of breast cancer. Trans-4-hydroxytamoxifen is 100 times more anti-oestrogenic than trans-tamoxifen. The cis isomers of tamoxifen and 4-hydroxytamoxifen are oestrogenic and weakly anti-oestrogenic or oestrogenic respectively. Both isomers of 4-hydroxytamoxifen have been detected in breast tumours of patients treated with trans-tamoxifen and it has been proposed that enzymatic isomerization of 4-hydroxytamoxifen occurs in vivo, resulting in resistance to tamoxifen therapy. We have investigated the isomerization of 4-hydroxytamoxifen by human liver microsomes and whether it is mediated by cytochromes P450. Microsomes from five of the 12 livers examined catalysed the interconversion of trans- and cis-4-hydroxytamoxifen (0.52 microM) when incubated for 40 min with an NADPH-generating system. Between 51 and 64% conversion of trans-4-hydroxytamoxifen was observed. Cis-4-hydroxytamoxifen was also converted to trans-4-hydroxytamoxifen (range 22-27%). Incubations with control, heat-treated microsomes resulted in approximately 1% isomerization of trans-4-hydroxytamoxifen. The extent of isomerization of trans- to cis-4-hydroxytamoxifen observed in microsomes from the other seven livers (range 2-8%) did not greatly exceed that seen in heat-inactivated microsomes. Enzymatic isomerization required NADPH and was inhibited by SKF 525A and ketoconazole, indicating the involvement of cytochromes P450. Enzymatic isomerization of trans-tamoxifen and trans-droloxifene (the 3-hydroxy synthetic analogue of tamoxifen) was not observed. These findings may have implications for the safe and effective use of tamoxifen.

The use of liquid chromatography/thermospray mass spectrometry with on-line ultraviolet diode array and radiochemical detection: characterization of the putative metabolites of U-78875 in female rat faeces.

The metabolites of an anxiolytic drug candidate U-78875 [3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-5-(1-methylethyl)- imidazo[1,5-alpha]quinoxalin-4(5H)-one; I] were investigated in female rat faecal extracts following a single oral dose of (14C)I. Initial metabolite profiling was performed by high-performance liquid chromatography incorporating homogeneous (i.e. liquid scintillant added post-column) radiochemical detection (radio-HPLC). This indicated the presence of parent drug and one minor metabolite. Because liquid scintillant is incompatible with thermospray interfaces, subsequent analysis by thermospray/HPLC/MS (TSP/LC/MS) incorporated radiochemical detection in heterogeneous (i.e. solid scintillant) mode and ultraviolet (UV) diode array detection. This revealed that the peak thought previously to be parent drug contained two components: a metabolite (major) and parent drug (minor). The UV spectrum and TSP/LC/MS/MS daughter ion analysis led to the proposition of a bisamide structure for the major metabolite. Chemical synthesis was used to confirm this structure. TSP/LC/MS indicated that the molecular weight of the minor metabolite was 16 u higher than the bisamide, suggesting an oxidized analogue. Attempts to obtain a daughter ion spectrum on this minor metabolite proved unsuccessful. On-line radiochemical and UV diode array detection greatly facilitates the TSP/LC/MS characterization of metabolites from studies using radiolabelled drugs.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is N-demethylated by cytochromes P450 2D6, 1A2 and 3A4--implications for susceptibility to Parkinson's disease.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induces a Parkinson-like syndrome through biotransformation by monoamine oxidase B to the neurotoxic metabolite 1-methyl-4-phenylpyridine. Neuroprotection may be provided by parallel N-demethylation and N-oxidation pathways mediated by the microsomal cytochrome P450 and flavin monooxygenase systems, respectively. The aims of this study were to characterise the N-demethylation of MPTP by human liver microsomes over a wide range of concentrations, and to identify the cytochrome P450 enzymes involved in this reaction. The kinetics of the N-demethylation of MPTP (1 microM - 3 mM) by microsomes from the liver of an extensive metabolizer with respect to cytochrome P4502D6 (CYP2D6) activity were biphasic (apparent Km1 and Km2 values = 48 and 2882 microM). The high affinity activity was abolished in the presence of quinidine (1 microM) and was absent in microsomes from a genotypically poor metabolizer with respect to CYP2D6. Yeast microsomes containing heterologously expressed CYP2D6 N-demethylated MPTP (Km = 39 microM), and there was a high correlation between the quinidine-inhibitable N-demethylation of MPTP (50 microM) (0.7-91%, mean 44%, of total activity) and the alpha-hydroxylation of metoprolol in microsomes from 11 human livers (rs = 0.92; P < .001). At 50 microM MPTP, N-demethylase activity in human liver microsomes was also inhibited by furafylline (10 microM) and ketoconazole (2 microM) (mean inhibition 39 and 13%, respectively; n = 11 livers). Yeast microsomes containing heterologously expressed human CYP1A2 N-demethylated MPTP with a Km of 2246 microM. These findings indicate that CYP2D6, CYP1A2 and, to a lesser extent CYP3A4, may have a role in protecting against Parkinson's disease induced by MPTP and other potential environmental neurotoxins. The data provide some biochemical support for the proposition that genotypically poor metabolizers with respect to CYP2D6 are overrepresented in some populations of Parkinson's patients, and that smokers (induced CYP1A2?) are underrepresented.

Tailoring the management of nonparasitic liver cysts.

OBJECTIVE: To determine the optimal management of symptomatic non-parasitic liver cysts. SUMMARY BACKGROUND DATA: Management options for symptomatic nonparasitic liver cysts lack substantiation through comparative studies with respect to safety and long-term effectiveness. METHODS: A retrospective review of the surgical management of patients with hepatic cysts between October 1988 and August 1997 was undertaken to determine morbidity rates and to assess long-term recurrence. RESULTS: Thirty-eight patients (35 women, 3 men) underwent 48 operations for symptomatic hepatic cysts of mean diameter 12 cm, with a mean follow-up of 41 months. Twenty-three patients had simple cysts, and 15 patients had polycystic liver disease (PCLD). The symptomatic recurrence rates after laparoscopic or open deroofing for simple cysts were 8% and 29%, and for PCLD 71% and 20%, respectively. There were no symptomatic recurrences after 14 hepatic resections. There were no perisurgical deaths; however, morbidity rates were significant after laparoscopic deroofing, open deroofing, and hepatic resection (25%, 36%, and 50%, respectively). CONCLUSIONS: Selection of patients with truly symptomatic hepatic cysts is crucial before considering interventional techniques. For simple cysts, radical laparoscopic deroofing is usually curative; open deroofing should be reserved for cysts inaccessible by laparoscopy. The latter technique is well tolerated; however, long-term symptom control is unpredictable in patients with PCLD. Hepatic resection for PCLD provides satisfactory long-term symptom control but has an appreciable morbidity rate. Although laparoscopic and open deroofing procedures are less reliable in the long term for solitary cysts, they might be useful steps before embarking on this major procedure.

Towards T-tube free laparoscopic bile duct exploration: a methodologic evolution during 300 consecutive procedures.

OBJECTIVE: To establish a simple, reproducible, and safe technique of laparoscopic common bile duct exploration (CBDE) with high clearance rates and low morbidity and mortality rates. SUMMARY BACKGROUND DATA: For most general surgeons, laparoscopic CBDE appears an unduly complex and demanding procedure. Since the introduction of laparoscopic cholecystectomy, many surgeons use endoscopic cholangiography (ERC) and endoscopic sphincterotomy as their only option in treating bile duct stones. ERC is more specific if used after surgery, but it carries an appreciable morbidity rate and has the disadvantage of requiring a second procedure to deal with bile duct stones. To this end, various methods of laparoscopic CBDE have been developed. METHODS: Between August 1991 and February 1997, 300 consecutive unselected patients underwent laparoscopic CBDE. RESULTS: Of 300 laparoscopic CBDE procedures, 173 (58%) were managed using a transcystic approach and 127 (42%) with choledochotomy. Successful laparoscopic stone clearance was achieved in 271 (90%). Of the 29 (10%) patients not cleared laparoscopically, 10 had an elective postsurgical ERC, 12 were converted to an open procedure early in the series, and 7 had unexpected retained stones. There was one death (mortality rate 0.3%) and major morbidity occurred in 22 patients (7%). The last 100 procedures were performed from July 1995 to February 1997, and stone clearance was unsuccessful in only two patients. CONCLUSIONS: Laparoscopic transcystic basket extraction of common duct stones under fluoroscopic guidance is a relatively quick, successful, and safe technique. Choledochotomy, when required, is associated with a higher morbidity rate, particularly with T-tube insertion, and the authors advocate primary bile duct closure with or without insertion of a biliary stent as a more satisfactory technique for both surgeon and patient. Most patients with gallbladder and common duct calculi should expect a curative one-stage laparoscopic procedure without the need for external biliary drainage or ERC.

[Insomnia in asthmatic patients]. / El insomnio en pacientes asmatícos.

In this paper, in order to assess the prevalence and features of insomnia as a subjective complaint in a sample of asthmatic outpatients. (n = 43; mean age = 36.39 +/- 12.85), items 44, 64 and 66 (that deal with insomnia complaints) of Derogatis' SCL-90-R (Symptom Check List 90 REvised), that was applied to the patients of the sample, are studied. A high prevalence of insomnia complaints is observed in our patients; over 70% of the sample manifests complaints of some type of insomnia. Insomnia complaints were higher (p < 0.0001) than in general population. No significant differences were evidenced according to sex and no correlation with age was observed in any of the items taken into account for insomnia complaints. A high positive intercorrelation was evidenced among the three items that we considered. Various factors associated with insomnia in asthma are discussed.