Pharmacokinetics and haemodynamic effects of ISDN following different dosage forms and routes of administration

The pharmacokinetics and haemodynamic effects of isosorbide dinitrate (ISDN) have been investigated following administration of single doses as a sublingual (SL) spray (2.5 mg), sublingual tablet (5 mg) and peroral tablet (10 mg) in a randomised, placebo-controlled double-blind cross-over trial in 16 healthy volunteers.After the sublingual spray C_max was higher (39.0 ng·ml^-1) and t_max was shorter (3.9 min) than after the sublingual (22.8 ng·ml^-1 and 13.8 min) and peroral (16.9 ng·ml^-1 and 25.6 min) tablets. The AUC of ISDN did not differ following any of the three formulations (1031; 879; 997 ng·ml^-1·min, for the spray, SL tablet and PO-tablet, respectively). Mononitrate metabolites of ISDN (IS-2-MN and IS-5-MN) and total nitrates in plasma increased in proportion to the administered dose. This indicates that the fraction of the dose absorbed was the same for all the formulations but that the extent of first-pass metabolism increased in the order sublingual spray < sublingual tablet < peroral tablet. Thus, compared to the spray, the relative bioavailability of ISDN was 48% and 28% from the sublingual and peroral tablets, respectively.The haemodynamic effects were quantified using the a/b ratio of the finger pulse wave and the systolic blood pressure and heart rate under orthostatic conditions. For the a/b ratio of the finger pulse, the maximal effect was higher (e_max=130%) and the time to e_max (t_emax) shorter (16.6 min) after the spray than the sublingual tablet (84.4% and 25.5 min) or peroral tablet (90.2 and 31.3 min). The onset of effect was within 3, 5 and 7.5 min after the spray, sublingual and peroral tablets, respectively. A larger change in the orthostatically-induced decrease in systolic blood pressure and increase in heart rate was obtained following peroral than sublingual administration despite the similar plasma concentrations of ISDN. This probably reflects the larger amount of pharmacodynamically active mononitrate metabolites formed after oral dosing. The integrated effect following administration of 2.5 mg ISDN as spray was similar to that of a sublingual tablet of 5 mg.     

Low doses of the 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH DPAT) increase ethanol intake

Previous work has reported that the 5-hydroxytryptamine (5-HT)_1A agonist, 8-hydroxy 2-(di-n-propylamino)tetralin (8-OH DPAT), reduces ethanol intake by rats. However, as 8-OH DPAT reduces 5-HT neurotransmission, these findings are inconsistent with the proposed inhibitory role of central 5-HT neurons on ethanol intake. We examined the effect of 8-OH DPAT on ethanol, water and food intake in rats maintained on a limited access schedule using a lower dose range (6–250 µg/kg) and by assessing concomitant changes in behaviour. Low doses of 8-OH DPAT enhanced ethanol intake even when food and water were offered as alternatives. Suppression in ethanol intake was observed at higher doses where elements of the 5-HT syndrome were apparent. Similar observations were made in both fluid and non-fluid deprived water drinking rats, suggesting the latter effect is non-selective. Therefore 8-OH DPAT may both increase or decrease ethanol consumption in the rat depending on the dose used.     

Phase I/II trial of dipyridamole, 5-fluorouracil,leukovorin, and mitoxantrone in metastatic breast cancer

Summary Based upon the hypothesis that dipyridamole would potentiate the cytotoxicity of mitoxantrone and the combination of 5-fluorouracil (5-FU) and leukovorin, we performed a phase I/II trial of the combination of dipyridamole, 5-FU, leukovorin, and mitoxantrone in patients with metastatic breast cancer. The dose of dipyridamole was fixed at 175 mg/m² by mouth every 6 h (700 mg/m²/day), based upon a previous phase I trial of oral dipyridamole with 5-FU and leukovorin. Dipyridamole therapy began 24 h prior to the first dose of chemotherapy and continued until 24 h after the last dose of chemotherapy for each course of treatment. At the initial dose level, leukovorin 200 mg/m² was given intravenously immediately prior to 5-FU 375 mg/ m² intravenously on days 1–5. Mitoxantrone 6 mg/m² was given as a single dose on day 3. Unacceptable toxicity was observed at this dose level, leading to successive dose decrements rather than dose increments. The maximum tolerated dose was leukovorin 200 mg/m² days 1–2, 5-FU 375 mg/m² days 1–2, mitoxantrone 6 mg/m² on day 2, and dipyridamole 175 mg/m² every 6 h on days 0–3. Two responses were produced in 15 patients. This regimen is not recommended for further investigation in the treatment of breast cancer.     

An investigation into the effects of structured music workshops with adults with mental handicap

This study investigated the effects of structured group workshops for a population with special needs. Twenty subjects, each with a mild or moderate mental handicap, attended a series of 10 weekly 1-hour music workshops on the structured group playing of a Javanese Gamelan. Twenty subjects formed a non-intervention control group. The experimental hypothesis was that participation in the experimental group would produce significant improvements in musical ability as measured by the Rossi test of musical ability, devised and validated for use in this study. Significant gains in communication skills as measured by the Communication Assessment Profile for Adults with a Mental Handicap (CASP) and self-esteem levels measured by the Khalid semantic differential technique were also postulated. It was also suggested that these gains would be significantly correlated. Results show significant gains in musical ability (instrumental rhythm production: t = 5.67, d.f. = 29, p < 0.01 and simple rhythm production: t = 8.42, d.f. = 29, p < 0.01) and communication skills (t = 4.69, d.f. = 29, p < 0.01). Moreover these results are significantly correlated (r = 0.59, p < 0.05, r = 0.75, p < 0.05, r = 0.56, p < 0.05). A ceiling effect was obtained in the measurement of self-esteem. It is suggested that these gains derive from certain aspects of the musical communicative environment at the workshops. Suggestions for future research involve examining the possible influences on these developments.     

Effect of pindolol on endocrine and temperature responses to buspirone in healthy volunteers

Ten healthy subjects received buspirone (30 mg orally) with and without pre-treatment with the 5-HT1A receptor antagonist, pindolol (80 mg over 3 days). Following pindolol treatment the growth hormone and hypothermic responses to buspirone were significantly decreased. There was also a delay in the onset of the prolactin response to buspirone but the total amount of prolactin secretion, calculated as area under the curve, was not significantly reduced. The data suggest that the growth hormone and hypothermic responses to buspirone in humans are mediated by 5-HT1A receptors, but an explanation founded on pharmacokinetic factors cannot presently be excluded. Both this latter possibility and the lack of selectivity of pindolol for 5-HT receptors indicate the need for the further neuroendocrine studies of the mode of action of buspirone, preferably with more selective 5-HT1A receptor antagonists.     

Analysis of the epsilon-sarcoglycan gene in familial and sporadic myoclonus-dystonia: evidence for genetic heterogeneity.

The epsilon-sarcoglycan gene (SGCE) on human chromosome 7q21 has been reported to be a major locus for inherited myoclonus-dystonia. Linkage to the SGCE locus has been detected in the majority of families tested, and mutations in the coding region have been found recently in families with autosomal dominant myoclonus-dystonia. To evaluate the relevance of SGCE in myoclonus-dystonia, we sequenced the entire coding region of the epsilon-sarcoglycan gene in 16 patients with either sporadic or familial myoclonus-dystonia. No mutations were found. This study suggests that epsilon-sarcoglycan does not play an important role in sporadic myoclonus-dystonia and supports genetic heterogeneity in familial cases.     

Opitz (BBB/G) syndrome: Oral manifestations

We studied a new case of the G (Opitz BBB/G) syndrome in a 12-year-old boy. Several relatives had partial manifestations of the disorder. A comprehensive dental evaluation of the propositus was conducted; included is, to our knowledge, the first published cephalometric analysis of a G syndrome patient. We reviewed 139 cases of the G syndrome; 48 of them had at least one oral abnormality. These included clefting, micrognathia, ankyloglossia, and high-arched palate. Male G syndrome patients are more likely to have oral anomalies than affected females. © 1992 Wiley-Liss, Inc.     

5-Methoxytryptophol and melatonin in children: Differences due to age and sex

Abstract: It seems clear that the pineal hormone, melatonin (N-acetyl-5-methoxytryptamine), is involved in the reproductive behavior of several animal species including humans. Moreover, several data also support a role for 5-methoxytryptophol (ML), another pineal hormone, in the control of sexual processes. To test the role of ML in human reproductive axis, 128 healthy children, 68 boys and 60 girls, were studied. Each of these groups was divided in three age subgroups of 6, 11, and 14 years. A single blood sample (0900 hours) was obtained from each subject to determine melatonin, ML, FSH, LH, estradiol (girls), and testoterone (boys) by RIA. Statistical analysis of the data included ANOVA-II (factor I: age, factor II: sex) and an analysis of covariance with age as covariate. A similar plasma melatonin concentration, with a significant decrease between 6 and 11 years, was found in boys and girls. Melatonin concentrations correlate well with initiation of the pubertal development in these children, although no sex differences were found. Concentrations of ML are approximately 50% of those of melatonin. In contrast to melatonin, ML levels show significant age and sex differences. Plasma ML concentration significantly increased in boys ( P < 0.001) and decreased in girls (P < 0.001) after 8 years of age. These results support the hypothesis that, besides melatonin, other pineal compounds such as ML may be involved in the maturation process in humans. The pineal indole ML may also be used as a marker of the different chronobiology in the pubertal development in boys and girls.     

Evaluation by dental students of a communication skills course using professional role-players in a UK school of dentistry

This paper reports student (n = 180) feedback on the role-play teaching methodology used in behavioural sciences teaching at The School of Dentistry in Birmingham (UK). The feedback received on this well-established (since 1995) educational programme was collected via questionnaire (100% response rate), requiring Likert scale and free text responses. Generally students reported that they had enjoyed and valued the session. Over two-thirds (69.7%) of students rated the role-players as 'very real' and over three-quarters (78.9%) rated their feedback as 'very fair'. The data collected from this study will inform future curriculum development. Student feedback was very positive and demonstrated that the cohort (86% of all students studying in years 1, 2 and 3) found the use of professional role-players involved in behavioural sciences teaching to be both acceptable and valuable.