Dyslexia and musical notation.

The authors examine the difficulties experienced by dyslexic musicians in the formalized study of music, in particular, musical notation. They describe case studies from the literature and from personal interviews they conducted with musicians about their educational histories, musical weaknesses and strengths, and successful compensatory strategies. The authors make instructional suggestions for educators and musicians with dyslexia on how to use multisensory approaches to teach musical notation.

Naloxone suppresses buprenorphine stimulation of plasma prolactin.

The effects of parenterally-administered buprenorphine and simultaneous injection of naloxone was evaluated in six healthy adult males. Each subject was studied on six occasions, an average of 10 days apart, and received either two simultaneous intramuscular injections of saline, buprenorphine 0.3 mg and saline, or buprenorphine 0.3 mg and 0.6 mg, 0.45 mg, 0.3 mg, or 0.15 mg of naloxone. Simultaneous injection of buprenorphine 0.3 mg and saline resulted in an average increase in plasma prolactin above baseline levels of approximately 10 and 25 ng/ml, 30 and 55 minutes after injection. Buprenorphine-induced stimulation of plasma prolactin levels was statistically significantly greater than basal prolactin values (p less than 0.01). When 0.6 mg of naloxone was simultaneously injected with 0.3 mg buprenorphine, peak plasma prolactin levels were significantly lower (p less than 0.05) than prolactin values after administration of 0.3 mg buprenorphine and saline. Simultaneous injection of 0.45 mg naloxone and 0.3 mg buprenorphine also resulted in a significant attenuation (p less than 0.05) of buprenorphine-stimulated prolactin levels. Injection of 0.3 mg or 0.15 mg of naloxone did not inhibit prolactin stimulation produced by buprenorphine 0.3 mg. These findings demonstrate a dose-effect relationship between naloxone concentration and suppression of the increase in plasma prolactin levels produced by administration of buprenorphine 0.3 mg. As prolactin stimulation occurs shortly after opioid agonist administration and is temporally concordant with the rapid induction of pharmacologic reinforcement associated with opiate abuse, naloxone added to buprenorphine parenteral preparations may reduce the abuse potential of buprenorphine.

The pharmacokinetics and metabolism of idazoxan in the rat.

1. [2'-14C]Idazoxan was rapidly and completely absorbed after its oral administration to rats. 2. After administration of either [2'-14C] or [6,7-3H]idazoxan, radioactivity was taken up by a wide range of tissues and became localized, especially in the organs of metabolism and excretion. Quantitative distribution patterns were route-dependent such that oral dosing resulted in lower radioactivity concentrations in all tissues apart from liver. 3. Clearance of idazoxan (94-144 ml/min per kg) was due mostly to metabolism and was independent of dose. Oral bioavailability in male rats at low oral doses of idazoxan (10 mg/kg) was about 1%, but increased with increasing dose to 23% at 100 mg/kg. Oral bioavailability in female rats was considerably higher than in male rats, at all doses studied. Brain idazoxan levels were in equilibrium with those in plasma, but ten-fold higher. 4. Elimination of radioactivity after administration of 14C-idazoxan was via the urine and the faeces (about 75% and 20% of dose respectively) and occurred essentially in the 24 h period immediately after dosing. By 96 h after dosing, elimination was virtually complete, with less than 0.5% dose remaining in the carcasses. 5. Biotransformation was by hydroxylation at positions 6 and 7 to form phenolic metabolites, which were excreted as glucuronide and sulphate metabolites in urine, but unconjugated in faeces. Other minor metabolic routes were 5-hydroxylation or oxidative degradation of the imidazoline ring, but these pathways were of quantitatively minor importance in the rat.

The pharmacokinetics after intravenous and oral administration in man of the alpha 2-adrenoreceptor antagonist idazoxan (RX781094).

A high performance liquid chromatographic method was developed for the quantitative determination of idazoxan in plasma. The assay was used to study the disposition of the drug after intravenous infusion and oral administration to five normal subjects. After i.v. administration the kinetics could be described by a two compartment model with a mean elimination half life of 4.20 h. The mean calculated volume of distribution during the elimination phase was 3.20 l/kg-1 and the mean plasma clearance was 824 ml min-1. After oral administration a lag period before onset of absorption was observed in all five volunteers, the plasma levels declining monoexponentially from the peak concentration with a mean elimination half life of 5.58 h. The absolute availability varied between 26% and 41% with a mean value of 34%. In-vitro measurements produced a blood/plasma ratio of 1.3 for idazoxan.

Long-term corticosteroids and cervical subluxation in non-rheumatoid patients.

Forty-five non-rheumatoid patients with chronic chest disease were examined radiographically for evidence of cervical subluxation. Twenty-six patients had received continuous corticosteroids for periods of between two and 20 years. The remainder (19 patients) had never been treated with steroids and acted as controls. There was no difference in atlanto-axial distance between the steroid-treated and control groups and in no patient did this measurement exceed 3 mm. However, subaxial subluxation was significantly increased in the steroid-treated group, directly related to the duration of steroid therapy (P less than 0.025).

Pharmacokinetics of intravenous and oral tolmesoxide.

A high pressure liquid chromatographic assay was developed for simultaneous measurement of the plasma levels of tolmesoxide and its principal metabolite, RX71112. The assay was used to study the disposition of intravenous and oral tolmesoxide in ten normotensive subjects. Two exponential terms were required to describe the disposition of the drug following intravenous administration, whilst a single exponential term sufficed to account for the decay in the plasma concentration after oral administration. The bioavailability of oral tolmesoxide from capsules averaged 84.5% and was independent of dose. The mean half-life after i.v. dosing was 2.6 h (+/- 0.3 SEM) compared to values of 1.9 h (+/- 0.1 SEM) and 2.7 h (+/- 0.5 SEM) following 200 and 400 mg oral doses respectively. In all subjects RX71112 appeared in plasma shortly after tolmesoxide following both routes of administration. The terminal half-life of the metabolite was significantly longer than tolmesoxide with a mean value of 4.9 h (+/- 0.9 SEM) following the 200 mg oral dose of tolmesoxide. The binding of tolmesoxide and RX71112 at therapeutic plasma concentration was 36.8% (+/- 0.5 SEM) and 58.5% (+/- 0.3 SEM) and this remained unchanged at higher concentrations.

The radioimmunoassay of buprenorphine.

Antisera to buprenorphine were obtained in rabbits immunised with 3-0-carboxymethylbuprenorphine and N-hemisuccinyl-norbuprenorphine conjugated to bovine serum albumin. Using the latter antiserum and tritium labelled buprenorphine a radioimmunoassay have good accuracy and precision was developed for concentrations as low as 50 picograms in 1 ml of plasma. The N-hemisuccinyl antiserum crossreacted with norbuprenorphine, and the 3-0-glucuronide conjugate with the 3-0-carboxymethyl antiserum. Cross-reactivity of both antisera to other pharmacologically related compounds was negligible. The assay was employed to determine plasma buprenorphine concentration following its parenteral administration to dog and man.

Pharmacokinetics of fenclofenac following single and multiple doses.

The plasma concentration of the anti-inflammatory drug fenclofenac was investigated in volunteers following single oral doses of 200, 500 and 600 mg, as well as multiple doses of 600mg b.i.d. over five days, using gas chromatography with electron capture detection. The pharmacokinetic parameters derived were independent of dose, and the terminal half-life, t1/2, varied independently of dose between 20 and 38 hours (27.23 +/- 1.8 at 600mg). The apparent volume of distribution (Vd area) had similar values at doses of 200, 500 and 600mg of 15.2 +/- 2.6, 18.2 +/- 1.5 and 14.7 +/- 1.7 litres respectively. These small volumes of distribution indicate that fenclofenac distributes mainly into extracellular space. A mean peak plasma concentration of 63.5 +/- 4.6microgram/ml developed after 3 to4 hours following a single 600mg dose whilst a mean steady state plasma concentration (600mg b.i.d.) of 86.9 +/- 5.7 microgram/ml was achieved within four days, and this decayed with a mean terminal half-life of 25.9 +/- 4.2 hours.

Plasma concentration and disposition of buprenorphine after intravenous and intramuscular doses to baboons.

Buprenorphine is a newly-developed strong analgesic. A selected ion monitoring method has been developed to measure its plasma levels over the concentration range 20-3000ng ml-1. Six baboons each received intravenous and intramuscular doses of buprenorphine hydrochloride at a level of 5mg/kg in a cross-over study. The mean peak plasma concentrations (+/-standard deviation) were 2290 +/- 357ng ml-1 and 805 +/- 416ng ml-1 respectively and the corresponding times to the peak levels were 4.0 +/- 1.5 minutes and 30.3 +/- 24.6 minutes suggesting the rapid release of the drug from intramuscular sites. Comparison of areas under the plasma concentration versus time curves to 24 hours after dosing showed the mean bioavailability of buprenorphine from the intramuscular doses was 70% of that from the reference intravenous doses.

The stereochemistry of hydrogen elimination from C-7 during biosynthesis of ecdysones in insects and plants.

1. [7alpha-(3)H(1)]- and [7beta-(3)H(1)]-Cholesterol were synthesized by a modified method. 2. The stereochemistry of Delta(7)-bond formation during ecdysone and ecdysterone biosynthesis in the insect, Calliphora erythrocephala and the plants, Taxus baccata and Polypodium vulgare was investigated by using [4-(14)C,7alpha-(3)H(1)]cholesterol and [4-(14)C,7beta-(3)H(1)]cholesterol. 3. In each case, the 7beta hydrogen was stereospecifically eliminated. 4. The possible significance of the results is discussed in relation to double-bond formation in other systems and the stage at which the Delta(7) bond is introduced during ecdysone biosynthesis.