ALMA Observations of the Water Fountain Pre-Planetary Nebula IRAS 16342-3814: High-Velocity Bipolar Jets and an Expanding Torus.

We have mapped 12CO J=3-2 and other molecular lines from the "water-fountain" bipolar pre-planetary nebula (PPN) IRAS 16342-3814 with [Formula: see text] resolution using ALMA. We find (i) two very high-speed knotty, jet-like molecular outflows, (ii) a central high-density (> few × 106 cm-3), expanding torus of diameter 1300 AU, and (iii) the circumstellar envelope of the progenitor AGB, generated by a sudden, very large increase in the mass-loss rate to > 3.5 × 10-4M⊙ yr-1 in the past ~455 yr. Strong continuum emission at 0.89 mm from a central source (690 mJy), if due to thermally-emitting dust, implies a substantial mass (0.017 M⊙) of very large (~mm-sized) grains. The measured expansion ages of the above structural components imply that the torus (age~160 yr) and the younger high-velocity outflow (age~110 yr) were formed soon after the sharp increase in the AGB mass-loss rate. Assuming a binary model for the jets in IRAS 16342, the high momentum rate for the dominant jet-outflow in IRAS 16342 implies a high minimum accretion rate, ruling out standard Bondi-Hoyle-Lyttleton wind accretion and wind Roche lobe overflow (RLOF) models with white-dwarf or main-sequence companions. Most likely, enhanced RLOF from the primary or accretion modes operating within common envelope evolution are needed.

Unexpectedly large mass loss during the thermal pulse cycle of the red giant star R Sculptoris.

The asymptotic-giant-branch star R Sculptoris is surrounded by a detached shell of dust and gas. The shell originates from a thermal pulse during which the star underwent a brief period of increased mass loss. It has hitherto been impossible to constrain observationally the timescales and mass-loss properties during and after a thermal pulse--parameters that determine the lifetime of the asymptotic giant branch and the amount of elements returned by the star. Here we report observations of CO emission from the circumstellar envelope and shell around R Sculptoris with an angular resolution of 1.3″. What was previously thought to be only a thin, spherical shell with a clumpy structure is revealed to also contain a spiral structure. Spiral structures associated with circumstellar envelopes have been previously seen, leading to the conclusion that the systems must be binaries. Combining the observational data with hydrodynamic simulations, we conclude that R Sculptoris is a binary system that underwent a thermal pulse about 1,800 years ago, lasting approximately 200 years. About 3 × 10(-3) solar masses of material were ejected at a velocity of 14.3 km s(-1) and at a rate around 30 times higher than the pre-pulse mass-loss rate. This shows that about three times more mass was returned to the interstellar medium during and immediately after the pulse than previously thought.

Attitudes about dental care among parents whose children suffer from severe congenital heart disease: a case-control study.

OBJECTIVES: To examine attitudes and experiences of parents whose children have complex congenital heart disease (CHD) with respect to dental health information and advice, dental care, and service and to compare the results with data from an age- and gender-matched control group without any medical problems. SETTING: Faculty of Medicine (Paediatric Cardiology and Paediatric Dentistry), Umeå University, Umeå, Sweden. SAMPLE AND METHOD: Each group comprised parents of 33 children; the children's mean age was 9.4 years. All the cases and the controls resided in the county of Västerbotten, northern Sweden. Data were collected with a questionnaire with 20 joint questions to both groups and four additional questions to the CHD group. RESULTS: Of the 20 joint questions, significant differences were displayed in the following areas: the professional group that provided the parents with dental health information and advice (P < 0.01), attitudes to reception at the dental clinic, and experience of sedation before operative dental treatment (P < 0.05). Parents to 11 children with CHD who were patients at a specialist clinic for paediatric dentistry scored the reception at the dental clinic as excellent in nine cases and satisfactory in two, compared to excellent (3), satisfactory (11), decent (4), and poor (4) among those who were patients in general dental practice (P < 0.01). No statistically significant differences in educational level or in parental experience of dental health were noted between the two groups (P > 0.05). CONCLUSION: Children with CHD in northern Sweden mainly receive their dental health information from a physician or a dentist, and healthy children mainly receive information from a dental hygienist indicating that children with CHD are given priority in the dental care system. Parental attitudes to reception in the dental service differed, and parents of healthy children scored the reception at the dental clinic better than parents of children with CHD. It is suggested that children with severe CHD should receive dental care in clinics for paediatric dentistry, particularly at early ages.

A thirteen week dietary toxicity study with 7-hydroxymatairesinol potassium acetate (HMRlignan) in rats.

Plant lignan 7-hydroxymatairesinol (7-HMR) is a novel precursor of the mammalian lignan enterolactone. A 13 week toxicity study at dietary levels of 0, 0.25, 1, and 4% (w/w) of potassium acetate complex of 7-HMR (HMRlignan) was conducted in the Wistar rat. These dietary levels resulted in an average daily intake of 160, 640, and 2600 mg HMRlignan/kg body weight/day, respectively. A considerable systemic exposure of HMRlignan was verified by dose-related increases in plasma total (conjugated and unconjugated) concentration of 7-HMR and metabolites enterolactone, 7-hydroxyenterolactone, and matairesinol. Enterolactone appeared to be the major metabolite. Most (>96%) of the circulating 7-HMR and enterolactone was in conjugated form as measured from the low-dose rat plasma samples. HMRlignan exposure did not significantly affect clinical signs, ophthalmoscopy or neurobehavioural observations, and motor activity. Transient reductions in food intake and body weight gain in the mid-and high-dose group were ascribed to decreased palatability of the test feed. Only in males of the high-dose group the body weights remained slightly reduced throughout the study. In the high-dose group the number of thrombocytes (females), and total white blood cell count (males) were increased. Plasma triglycerides were dose-dependently depressed in males of all test groups and in females of the mid- and high-dose group, while plasma total cholesterol, and phospholipids were decreased in high-dose males. These changes, which have also been reported for other (flaxseed) lignans, were not considered to represent adverse effects. The relative weight of the kidneys was increased in males of the high-dose group. The weight of the full and empty caecum showed dose-related increases in males of all treatment groups and in females of the high-dose group. Absolute ovary weights were decreased in all treatment groups while decreases in relative ovary weights were confined to the mid- and high-dose group. In addition, a marginal lengthening of the estrus cycle was noted in high-dose females. Apart from prevention of hyaline droplet nephropathy in all high-dose male rats, there were no treatment-related histopathological alterations. It was concluded that HMRlignan showed weak antiestrogen-like activity which may be mediated through enterolactone metabolite. Based on declined ovary weight, the no observed adverse effect level of HMRlignan was set at 0.25% in feed corresponding to 160 mg/kg body weight/day.

Dental caries experience in children with congenital heart disease: a case-control study.

OBJECTIVES: To compare the dental health of a group of children with complex congenital heart disease with that of age and gender matched healthy controls. DESIGN: Case-control study. SETTING: Faculty of Medicine and Odontology/Pediatric cardiology and Pedodontics, Umeå University, Sweden. SAMPLE AND METHODS: All the cases and their controls lived in the county of Västerbotten in northern Sweden. Each group comprised 41 children with a mean age of 6.5 years. Data were collected from medical and dental records while all bitewing radiographs were read separately by one of the authors. RESULTS: Children with congenital heart disease had significantly more caries in their primary teeth than the control group. The mean dmfs-value was 5.2 +/- 7.0 in the cardiac group compared to 2.2 +/- 3.5 in the control group (P < 0.05). Twenty-six of the children had all four 6-year-molars, and their mean DMFS-values were 0.9 +/- 1.9 in the cardiac group compared to 0.3 +/- 0.6 in the control group (P > 0.05). The children with congenital heart disease had received more caries prevention based on the use of fluorides than the control group. There was a significant correlation between the number of fluoride varnish treatments and the dmfs value of the child (r = 0.411, P < 0.01). Fifty-two per cent of the children in the cardiac group had been prescribed fluoride tablets on one or more occasions compared to 17% in the control group (P < 0.01). Number of months on digoxin medication and the dmfs-value had a significant correlation (r = 0.368, P < 0.05). Ten of the children had been on digoxin medication between 6 and 87 months; this subgroup had a mean dmfs-value of 10.1 +/- 8.5. CONCLUSION: Swedish children with complex congenital heart disease have poorer dental health than healthy age and gender matched controls in spite of intensive preventive efforts. In many cases, intervention had been given when caries were present. A closer cooperation between paediatric cardiology and paediatric dentistry is needed.

Are needle-free injections a useful alternative for growth hormone therapy in children? Safety and pharmacokinetics of growth hormone delivered by a new needle-free injection device compared to a fine gauge needle.

The clinical safety, use and pharmacokinetics of a new needle-free device for delivery of growth hormone (GH) were compared with those of conventional needle injection devices. In an open-label, randomized, 4-period crossover study, 18 healthy adults received single subcutaneous injections of Genotropin administered by the Genotropin ZipTip needle-free device and by conventional injection. Bioequivalence was established between the devices. In a separate open-label, randomized, multicenter, 2-period crossover study, pediatric patients underwent 2-weeks Genotropin treatment administered by the Genotropin ZipTip and by a fine-gauge needle device (>95% used the Genotropin Pen). In total, 128/133 patients who were treated completed the study. Genotropin ZipTip was well tolerated and >50% of patients found no difference between the devices for all parameters assessed. After study completion, >20% patients preferred to continue using Genotropin ZipTip. Although statistical analyses demonstrated superiority of the Genotropin Pen versus Genotropin ZipTip for bleeding, pain, soreness, and bruising, Genotropin ZipTip was considered to provide a safe and bioequivalent alternative to needle injection.

CYP2B6 and CYP2C19 as the major enzymes responsible for the metabolism of selegiline, a drug used in the treatment of Parkinson's disease, as revealed from experiments with recombinant enzymes.

In view of conflicting data in the literature regarding the enzyme(s) responsible for metabolism of selegiline, a drug used in the treatment of Parkinson's disease, investigations were carried out in vitro using the human cytochrome P450 enzymes CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 recombinantly expressed in yeast to elucidate the enzyme specificity in selegiline metabolism. In the yeast microsomes used, desmethylselegiline and levomethamphetamine were formed from selegiline at significant rates. The highest contribution to the hepatic clearance of selegiline was calculated to be exerted by CYP2B6 (124 l/h) CYP2C19 (82 l/h), whereas CYP3A4 (27 l/h) and CYP1A2 (21 l/h) were of less importance. Antibodies against CYP2B6 inhibited metabolism of selegiline in microsomes containing CYP2B6 but not in microsomes without significant amounts of the enzyme. In contrast to previous reports, we could not find any role for CYP2D6 in the metabolism of selegiline. The data strongly indicate that the high extent of interindividual variation seen in vivo for selegiline clearance is caused by the metabolism of the compound by the highly polymorphic CYP2B6 and CYP2C19.

Inhibition of MAO-A activity enhances behavioural activity of rats assessed using water maze and open arena tasks.

To determine if the inhibition of MAO-A and/or MAO-B activities can influence cognitive processes in adult rats, we analysed whether chronic treatment with clorgyline, 1-deprenyl and pargyline could modify the performance of adult rats in a modified version of the water maze task. The effects of these treatments on locomotor activity and enzyme activities were also assessed. Rats were treated for 24 days with clorgyline (0.2 mg/kg), 1-deprenyl (0.25 mg/kg) and pargyline (I or 10 mg/kg). The treatments were started two weeks before the water maze experiment and continued until the end of testing. The rats were trained to find a submerged platform (6 days: I trial/day; 7 th day: probe trial). Over the next three days, locomotor activity was assessed in an open arena. Treatments with clorgyline (MAO-A inhibitor), 1-deprenyl (MAO-B inhibitor) and pargyline (non-selective MAO inhibitor) did not improve the finding of the hidden platform, when compared to treatment with saline, but significantly increased the swimming speed of the rats. The different treatments, when compared to saline, failed to modify the distance covered and the number of groomings performed in the open arena. However, clorgyline and pargyline, 10 mg/kg, increased the number of faecal boli and clorgyline enhanced the number of rearings made when compared to saline, 1-deprenyl and pargyline, 10 mg/kg. These results indicate that near total inhibition of MAO-A by clorgyline and pargyline as assessed by MAO activity measurement induces an increase in locomotor activity but that inhibition of MAO-A or MAO-B, either alone or combined, does not facilitate spatial learning in adult rats.

CYP2C19 polymorphism is not important for the in vivo metabolism of selegiline.

OBJECTIVES: To address the relevance of cytochrome P-450 (CYP) 2C19 polymorphism for the pharmacokinetics and dynamics of selegiline and its two known primary metabolites, desmethylselegiline and l-methamphetamine. METHODS: Six extensive (mephenytoin S/R ratio < 0.3; EM) and six poor (mephenytoin S/R ratio > 0.8; PM) hydroxylators of S-mephenytoin ingested a single 10-mg oral dose of selegiline hydrochloride. Serum concentrations of selegiline, desmethylselegiline and l-methamphetamine were measured by gas chromatography--mass spectrometry for up to 48 h. In addition, the platelet monoamine oxidase type B (MAO-B) activity was measured for 14 days to describe possible differences in the pharmacodynamics of selegiline and its metabolites between EM and PM. RESULTS: The CYP2C19 phenotype had no significant effects on the pharmacokinetic variables of selegiline. PM of S-mephenytoin had 68% higher mean AUC of desmethylselegiline (P = 0.0017) than EM, but no significant differences were observed in other pharmacokinetic parameters of desmethylselegiline. Contrary to desmethylselegiline, the serum l-methamphetamine concentrations were slightly lower in PM, but no statistically significant differences were observed in l-methamphetamine pharmacokinetics between the two CYP2C19 phenotypes. Accordingly, the magnitude of MAO-B inhibition showed no significant differences between the study groups. CONCLUSIONS: CYP2C19 polymorphism does not seem to be crucial for the metabolism or clinical effects of selegiline.

Selegiline pharmacokinetics are unaffected by the CYP3A4 inhibitor itraconazole.

OBJECTIVE: To characterise the effects of itraconazole, a potent inhibitor of CYP3A4, on the pharmacokinetics of selegiline in healthy volunteers. METHODS: In this randomised, placebo-controlled crossover study with two phases, 12 healthy volunteers took either 200 mg itraconazole or matched placebo once daily for 4 days. On day 4, a single 10-mg oral dose of selegiline hydrochloride was administered. Serum concentrations of selegiline and its primary metabolites desmethylselegiline and l-methamphetamine were determined up to 32 h. A caffeine test was performed on day 3 of both phases, by measuring the plasma paraxanthine/caffeine concentration ratio 6 h after caffeine intake, to examine the role of CYP1A2 in selegiline pharmacokinetics. In addition, the effects of itraconazole on the metabolism of selegiline in vitro were characterised by using human liver microsomes. RESULTS: Itraconazole had no significant effects on the pharmacokinetic variables of selegiline, desmethylselegiline or l-methamphetamine, with the exception that the AUC of desmethylselegiline was increased by about 10% (P < 0.05). There was a significant correlation between the AUC(desmethylselegiline)/AUC(selegiline) ratio and the paraxanthine/caffeine ratio (r = 0.41; P < 0.05), suggesting involvement of CYP1A2 in the formation of desmethylselegiline. In experiments with human liver microsomes, itraconazole had no inhibitory effect on the formation of either desmethylselegiline or l-methamphetamine from selegiline. CONCLUSIONS: The pharmacokinetics of selegiline in healthy volunteers were unaffected by the potent CYP3A4 inhibitor itraconazole. In addition, itraconazole showed no inhibitory effect on the biotransformation of selegiline to desmethylselegiline and l-methamphetamine by human liver microsomes. These findings suggest that selegiline is not susceptible to interaction with CYP3A4 inhibitors.

MAO-B inhibition by a single dose of l-deprenyl or lazabemide does not prevent neuronal damage following focal cerebral ischaemia in rats.

The present study investigated the effect of postischaemic infusion of an irreversible monoamine oxidase B (MAO-B) inhibitor, l-deprenyl, an equipotent dose of a reversible MAO-B inhibitor, lazabemide, or 0.9% NaCl on infarct volumes following focal cerebral ischaemia in rats. The drug doses (0.3 mg/kg) were selected to induce selective MAO-B inhibition (45-55%), but not MAO-A inhibition. The infarct volumes in the cortex or in the striatum did not differ between the experimental groups 72 hr after transient occlusion of the middle cerebral artery, which suggests that during ischaemia/reperfusion, suppressed oxidative stress by partial MAO-B inhibition or MAO-B independent mechanisms such as induction of trophic factors, does not protect against ischaemia/reperfusion damage.

Selegiline metabolism and cytochrome P450 enzymes: in vitro study in human liver microsomes.

Although being a drug therapeutically used for a long time, the enzymatic metabolism of selegiline has not been adequately studied. In the current work we have studied the cytochrome P450 (CYP)-catalyzed oxidative metabolism of selegiline to desmethylselegiline and 1-methamphetamine and the effects of selegiline, desmethylselegiline and 1-methamphetamine on hepatic CYP enzymes in human liver microsomes in vitro. The apparent Km values for desmethylselegiline and 1-methamphetamine formation were on an average 149 microM and 293 microM, and the apparent Vmax values, 243 pmol/min./mg and 1351 pmol/min./mg, respectively. Furafylline and ketoconazole, the known reference inhibitors for CYP1A2 and CYP3A4, respectively, inhibited the formation of desmethylselegiline with Ki value of 1.7 microM and 15 microM. Ketoconazole inhibited also the formation of 1-methamphetamine with Ki of 18 microM. Fluvoxamine, an inhibitor of CYP1A2, CYP2C19 and CYP3A4, inhibited the formation of desmethylselegiline and 1-methamphetamine with Ki values of 9 and 25 microM, respectively. On the basis of these results we suggest that CYP1A2 and CYP3A4 contribute to the formation of desmethylselegiline and that CYP3A4 participates in the formation of 1-methamphetamine. In studies with CYP-specific model activities, both selegiline and desmethylselegiline inhibited the CYP2C19-mediated S-mephenytoin 4'-hydroxylation with average IC50 values of 21 microM and 26 microM, respectively. The Ki for selegiline was determined to be around 7 microM. Selegiline inhibited CYP1A2-mediated ethoxyresorufin O-deethylation with a Ki value of 76 microM. Inhibitory potencies of selegiline, desmethylselegiline and 1-methamphetamine towards other CYP-model activities were much lower. On this basis, selegiline and desmethylselegiline were shown to have a relatively high affinity for CYP2C19, but no evidence about selegiline metabolism by CYP2C19 was obtained.

Associations among oral estrogen use, free testosterone concentration, and lean body mass among postmenopausal women.

Circulating concentrations of sex hormone-binding globulin (SHBG) are increased by use of oral estrogen. The objective of this study was to determine whether postmenopausal women who used oral estrogen had higher serum concentrations of SHBG and lower serum concentrations of free testosterone (T) than nonusers, and whether free T was associated with lean body mass, particularly skeletal muscle mass. Subjects were 70 postmenopausal women, 46-55 yr old, 46 of whom used oral estrogen. Total and regional body composition were determined by dual-energy x-ray absorptiometry. Serum concentrations of SHBG, total T, and estradiol (E(2)) were determined by RIA. Free T was calculated from concentrations of total T and SHBG. Hormone users had higher serum concentrations of E(2) and SHBG (182.0 +/- 58. 5 vs. 82.9 +/- 41.1 nmol/L, mean +/- SD, P: < 0.001) and lower concentrations of free T (3.7 +/- 2.2 vs. 7.9 +/- 4.1 pmol/L, mean +/- SD, P: < 0.001); total T did not differ. Total lean mass and leg lean mass were significantly correlated with free, but not total T [r values of 0.29 (P: < 0.05) and 0.31 (P: < 0.01) for total and leg lean mass, respectively, vs. free T]; arm lean mass was not correlated with either measure of T. Serum E(2) was significantly correlated with SHBG (r = 0.50, P: < 0.001) and free T (r = -0.33, P: < 0.01). These observations imply that, by reducing the concentration of bioavailable T, oral estrogen therapy may accelerate or augment lean mass loss among postmenopausal women. This conclusion awaits confirmation by longitudinal observation.

CYP2D6 polymorphism is not crucial for the disposition of selegiline.

OBJECTIVE: To determine the possible impact of CYP2D6 polymorphism on the pharmacokinetics and pharmacodynamics of selegiline. METHODS: Five poor metabolizers and 8 extensive metabolizers of debrisoquin (INN, debrisoquine) were given 10 mg selegiline hydrochloride. The concentrations of selegiline and its main metabolites in serum were determined for 4 days. The pharmacodynamics were quantitated by measuring platelet monoamine oxidase type B activity for 3 weeks. In addition, the effect of selegiline and its main metabolites on the CYP2D6-catalyzed dextromethorphan O-demethylase activity and the effect of quinidine on the metabolism of selegiline were studied in human liver microsomes. RESULTS: Peak serum concentrations of selegiline were reached rapidly and ranged from 1 to 32 nmol/L. The metabolite concentrations were considerably higher and remained so for a longer period. There were no significant differences in the pharmacokinetic parameters of selegiline, desmethylselegiline, and l-amphetamine between poor metabolizers and extensive metabolizers. However, the area under the serum concentration-time curve (AUC) values of l-methamphetamine were, on average, 46% higher (P = .01) in poor metabolizers than in extensive metabolizers. No significant correlations were found between debrisoquin metabolic ratio and AUC values of selegiline or its metabolites, except for l-methamphetamine (rs = 0.90; P < .001). The maximum monoamine oxidase type B inhibition was 97% in both groups. The inhibitory potency of selegiline, desmethylselegiline, and l-methamphetamine toward dextromethorphan O-demethylase was very low (50% inhibitory concentration values from 160 to 580 mumol/L). Quinidine (< or = 100 mumol/L) did not inhibit the formation of desmethylselegiline or l-methamphetamine from selegiline. CONCLUSIONS: CYP2D6 is not important in the primary elimination of selegiline, and the biological effect of selegiline seems to be similar in poor metabolizers and extensive metabolizers of debrisoquin. The inhibitory effect of selegiline and its main metabolites on CYP2D6 activity seems to be negligible.

Tamoxifen and toremifene concentrations in plasma are greatly decreased by rifampin.

BACKGROUND: Rifampin (INN, rifampicin) is a potent inducer of cytochrome P450 (CYP) enzymes involved in drug metabolism and therefore causes many drug interactions. METHODS: The effects of rifampin on the pharmacokinetics of tamoxifen (study I) and toremifene (study II) were examined in 2 randomized, placebo-controlled crossover studies. Ten (study I) or 9 (study II) healthy male volunteers took either 600 mg rifampin or placebo orally once a day for 5 days. On the sixth day, 80 mg tamoxifen or 120 mg toremifene was administered orally. Blood samples were collected up to 336 hours after drug administration. RESULTS: Rifampin reduced the area under the plasma concentration-time curve (AUC) of tamoxifen by 86% (P < .001), peak plasma concentration (Cmax) by 55% (P < .001), and elimination half-life (t1/2) by 44% (P < .001). The AUC of toremifene was reduced by 87% (P < .001), Cmax by 55% (P < .001), and t1/2 by 44% (P < .01) with rifampin. During the rifampin phase, the AUC of N-demethyltamoxifen was 38% (P < .001) and the AUC of N-demethyltoremifene was 20% (P < .01) of that during the placebo phase. CONCLUSIONS: Rifampin markedly reduces the plasma concentrations of tamoxifen and toremifene by inducing their CYP3A4-mediated metabolism. Concomitant use of rifampin or other potent inducers of CYP3A4 with tamoxifen and toremifene may reduce the efficacy of these antiestrogens.

Inhibition of platelet monoamine oxidase type B by selegiline.

Selegiline is an irreversible inhibitor of monoamine oxidase type B (MAO-B). No comparative data are available on the MAO-B inhibition caused by orally and intravenously administered selegiline. This study aimed to clarify this matter and to investigate the dose-response of MAO inhibition caused by orally administered selegiline. Sixteen healthy volunteers were given selegiline as a single intravenous dose (0.5 mg) and in three low oral doses (0.5 mg, 1.0 mg, and 1.5 mg) in an open-label randomized crossover trial. The MAO-B inhibition after the 0.5-mg intravenous dose was 79.6 +/- 15.1%. The dose-response of the three oral doses causing MAO-B inhibition was logistic. To check whether this equation could be applied to higher doses, eight of the volunteers were given 5-mg and 10-mg oral doses. The MAO-B inhibition after these doses (84.9 +/- 11.9% and 95.6 +/- 4.5, respectively) fitted well with the logistic model. With this equation obtained, it was calculated that a 3.4-mg oral dose of selegiline would be needed to obtain the same degree of MAO-B inhibition as after the intravenous dose of 0.5 mg. Therefore, the ratio of MAO-B inhibitory potential of intravenously and orally given selegiline is approximately 7 to 1, which fits well with the low bioavailability of the drug after oral administration.

Desmethylselegiline, a metabolite of selegiline, is an irreversible inhibitor of monoamine oxidase type B in humans.

Selegiline, an irreversible and selective inhibitor of monoamine oxidase type B (MAO-B), is metabolized into desmethylselegiline, levomethamphetamine, and levoamphetamine. In animal experiments, desmethylselegiline also has been shown to be an irreversible inhibitor of MAO-B. This study investigated the inhibitory potential of MAO-B and the pharmacokinetics of desmethylselegiline in humans. A double-blind, crossover trial was performed to compare the effects of a single dose (10 mg) of selegiline or desmethylselegiline on MAO-B platelet activity. The urinary excretion of phenylethylamine, which is considered to be a parameter of MAO-B inhibition, also was measured. The concentrations of selegiline, desmethylselegiline, and their metabolites were measured in plasma after administration of the two compounds. Ten healthy volunteers participated in the study. There was a clear inhibition of platelet MAO-B by both compounds. Desmethylselegiline caused a 63.7 +/- 12.7% inhibition of platelet MAO-B compared with 96.4 +/- 3.9% caused by selegiline. The maximal inhibition by desmethylselegiline was reached significantly later after desmethylselegiline (time to reach maximal inhibition [tmax], 27 +/- 20 hours) than after selegiline administration (tmax, 1.4 +/- 1.4 hours). The platelet MAO-B activity returned to baseline levels within 2 weeks, thus reflecting the irreversible nature of the inhibition by both compounds. The cumulative 48-hour excretion of phenylethylamine was 33% lower after desmethylselegiline than after selegiline administration. All three major metabolites of selegiline could be detected in plasma after selegiline administration. Levoamphetamine was the only metabolite of desmethylselegiline. The area under the concentration-time curve from time 0 to 24 hours (AUC0-24) of desmethylselegiline was 33 times higher than that of selegiline, suggesting a better bioavailability of desmethylselegiline. Desmethylselegiline is an orally active, irreversible inhibitor of MAO-B and could possibly be used to treat Parkinson's disease in the same way as selegiline.

The effects of metabolic inhibition and acidification on force production in the rat uterus.

The effects of hypoxia and intracellular acidification were examined on the mechanical properties of the non-pregnant and pregnant rat uterus. Isolated uteri were investigated during control conditions and in the presence of cyanide, to simulate hypoxia or the salts of weak acids and bases to change intracellular pH at constant external pH (pH 7.4). Both spontaneous contractions and high-K contractures (i.e. fully activated preparations) were investigated at 37 degrees C. In control solutions both pregnant and non-pregnant uteri were spontaneously active and gave a contracture when bathed with a high-K+ solution. When oxidative phosphorylation was inhibited by cyanide, spontaneous contractions were either greatly reduced or abolished. The effects on spontaneous contractions were more pronounced in the non-pregnant than the pregnant uterus. If high-K solution was added after cyanide had abolished spontaneous contractions, then a small amount of force was produced. High-K-induced contractures were not maintained in the presence of cyanide and quickly fell to baseline levels in both pregnant and non-pregnant uteri. All the effects of cyanide were fully reversible. When only intracellular pH was changed by adding weak acids (50 mM-butyrate or propionate), spontaneous contractions were greatly diminished or abolished in both pregnant and non-pregnant uteri. However, the application of weak acids had no effect upon the KCl-induced contractures in both pregnant and non-pregnant uteri. The effects of cyanide on the uterus include both an acidification and changes in metabolites, e.g. a fall in [ATP]. To investigate the changes in metabolites without a change in pHi, cyanide was applied with the weak base trimethylamine (40-50 mM). 31P Nuclear magnetic resonance spectroscopy was used to show that the alkalinization which occurs with trimethylamine alone abolished the acidification ordinarily associated with cyanide. Spontaneous and high-K-induced contractions were greatly reduced or abolished, i.e. the result was the same as with cyanide alone. This occurred in both pregnant and non-pregnant uteri. It is concluded that spontaneous force production is affected by both changes in metabolites (e.g. decreased [ATP] and increased inorganic phosphate) and pHi, and that both can depress activation of the uterus. Only the changes in metabolites can depress force production in fully activated preparation. The greater effect on force in the non-pregnant uterus compared to the pregnant uterus may be due to the lower initial levels of [ATP] and the greater fall in ATP seen in non-pregnant compared to pregnant uterus, and gestational changes in metabolism.(ABSTRACT TRUNCATED AT 400 WORDS)