The protective effects of oxyphenonium bromide, terbutaline and theophylline were compared in 8 asthmatic patients by determination of the degree of non-specific airway reactivity after 1 week of oral treatment according to a fixed dose scheme in a double-blind random order: oxyphenonium bromide 3×10 mg; terbutaline 3×5 mg; theophylline 2×300 mg and placebo. Controlled, standardized inhalation provocation tests were carried out with histamine, acetylcholine and propranolol. The study was monitored by measuring blood concentrations of the 3 drugs, and their effect on the plasma cAMP concentration was also determined. Significant protection by oxyphenonium bromide against the bronchial obstructive effects of acetylcholine and propranolol was observed, but not against the effect of inhaled histamine. The other two drugs provided no significant protection against the inhaled agents. The absence of any protective effect of terbutaline and theophylline might have resulted from too low a blood concentration. The observed differences in protection could not be explained by changes in pulmonary function. The study suggests dissociation between the bronchodilating effect of a drug and its protective effect against inhaled substances.

Three healthy volunteers received single doses of reproterol (D 1959) by means of intravenous infusion, oral and aerosol application, respectively. Administrations were separated by at least 1 week. Plasma levels were measured by means of high performance liquid chromatography. After infusion, plasma levels showed a steep decline, indicative for a rapid distribution. Even though relatively large amounts of drug were given (up to 540 micrograms), this phenomenon caused reproterol levels to drop to values near or below the limit of reliable quantitation (1 ng ml-1) within 60 to 90 min. After oral administration of one or two tablets (containing 20 mg reproterol HCl per tablet), a very short lag time could be observed, indicating fast absorption. After one tablet, plasma level maxima (of plateau-type) were 5-6 ng ml-1 and 2-3 ng ml-1 in two subjects, respectively. After two tablets, plateau level maxima around 18 ng ml-1 and 9 ng ml-1 were found, respectively. After inhalation of a metered aerosol (two puffs of 500 micrograms each) the drug appeared in plasma within minutes, albeit at very low levels, and usually remained detectable at the sub-nanogram level during the time of the experiment (2 h). Due to the very low levels and to some oscillations in the plasma concentration-time curves, a detailed pharmacokinetic assessment could not be carried out. Effects on heart rate and blood pressure were negligible. Only during the infusion of high doses (540 micrograms) was there an increase in heart rate of about 50 to 120 beats min-1. Other side-effects were also negligible.

The disposition of the quaternary ammonium compound thiazinamium methyl sulfate is described after intramuscular injection in humans. The plasma concentration-time curves could be resolved into two exponential components, suggesting an open two-compartment model with absorption phase. Absorption was found to be extremely fast. Peak concentrations were always reached within 20 min, but in the majority of cases they were found to be between 6 and 10 min. Occasionally, the first sample (t = 3 min) proved to contain the highest concentration. Apparently the high solubility of the drug in the interstitial fluid is of prime importance for rapid absorption. Injection technique and the injection site seemed to be important for the final profile of the plasma concentration-time curve. Distribution was found to be very fast as well, with a half-life of approximately 20 min, and the apparent volume of distribution for the central compartment was about 40-60 l. Muscle activity and hence increased capillary blood flow during the distribution phase may result in a second peak in the plasma concentration-time curve. The distribution phase is followed by an elimination phase with a much longer half-life (mean value 375 min) and a volume of distribution of approximately 200-400 l. The total body clearance for thiazinamium methyl sulfate was found to be high (mean value about 800 ml/min), suggesting an active excretion process.

A method is described to determine nanogram quantities of reproterol in plasma. It consists of deproteinization of the plasma samples, on-line trace enrichment, and liquid chromatographic separation of the compounds brought on the analytical column, coupled with amperometric detection. Reliable quantitation can be done down to levels of 1 ng/ml.

1 The in vitro characteristics (dissolution rate) of a sustained release theophylline preparation (Theo-Dur were first measured in acid medium (pH = 1) for 2 h and after that in a phosphate buffer (pH = 6.8) for 6 h. 2 The tablets released more than 95% of the active ingredient within 5 h at a rate of approximately 11% of the dose per hour at pH = 1 and about 18% at pH = 6.8. 3 Dose dependency of the pharmacokinetics of theophylline was tested in seven healthy volunteers by giving them either 300 mg Theo-Dur or 900 mg Theo-Dur in two doses a day for 5 days in a cross over design. After the last tablet on day 6 the fall-off curve was followed in order to calculate the pharmacokinetic parameters. 4 Theophylline (300 mg) resulted on day 6 in a mean serum concentration of 4.4 +/- 0.8 microgram ml-1. The dose of 900 mg resulted in a proportional increase in the serum concentration. The result was 13.3 +/- 2.2 micrograms ml-1. 5 The T1/2 (300 mg) was 9.3 +/- 1.4 h and the T1/2 (900 mg) was 8.5 +/- 2.0 h. These values do not significantly differ (0.10 less than P less than 0.20). 6 It was concluded that theophylline exhibits the rules of linear pharmacokinetics when serum concentrations are in the therapeutic range.

The correlation between serum and saliva levels of theophylline was investigated in seven healthy volunteers after multiple dose administration of a low dose (300 mg/day) and a high dose (900 mg/day) of a sustained release theophylline preparation (Theo-Dur®). Tablets were taken for five days, at 8 a.m. and 8 p.m. and a last dose was taken on Day 6 at 8 a. m. Fourteen serum and saliva samples were collected simultaneously during the dosing period and for up to 32 h after the last dose. On the 300 mg/day regimen the level in saliva was 55.3% of the serum level, with an overall variability of 6.7% and an intrasubject variability of 10.5%. After 900 mg/day, the saliva concentration was 55.5% of the serum concentration, with an overall variability of 7.6% and an intrasubject variability of 12.7%. A good correlation was found between both determinations (r=0.99), which suggests that saliva levels could be used to monitor theophylline after administration of a sustained release tablet.

Variation in the systemic disposition of theophylline after ingestion of a new microcrystalline product (Theolair®) has been investigated in 7 hospitalized patients with generalized obstructive lung disease. Disposition (absolute bioavailability) was determined by comparing in the same patients the areas under the serum concentration-time curves after a single oral dose of microcrystalline theophylline and after an intravenous infusion of aminophylline. Oral absorption appeared to be fast. The half-life of absorption was 19±9 min (mean±SD). Maximal serum concentrations reached after 100±30 min were found to be in a rather narrow range: 9.8±2.5 mg · 1−1. The absolute bioavailability of the microcrystalline preparation was high and it showed only small variation: 102.7±10.2% of the dose. Relevant pharmacokinetic parameters (half-life of elimination, volume of distribution and total body clearance) were determined after both routes of administration. Individual dosage regimens required to obtain a therapeutic serum concentration were calculated for each individual patient on the basis of the observed pharmacokinetic parameters.

SummaryA study was carried out to investigate the variation in the systemic availability of theophylline after ingestion of a new microcrystalline tablet (‘Theolair”). Serum concentrations obtained after oral administration of the drug were compared with those after intravenous infusion of aminophylline in the same patient. The absolute bioavailability was calculated and oral absorption appeared to be very fast, resulting in maximum serum concentrations after 100±30 min (mean ± S.D.J. Inter-patient variation of maximum serum concentrations was low: 9.8±2.5 μg/ml (mean ± S.D.). The fast absorption resulted in a complete absolute bioavailability with a very low variation: 102.7±10.2 (mean ± S.D.).

In this study we have investigated to what extent the concept of ‘ion pair’ absorption is valid after administering the quaternary ammonium ion thiazinamium rectally to humans. Salicylate has been selected as counter ion. The bioavailability was estimated by determining the amount of unchanged drug excreted in urine over a period of 24 hours. The ion pair was administered either alone or in the presence of an excess of counter ions.

A simple and rapid method for the identification of ergot-peptide alkaloids is described. At temperatures around 300° instantaneous degrations of the free alkaloids occurs in the injection port of the gas chromatograph, each alkaloid yielding a specific set of peptide degradation products, which are subsequently separated on a SE-30 column. Since the lysergic acid moiety cannot be seen in the gas chromatogram, the separation of alkaloids which differ in that part of the molecule is not possible and should be done by thin-layer chromatography or high-performance liquid chromatography. However, combination of these two techniques with the present method provides an excellent identification of all of the possible ergot-peptide alkaloids, including stereoisomers.

A general approach to the ion-pair adsoption chromatography of basic drugs on silica gel thin layers is described. Under acidic or neutral conditions, basic drugs will migrate as uncharged ion pairs if a suitable inoraganic counter ion such as Br− or Cl− is present in sufficient amounts. The latter can be achieved by dissolving halide salts in the developing solvent, or by impregnating the sorbent with halide salts prior to the development. The ion-pair chromatographic systems tested are compared with systems in which the drugs migrate in their basic form and the results suggest that the use of ion-pair system has great potential as a great general screening technique for basic-drugs when carried out in combination with a general basic development system. system.

A method is presented for the determination of picomole quantities of carboxylic acids by gas chromatography in combination with electron capture detection. The acids are extracted from aqueous media into dichloromethane by ion-pair extraction with tetrapentylammonium ions, and derivatized as their pentafluorobenzyl esters. These derivatives have good chomatographic properties with minimum detectable amounts of ca. 0.15 pg 250 pg or greater quantities of the acids can be used. Recoveries are ca. 90% with a precision of ca. 6% at the 10-ng level.

A sensitive and selective method for the determination of the quaternary ammonium compound oxyphenonium bromide (Antrenyl), a drug with strong anticholinergic properties, in human plasma and urine is described. The method is based on ion-pair extraction of the cation with perchlorate, a re-extraction according to ion-pair principles with tetrapentylammonium as the counter ion, hydrolysis to cyclohexylphenylglycolic acid, derivatization of this acid to its pentafluorobenzyl ester and determination of the ester by gas chromatography and electron-capture detection. Quantitation is possible down to 2 ng/ml of oxyphenonium bromide using 1 ml of plasma and down to 200 ng/ml using 0.1 ml of urine. The method described can also be applied to other anticholinergic drugs with an ester function.

A 29-year-old male drug addict was found dead at the bottom of a staircase. Analysis of the acid-hydrolized blood showed the presence of pentazocine and two characteristic compounds that contained L-phenylalanine and D-proline, linked together by peptide bounds. It was shown that the latter two components could emanate from the peptide part of ergotamine under the conditions used. It seemed likely that, at the time of analysis, pentazocine and ergotamine were present at concentrations far above therapeutic values. A third component in the blood could not be identified.