Socioeconomic status in relation to incident fracture risk in the Study of Women's Health Across the Nation.

UNLABELLED: We examined baseline and annual follow-up data (through annual follow-up visit 9) from a cohort of 2,234 women aged 42 to 52 years at baseline. Independent of financial status, higher educational level was associated with lower fracture incidence among non-Caucasian women but not among Caucasian women. INTRODUCTION: This study was conducted to determine the associations of education and income with fracture incidence among midlife women over 9 years of follow-up. METHODS: We examined baseline and annual follow-up data (through annual follow-up visit 9) from 2,234 participants of the Study of Women's Health Across the Nation, a cohort of women aged 42 to 52 years at baseline. We used Cox proportional hazards regression models to examine the associations of socioeconomic predictors (education, family-adjusted poverty-to-income ratio, and difficulty paying for basics) with time to first incident nontraumatic, nondigital, noncraniofacial fracture. RESULTS: Independent of family-adjusted poverty-to-income ratio, higher educational level was associated with decreased time to first incident fracture among non-Caucasian women but not among Caucasian women (p(interaction) 0.02). Compared with non-Caucasian women who completed no more than high school education, non-Caucasian women who attained at least some postgraduate education had 87% lower rates of incident nontraumatic fracture (adjusted hazard ratio 0.13, 95% confidence interval [CI] 0.03-0.60). Among non-Caucasian women, each additional year of education was associated with a 16% lower odds of nontraumatic fracture (adjusted odds ratio 0.84, 95% CI 0.73-0.97). Income, family-adjusted poverty-to-income ratio, and degree of difficulty paying for basic needs were not associated with time to first fracture in Caucasian or non-Caucasian women. CONCLUSIONS: Among non-Caucasian midlife women, higher education, but not higher income, was associated with lower fracture incidence. Elucidation of the mechanisms underlying the possible protective effects of higher educational level on nontraumatic fracture incidence may allow us to better target individuals at risk of future fracture.

The interactions of human neutrophils with the constituents of an experimental dental biofilm.

Despite the antibacterial properties of neutrophils, their ability to prevent colonization of the dental biofilm by pathogenic bacteria is limited. The present study examined the ability of human neutrophils to attach to an experimental dental biofilm and tested their antibacterial functions following adhesion. Neutrophil adhesion was greatest to hydroxyapatite (HA) in the absence of biofilm. Among the biofilms, glucosyltransferase or fructosyltransferase adsorbed onto saliva-coated HA showed the highest adhesion of cells. The adhesion of neutrophils was directly related to their initial concentration in the solution and to the duration of incubation. Plasma was found to reduce neutrophil attachment significantly, while stimulation of the cells had no effect. Stimulation of attached neutrophils induced superoxide secretion with levels significantly lower than that secreted by suspended cells. The presence of neutrophils on the biofilm reduced the number and the viability of Streptococcus mutans attached to the beads. The present findings suggest that neutrophils are able to attach to dental biofilms and that the attached neutrophils retained their antibacterial activity.

[Clinical and laboratory characteristics of patients with pathologic chronic gastroesophageal reflux]. / Características clínicas y de laboratorio de pacientes con reflujo gastroesofágico crónico patológico.

BACKGROUND: Sixty percent of adults has typical symptoms of gastroesophageal reflux in Chile. AIM: To report the clinical and laboratory features of patients with gastroesophageal reflux. PATIENTS AND METHODS: Five hundred thirty-four patients (255 male) with gastroesophageal reflux were included in a prospective protocol that included clinical analysis, manometry and endoscopy in all patients, barium swallow in 427, scintigraphy in 195, acid reflux test in 359, 24 h pH in 175, and differential potential of gastroesophageal mucosa in 73 patients. RESULTS: There was no correlation between the severity of symptoms and the endoscopical severity. Patients with Barret esophagus were 12 years older, were male in a greater proportion and had a higher proportion of manometrically incompetent sphincters than patients with esophageal reflux but without esophagitis or with erosive esophagitis. Severity of acid reflux, measured with 24 h pH monitoring was proportional to the endoscopical damage of the mucosa. There was a close relationship between the mucosal change limit determined with differential potentials and with endoscopy. No short esophagi were found. CONCLUSIONS: Patients with symptoms of gastroesophageal reflux must be assessed using several objective measures to determine the severity of their pathological alterations.

New antipsychotic agents with serotonin and dopamine antagonist properties based on a pyrrolo[2,1-b][1,3]benzothiazepine structure.

The development of a synthetic approach to the novel pyrrolo[2, 1-b][1,3]benzothiazepine and its derivatives and their biological evaluation as potential antipsychotic drugs are described. In binding studies these compounds proved to be potent 5-HT2, D2, and D3 receptor ligands. The more potent benzothiazepine (+/-)-3b was resolved into its enantiomers by using HPLC techniques. In vitro testing confirmed that (-)-3b is a more potent D2 receptor ligand, maintaining high affinity for 5-HT2 receptors. In contrast, the (+)-3b enantiomer presents a 35 times higher affinity for 5-HT2 than for dopamine D2 receptors with a similar dopamine D1 receptor affinity to that of (-)-3b. Overall, (+)-3b shows an "atypical" neuroleptic binding profile, while (-)-3b has a more "classical" profile. Furthermore pharmacological and biochemical testing displayed that the novel benzothiazepine (+/-)-3b is able to increase the extracellular levels of dopamine in the rat striatum and causes a dose-related suppression of apomorphine-induced locomotor activity. At low doses (+/-)-3b does not induce catalepsy, showing atypical antipsychotic properties similar to those of olanzapine. These heterocyclic compouds represent new leads for the development of novel antipsychotic drugs with atypical properties.

Affinity for dopamine D2, D3, and D4 receptors of 2-aminotetralins. Relevance of D2 agonist binding for determination of receptor subtype selectivity.

A series of 2-aminotetralins, substituted with a methoxy or a hydroxy group on the 5- or 7-position, and with varying N-alkyl or N-arylalkyl substituents, were prepared and evaluated in binding assays for human dopamine (DA) D2, D3, and D4 receptors. Some members of this series were prepared in former studies, but were never tested in vitro with single receptor subtypes, and these were examined again. None of the tested 2-aminotetralins showed high affinity for the dopamine D4 receptor. However, a number of the 2-aminotetralins showed high affinity for both the D2 and the D3 DA receptors, as exemplified by compounds 11-15 and 21-26, while some had a reasonable selectivity for the DA D3 receptors. The affinities of the 2-aminotetralins for the D21, receptor depended on the type of radioligand (agonist or antagonist) used. The agonist affinity data, obtained by using the agonist ligand [3H]N-0437, are thought to be more relevant for calculating DA receptor subtype selectivity.

Affinities and intrinsic activities of dopamine receptor agonists for the hD21 and hD4.4 receptors.

The affinity and intrinsic activity of dopamine receptor agonists were determined at the human dopamine hD21 and hD4.4 receptors. (-)-3-Hydroxy-N-n-propylpiperidine ((-)3-PPP) had an intrinsic activity of 46% and 83%, whereas (+)-N-propylnorapomorphine ((+)-NPA) had intrinsic activities of 61% and 58% at the dopamine hD21 and hD4.4 receptors, respectively. Affinities also varied. A single, or multiple, dopamine D2-type receptor(s) may be involved in schizophrenia and agonists are being tested as therapy. Understanding their properties at the individual dopamine D2-family receptors is important.

Thiamin deficiency impairs endotoxin-induced increases in hepatic glucose output.

We addressed the role of thiamin, a cofactor for several enzymes involved in glucose metabolism, in the glucose metabolic response to endotoxin. Characterized by hyperglycemia, increased hepatic glucose production exceeding elevated rates of whole-body glucose utilization, this response is mediated by hormones and cytokines and is dependent on the immune and nutritional status of the host. We hypothesized that a thiamin-deficient state would impair the metabolic response to endotoxin. Rats were fed a thiamin-deficient or control diet for 6 wk before in vivo assessment of glucose kinetics. In control rats, Escherichia coli endotoxin increased the rate of glucose appearance (+76%), disappearance (+70%), and metabolic clearance (+50%). Thiamin deficiency resulted in increased plasma glucose (18%) and lactate (3- to 4-fold) as well as in a 30% decrease in insulin and an increase in glucagon (2.6-fold) and corticosterone (3.6-fold). Thiamin deficiency inhibited the endotoxin-induced hyperglycemia and the rise in hepatic glucose production, glucose utilization, and metabolic clearance rate.

Nutritional and metabolic characterization of a thiamine-deficient rat model.

The effects of a thiamine-deficient diet on plasma and tissue vitamin concentrations and on whole-body glucose metabolism were assessed. Male Sprague-Dawley rats (175 to 200 g body weight) fed a thiamine-deficient (TD) or nutritionally complete purified diet were used for plasma thiamine mononitrate and monophosphate and for red blood cell and tissue thiamine pyrophosphate (TPP) determinations weekly for up to 5 weeks. Additional rats were used for assessment of basal glucose kinetics by using a primed constant infusion of [3-3H]glucose. Plasma thiamine mononitrate levels decreased 60% at 1 week and were undetectable after 5 weeks on the diet. Plasma thiamine monophosphate decreased 80% after 1 week on the TD diet, and levels were undetectable after 4 weeks on the diet. Red blood cell TPP in the TD group decreased progressively with time: 54% at 1 week, 86% at 3 weeks, and 92% at 5 weeks. At 1 and 4 weeks, the decrease in tissue TPP was significant in the liver (65% and 89%, respectively), gut (52% and 94%, respectively), spleen (40% and 60%, respectively), and skeletal muscle (37% and 76%, respectively), with the brain (7% and 84%, respectively) showing the slowest initial rate of depletion. The TD diet did not alter plasma glucose concentrations, but it increased plasma lactate by 75% and plasma pyruvate by 50% to 75%. Rates of hepatic glucose production and peripheral glucose utilization were not different between the control and TD rats at 2 weeks, but they were 25% higher in the TD rats after 6 weeks on the diet.(ABSTRACT TRUNCATED AT 250 WORDS)

Determination of the dopamine D2 agonist N-0923 and its major metabolites in perfused rat livers by HPLC-UV-atmospheric pressure ionization mass spectrometry.

The metabolism of the dopamine D2 agonist N-0923 was investigated by an in vitro isolated liver perfusion. Determining the metabolic profile and identity of the different metabolites was achieved by using high-performance liquid chromatography with UV detection, combined with atmospheric pressure ionization mass spectrometry. Using this technique, no extensive sample cleanup is required, and the studies can be performed without radioactivity. In addition to previously observed metabolites, nine new metabolic products were identified. All metabolites were exclusively excreted into the bile, except for the despropyl metabolite, which was also detectable in the perfusate. 5-O-Glucuronidation and N-depropylation followed by 5-O-glucuronidation are the most important metabolic routes. N-dealkylation of the thienylethyl group followed by 5-O-glucuronidation and sulfation is a second major metabolic pathway. Catechol formation of the despropyl metabolite with or without subsequent conjugation was not found. Catechol formation of the desthienylethyl metabolite occurred, but only its glucuronide conjugates were found. This study complements previous results of in vivo metabolic studies using the radiolabeled racemate N-0437, and it explains differences in bile excretion during isolated liver perfusions using N-0923 and radiolabeled N-0923.

Differential control of glucoregulatory hormone response and glucose metabolism by NMDA and kainate.

The aim of the present study was to elucidate the effect of kainate and N-methyl-D-aspartate (NMDA), two different excitatory amino acid (EAA) agonists, on glucoregulatory hormone production and whole body glucose metabolism. Rates of hepatic glucose production (HGP) and peripheral glucose utilization (GU) were assessed in overnight fasted, catheterized, conscious rats using [3-3H]glucose. At the highest dose of kainate examined (16 mg/kg), glucose levels increased 97% after 1 h; thereafter, glucose fell towards basal values but was still elevated 25% at the end of the 3 h experiment. This hyperglycemia resulted from a rapid increase in HGP that exceeded an increased rate of GU. Both HGP and GU were elevated 86% throughout the final 2 h of the experiment. NMDA induced changes in glucose flux that were qualitatively similar, yet of smaller magnitude and of shorter duration, than those produced by kainate. Kainate-induced increases in glucose metabolism were associated with an early transient hyperinsulinemia followed by a period of insulinopenia, and sustained increases in the plasma concentrations of glucagon, corticosterone, epinephrine and norepinephrine. In contrast, sustained increases in glucagon and catecholamines, as well as the late hypoinsulinemia were not detected in NMDA-treated rats. Adrenergic blockade attenuated the kainate- but not the NMDA-induced increase in glucose metabolism. These results indicate that EAA agonists that bind preferentially to different receptor subtypes produce qualitatively similar changes in glucose metabolism. Whereas the increased HGP in kainate-injected rats was associated with sustained elevations in glucagon, catecholamines and corticosterone, NMDA only transiently elevated circulating glucocorticoid levels, suggesting a different mechanism of action. These data, support the involvement of EAA in various aspects of glucoregulation.

Central NMDA enhances hepatic glucose output and non-insulin-mediated glucose uptake by a nonadrenergic mechanism.

One of the hallmarks of the stress response is an increased rate of hepatic glucose production (HGP) which, in conjunction with the presence of insulin resistance, leads to hyperglycemia. Excitatory amino acids (EAA) within the brain mediate some of the cardiovascular responses to stress, but their role in the hormonal and metabolic alterations is poorly defined. The aim of the present study was to determine whether the intracerebroventricular (i.c.v.) injection of either N-methyl-D-aspartate (NMDA) or kainate would produce metabolic alterations comparable to those observed under stress conditions. An i.c.v. cannula and vascular catheters were placed in rats prior to the experiment. After an overnight fast, HGP and peripheral glucose utilization (GU) were assessed in conscious unrestrained rats using [3-3H]glucose. Arterial glucose levels were increased 34% by 15 min after the i.c.v. injection of NMDA (1 microgram) and remained elevated throughout the 3-h protocol. The hyperglycemia resulted from an early increase in HGP (84%) that exceeded a smaller elevation (66%) in GU. The increased glucose flux was associated with sustained insulinopenia (-30%), and elevated levels of corticosterone (40-100%) and epinephrine (75-216%). The hormonal and glucose metabolic responses were quantitatively similar, although of shorter duration, in rats injected with kainate (10 ng). Intravenous adrenergic blockade completely prevented the NMDA-induced hyperglycemia. Adrenergic blockade blunted the early rise in HGP, so that in this group the NMDA-induced increase in HGP was offset by a comparable elevation in GU.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacological aspects of R-(+)-7-OH-DPAT, a putative dopamine D3 receptor ligand.

The R-(+)-isomer of 7-hydroxy-2-(N,N-di-n-propylamino)tetralin (7-OH-DPAT) bound with a more than 200-fold higher affinity to cloned human dopamine D3 receptors (Ki = 0.57 nM) than to dopamine D2 receptors; the corresponding S-(-)-enantiomer had considerably less affinity for both dopamine receptor subtypes, indicating that the known enantiomer selectivity of 7-OH-DPAT for the 'classical' dopamine D2 receptor subtype extends to the recently discovered dopamine D3 receptor subtype. In rats R-(+)-7-OH-DPAT dose dependently (10-1000 nmol/kg) decreased dopamine release and induced yawning, while sniffing behaviour occurred at the highest dose tested (1000 nmol/kg). The possibility that the inhibition of dopamine release and the elicitation of yawning are mediated by dopamine D3 receptors is considered.

2-Amido-8-methoxytetralins: a series of nonindolic melatonin-like agents.

A series of unsubstituted and methoxy-substituted 2-amidotetralins (4a-q) was prepared and evaluated for their ability to compete for 2-[125I]iodomelatonin binding to chicken retinal membranes and for their potency to inhibit the calcium-dependent release of [3H]dopamine from rabbit retina. The lead compound, 2-acetamido-8-methoxytetralin (4j), showed a moderate affinity (Ki = 46 nM) and potency (IC50 = 1.4 nM) at the melatonin receptor. The structural requirements necessary for optimal agonistic activity at the melatonin receptor are as follows. First, the amido group, which should have a small, nonbranched alkyl group, is essential for affinity, and second, the methoxy substituent at the 8-position of the 2-amidotetralin ring is essential for optimal agonistic activity at the melatonin receptor. We concluded that this series of unsubstituted and methoxy-substituted 2-amidotetralins constitutes a class of nonindolic melatonin-like agents that can be used as pharmacological tools to further characterize melatonin receptors and to elucidate the mode of action of melatonin.

Role of IL-1 alpha in central nervous system immunomodulation of glucoregulation.

Hyperglycemia is a hallmark of the stress response, and has been largely attributed to elevated plasma levels of catabolic hormones. Recently, various cytokines have been shown to be endogenously produced within the brain and may represent an important component of the central regulation of this metabolic response. Therefore, the aim of the present study was to determine whether the intracerebroventricular (i.c.v.) injection of one such peptide, interleukin (IL)-1, can produce hormonal and metabolic alterations comparable to those observed under stress conditions. An i.c.v. cannula and vascular catheters were placed in rats prior to the experiment. Whole body glucose flux was assessed in overnight fasted conscious unrestrained rats using [3-3H]glucose. A mild hyperglycemia was elicited 20 min after the i.c.v. injection of IL-1 alpha (human recombinant, 100 ng) that was not detected in control rats. Glucose levels gradually increased and were 26% higher than control values during the last hour of the 3 h experimental period. The hyperglycemia resulted from a 44% increase in the rate of hepatic glucose output (HGO), which preceded a proportional rise in peripheral glucose utilization. No increase in metabolic clearance rate was observed, suggesting that the increased glucose uptake was the result of mass action. The increased glucose flux was associated with a transient hyperinsulinemia (+95%), and sustained elevations in the arterial concentrations of glucagon (56%) and corticosterone (175%). In contrast, glucose flux was not altered by intravenous administration of the same dose of IL-1 alpha, or i.c.v. injection of IL-1 beta, or heat-inactivated IL-1 alpha.(ABSTRACT TRUNCATED AT 250 WORDS)

Enantiomers of monohydroxy-2-aminotetralin derivatives and their activity at dopamine autoreceptors as studied by brain dialysis.

The enantiomers of a series of dopamine (DA) agonists, monohydroxy-2-aminotetralin derivatives, were investigated using brain microdialysis. We used a 5-OH-substituted derivative, N-0437 (2-(N-propyl-N-2-thienylethylamino)-5-hydroxytetralin), and three 7-OH-substituted derivatives, N-0438 (2-(N-propyl-N-2-thienylethylamino)-7-hydroxytetralin), 7-OH-DPAT (7-hydroxy-2-(N,N-di-n-propylamino)tetralin) and PHNO (4-propyl-9-hydroxynaphthoxazine; position 9 of the naphtoxazines corresponds to position 7 of the aminotetralins). We studied the activity of the enantiomers at autoreceptors regulating the release of DA following their local infusion into the striatum of the rat. We were particularly interested in the activity of R(+)-N-0437, S(-)-N-0438, S(-)-7-OH-DPAT and S(-)-PHNO, which are enantiomers that have been classified as less potent or inactive in previous studies. S(-)-N-0437, R(+)-N-0438, R(+)-7-OH-DPAT and R(+)-PHNO decreased DA release by 45-60%. Thus, these enantiomers are potent agonists at autoreceptors regulating the release of DA. The R(+) enantiomer of the 5-OH-substituted derivative N-0437 possessed antagonistic activity at autoreceptors controlling DA release, increasing DA release by 100%. This finding is consistent with reports showing that one enantiomer of other 5-OH DA agonists displays agonistic activity, while the other has antagonistic properties at DA autoreceptors. The less potent enantiomers of the 7-OH-substituted derivatives S(-)-N-0438, S(-)-7-OH-DPAT and S(-)-PHNO, however, all showed weak agonistic activity at DA autoreceptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacological profile of non-hydroxylated and ether derivatives of the potent D2-selective agonist N-0437.

Derivatives of the potent dopamine D2-selective agonist 2-(N-propyl-N-2-thienylethylamino)-5-hydroxytetralin (N-0437) were designed, aimed at producing drugs with less sensitivity towards metabolic inactivation (in particular glucuronidation at the 5-OH position). Since aminotetralins with a 5-methoxy substituent or lacking the 5-hydroxy group have been reported to retain dopaminergic activity, the non-5-hydroxylated N-0437 (N-0918) and two ethers of N-0437 [5-methoxy-N-0437 (N-0724) and 5-cyclopentoxy-N-0437 (N-0953)] have been prepared and tested. Three indices for activity at central dopamine receptors are considered: (1) the displacement of (3H)-SCH-23390 and (3H)-spiperone from calf caudate membranes, (2) the effects on dopamine release and metabolism in the striatum of freely moving rats after systemic and intrastriatal administration as assessed by brain microdialysis, and (3) the ability to elicit contralateral turning in rats with a unilateral 6-OH-dopamine lesion of the nigrostriatal pathway. In order to differentiate between direct dopaminergic activity and metabolic activation, brain and plasma levels of N-0437 after administration of N-0724 and N-0953 were measured. The results show the necessity of the 5-OH group for direct dopaminergic activity: N-0918, N-0724 and N-0953 are all inactive after intrastriatal administration in the microdialysis model and all three drugs show a weak in vitro affinity for both D1 and D2 receptors. Although N-0918 is also inactive after systemic administration in the microdialysis and turning model, N-0724 and N-0953 do exhibit dopaminergic activity after systemic administration in these models.(ABSTRACT TRUNCATED AT 250 WORDS)

Effectiveness of radiotherapy with radical neck dissection in cancers of the head and neck.

A retrospective analysis of 457 radical neck dissections performed over a 30-year period for cancers of the oral cavity, pharynx, and larynx was carried out. Two hundred thirteen patients underwent radiotherapy to the primary cancer site and/or to the neck. Of these, 164 underwent perioperative adjuvant radiotherapy and 24 underwent definitive radiation for cure and were followed up by salvage surgery. Thus, 188 patients received radiotherapy for nonrecurrent disease. Twenty-five additional patients underwent radiation for surgical failure following radical neck dissection. The goal of the study was to determine whether radiotherapy altered the course or end result of the disease. The T and N stage at onset of disease was similar for the radiotherapy and nonradiotherapy groups. Preoperative radiotherapy was effective in down staging the disease at the primary site and, to a lesser extent, in the lymph nodes, but had limited impact on survival. Failure to control the disease in the neck occurred in 60 (32%) of the 188 patients who received radiotherapy for primary disease; recurrence rates were lower in the combined therapy group than in the surgical group of patients with N2 and N3 stages of disease. The 3-year disease-free survival was 45%; this was no better than the 63% survival rate in patients who did not receive radiotherapy, although survival was better in the combined therapy group for patients with N3 stage of disease. The worst results were in those patients who were irradiated for surgical failure (14% survival); the 24 patients who required salvage radical neck dissection following failure of definitive radiotherapy for cure had a 42% survival.

Orally active carbamate prodrugs of the selective dopamine agonist N-0437: in-vivo activities in the 6-OHDA turning model and in-vitro activities.

The in-vivo activities of eight carbamate prodrugs of the D2-agonist N-0437 were determined by examining the effects of the prodrugs, after their oral administration in rats with unilateral 6-OHDA lesions of the striatum. The resulting contralateral turning was used as an index of the activity of the compounds. A comparison of the area under the curve of the time-effect curves of the prodrugs, revealed a significantly improved duration of action compared with N-0437 during the period 11-15 h after administration, for the propylcarbamate and the dimethoxyphenylcarbamate derivatives. The 2,4-dimethylphenylcarbamate showed a significantly enhanced turning behaviour over the whole 15 h time interval in comparison with N-0437. Three of the nine carbamates were virtually unhydrolysed in rat serum at 37 degrees C, while the other test compounds were hydrolysed relatively slowly, with t1/2 values ranging from 1.5-6 h. The test compounds differed greatly in partition coefficients, which were estimated by RP-HPLC (1-12 times more lipophilic than N-0437). The potential cholinesterase inhibiting properties of the carbamate prodrugs were assessed by a simple in-vitro incubation assay, which showed that only two carbamates were very weak cholinesterase inhibitors.

Elective radical neck dissection in epidermoid cancer of the head and neck. A retrospective analysis of 853 cases of mouth, pharynx, and larynx cancer.

A retrospective analysis of 853 patients with cancer of the mouth, pharynx, and larynx operated on over a 30-year period was performed. Four hundred fifty-seven of them had a radical neck dissection (RND) at some point. Five hundred ninety patients had no clinically positive nodes (N-o) necks at the time of primary treatment; 99 of these had elective neck dissection, whereas 95 others had a delayed RND when nodes became clinically involved. Twenty-three percent of all N-o patients had microscopically involved nodes and less than half of these were among those patients selected for elective RND. Furthermore, 58% of those patients who had elective RND did not have positive nodes. Comparative analysis of elective RND, delayed therapeutic RND after clinical appearance of nodes, and composite operations for patients with N1-N3 disease indicates little difference in disease-free survival when the nodes in the elective RND were positive microscopically for tumors (56%, 49% and 47% respectively). It thus seems that elective RND offers no real advantage over a careful watchful waiting approach in most patients.

Transdermal administration of the dopamine agonist N-0437 and seven ester prodrugs: comparison with oral administration in the 6-OHDA turning model.

The potent and selective D2-agonist N-0437 [2-(N-propyl-N-2-thienylethylamino)-5-hydroxytetralin] undergoes considerable first-pass metabolism after oral administration due to glucuronidation of the phenolic group. In an attempt to improve its bioavailability, seven ester prodrugs of N-0437 were synthesized, i.e. the acetyl-, propionyl-, isobutyryl-, pivaloyl-, 2-amino-phenyl-, 2-methoxy-phenyl- and 2,4-dimethylphenyl-analogues. In vivo activities were assessed by measuring contralateral turning after transdermal administration of N-0437 and its prodrugs to rats with unilateral 6-OHDA lesions of the nigrostriatal pathway. From time-effect curves the area under the curve for separate time intervals was taken as a measure of dopaminergic activity during that interval. It was found that slowly hydrolyzing prodrugs, which are known to show an improved duration of action after oral administration, are devoid of activity after transdermal application. The acetyl-, the propionyl- and the isobutyryl analogues, which are prodrugs with a relatively high hydrolysis rate, were found to have interesting and promising profiles following transdermal application.