Gallium maltolate, tris(3-hydroxy-2-methyl-4H-pyran-4-onato)gallium (GaM), is an orally active gallium compound for therapeutic use. It is moderately soluble in water (10.7 ± 0.9 mg/mL at 25∘C) with an octanol partition coefficient of 0.41±0.08. The molecule is electrically neutral in aqueous solution at neutral pH; a dilute aqueous solution (2.5 ×10−-5 M) showed little dissociation at pH 5.5-8.0. Single crystal X-ray diffraction analysis found the GaM molecule to consist of three maltolate ligands bidentately bound to a central gallium atom in a propeller-like arrangement, with one of the ligands disordered in two possible orientations. The compound is orthorhombic, space group Pbca, unit cell a = 16.675(3), b = 12.034(2), c = 18.435(2) Å at 158K. GaM was administered to healthy human volunteers at single doses of 100, 200, 300, and 500 mg (three subjects per dose). GaM was very well tolerated. Oral absorption of Ga into plasma was fairly rapid (absorption half life = 0.8-2.0h), with a central compartment excretion half life of 17-21h. Absorption appeared dose proportional over the dosage range studied. Estimated oral gallium bioavailability was approximately 25-57%, based on comparison with published data on intravenous gallium nitrate. Urinary Ga excretion following oral GaM administration was approximately 2% of the administered dose over 72h, in contrast to 49-94% urinary Ga excretion over 24h following i.v. gallium nitrate administration. We suggest that oral administration of GaM results in nearly all plasma gallium being bound to transferrin, whereas i.v. administration of gallium nitrate results in formation of considerable plasma gallate [Ga(OH)4−], which is rapidly excreted in the urine. These data support the continued investigation of GaM as an orally active therapeutic gallium compound.

Background: There are many advantages to administering drugs by routes that bypass the gastrointestinal tract. One such route is the transdermal in which the drug agent is applied to the skin in a patch or device of some type so that sufficient quantity penetrates the skin to exert a systemic effect. There are several theoretical advantages to this approach not the least of which is that the drug avoids being metabolized by the liver after absorption and that gastrointestinal irritation is avoided. Aims: To discuss the various ways in which drugs can be persuaded to cross the skin barrier and also to discuss the

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BackgroundIbuprofen and paracetamol differ in their mode of action and related therapeutic effects, suggesting that combined administration may offer improved analgesia. Reported here are the results of two studies on the pharmacokinetic properties of a novel ibuprofen (200 mg) and paracetamol (500 mg) fixed-dose combination tablet.MethodsBoth studies were open-label, randomised studies in healthy volunteers: Study 1 was a four-way crossover, single-dose study; Study 2 was a two-way cross-over, repeat-dose study.ResultsPharmacokinetic parameters for ibuprofen and paracetamol were similar for the combination and monotherapy tablets (values falling within the 80% to 125% acceptable bioequivalence range) except for the rate of absorption of paracetamol from the combination (tmax), which was significantly faster compared with monotherapy (median difference 10 minutes; p < 0.05). Mean plasma concentrations of both drugs were higher, earlier, following administration of the combination tablet compared with monotherapy. Mean plasma levels at 10 and 20 minutes were 6.64 μg.mL-1 and 16.81 μg.mL-1, respectively, for ibuprofen from the combination, compared with 0.58 μg.mL-1 and 9.00 μg.mL-1, respectively, for monotherapy. For paracetamol, mean plasma levels at 10 and 20 minutes were 5.43 μg.mL-1 and 14.54 μg.mL-1, respectively, for the combination compared with 0.33 μg.mL-1 and 9.19 μg.mL-1, respectively, for monotherapy. The rate of absorption of both ibuprofen and paracetamol was significantly delayed when the combination tablet was administered in the fed versus fasted state; median delay was 25 minutes for ibuprofen (p > 0.05) and 55 minutes for paracetamol (p < 0.001). The pharmacokinetic parameters were comparable irrespective of whether the combination tablet was given twice or three times daily; systemic exposure was, however, approximately 1.4 times greater for both drugs when given three times daily.ConclusionsAdministration of ibuprofen and paracetamol in a fixed-dose combination tablet does not significantly alter the pharmacokinetic profiles of either drug, except for enhancing the rate of paracetamol absorption, offering potential therapeutic benefits in relation to the onset of analgesia. Concentrations of both drugs reached previously reported therapeutic levels when the combination tablet was administrated in the fed or fasted state. Three times daily dosing may offer enhanced therapeutic effect for longer than twice daily dosing.

Mass spectrometers produce distorted measurements of gas concentrations because of the time delays and rise times inherent in their responses. Three techniques for numerically correcting such distortion were applied to the acetylene step responses of a Perkin-Elmer MGA1100 mass spectrometer and to simulated data. The techniques investigated were 1) a simple time-delay correction, 2) an exponential model method that assumes a biexponential form for the peak of the impulse response, and 3) a Fourier transform method of deconvolution known as Wiener filtering. The time-delay correction produced an order of magnitude reduction in measurement error. The exponential model method improved on the time-delay correction, and the Wiener filter gave the most accurate corrections in all cases examined.