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The chemotherapeutic benefit of synergistic drug combinations and higher drug dosages has generated interest in the application of these regimens to cancer patients. A major obstacle in the application of these strategies to the treatment of cancer is the dose-limiting toxicities of drug combinations. Sodium 2-mercaptoethane-sulfonate (mesna), a chemoprotective drug, may reduce the nephrotoxicity of carboplatin [CBDCA, paraplatin, JM-8, cis-diammine (1,1-cyclobutane dicarboxylato) platinum II] when administered in combination chemotherapy. The purpose of this study was to evaluate, compare and contrast in vitro the interaction of mesna with carboplatin in aqueous solution, human plasma and urine. Carboplatin and mesna were incubated separately and together at clinically relevant concentrations in plasma and urine. The concentration of carboplatin was assayed by HPLC, and the decay of carboplatin alone and in combination with mesna was compared. The incubation of carboplatin with mesna in human plasma up to 8 days did not result in a statistically significant interaction: the half-life of carboplatin in plasma when it was combined with mesna was 1.62 +/- 0.08 (SE) days compared to 1.85+/- 0.04 (SE) days for carboplatin by itself. The incubation of drugs in fresh human urine up to 15 days gave a half-life of 3.43+/- 0.8 (SE) days for carboplatin alone and 2.78 +/- 0.7 (SE) days for carboplatin when it was combined with mesna. Our results show that carboplatin and mesna do not significantly interact in plasma. Although a statistically significant difference between the half-life of carboplatin and the half-life of the carboplatin/mesna combination is detected in urine, it is not likely to be clinically significant, as there is no significant interaction detected in the first 48 h). It is thus unlikely that mesna would substantially affect the pharmacokinetics of carboplatin when both are given together to patients as part of combination chemotherapy regimens.

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N-(phosphonacetyl)-L-aspartate (PALA) modulates the activity of 5-fluorouracil (5-FU) by inhibiting pyrimidine biosynthesis. A cross-over study was conducted to determine whether PALA affects the pharmacokinetic parameters of 5-FU in patients given 5-FU/folinic acid (FA). Six patients (3 males, 3 females) aged 63 4.3 (mean SD) years (body surface area of 1.84 18 m2) with metastatic colorectal carcinoma were given two courses of treatment. The treatment consisted of 250 mg/m2 of PALA on day 1 followed by 20 mg/m2 FA and 400 mg/m2 5-FU (5 min i.v. bolus injection) on days 2-5 in one cycle of treatment (PALA+). In another treatment cycle, these doses of 5-FU and FA were given for all 5 days without PALA (PALA-). The two courses were given four weeks apart. It was determined by random selection whether the course with PALA was given before or after the course without PALA. Blood samples were collected over a period of three hours, starting from the beginning of 5-FU infusion on days 2 and 5 of both courses. Plasma concentrations of 5-FU were determined by an HPLC technique. Pharmacokinetic parameters were calculated using a non-compartmental model. While there were no significant differences between pharmacokinetic parameters in the PALA+ vs PALA- courses, there was a trend towards a decreasing area under the curve (AUC) and increasing clearance (Cl) in PALA+ courses of treatment.

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UNLABELLED: Three-dimensional assessment of pulmonary deposition of inhaled aerosol may be performed using SPECT. The use of aligned anatomical images enables improved accuracy of quantification and anatomical localization of deposition. METHODS: Techniques of analyzing these data and their application to deposition studies of two nebulizer-generated aerosols (mass median diameter 1.5 and 6.5 microM respectively) in 12 normal subjects are described. The deposition data were transformed to a standard hemispherical shape and the mean distribution pattern for each aerosol evaluated. Deposition by airway generation was then calculated using a spatial model of airway morphology. The results were compared to those from planar image analysis. RESULTS: The hemispherical transform yielded considerably more qualitative information on deposition pattern. The central-to-peripheral concentration ratio between conducting and alveolated airways was 5.27 for the coarser aerosol and 2.43 for the fine. The two-dimensional spatial estimates of the ratio were 2.61 and 2.03 respectively. CONCLUSION: Analysis of multimodality imaging data considerably enhanced information on deposition compared to planar imaging. It provides new data on aerosol deposition which will be of value to physicians involved in drug inhalation therapy.

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The pulmonary deposition and pharmacokinetics of fine and coarse radioactive aerosols of nedocromil sodium, of mass median aerodynamic diameters 16 microns and 24 microns respectively, delivered by metered dose inhaler (MDI) have been investigated. The corresponding geometric standard deviations of the particle size distributions were 5.32 and 3.93. Pulmonary deposition was assessed by both planar radionuclide scintigraphy and multi-modality three dimensional imaging using single photon emission computed tomography (SPECT) and x-ray computed tomography (CT). The three dimensional data were analysed by transformation to a hemispherical shape based on the fractional radial distance of each point in the lung from the centre to the corresponding extrapolated point on the periphery. This enabled parameters on the variation of both concentration of deposition and total amount deposited with penetration distance to be calculated. For both planar and SPECT data the central to peripheral concentration ratio (C/P ratio) was calculated. The three dimensional C/P ratio showed a median value (3.21) which was significantly higher than for the planar imaging (2.03) (p < 0.001). The parameter used to express the variation of total amount deposited was the median dose position. This showed that for both aerosols 50% of the dose was deposited at sites with a percentage central to peripheral distance of greater than 68%. There was a trend for total percentage of the fine aerosol in the lungs to be higher than for the coarse and for its deposition to be more peripheral. In addition the mean concentrations in blood were measured to be greater for the fine aerosol. However these differences were relatively small and none were individually statistically significant. The technique of combined SPECT and CT imaging was shown to be valuable in obtaining more accurate information on pulmonary distribution of inhaled aerosol deposition. The merits, limitations and potential applications of the technique are discussed.

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Multimodality medical imaging enables measurement of the three-dimensional spatial distribution of a radiolabeled aerosol within the lung. Using a conceptual spatial morphological model these data may be transformed to provide information on deposition per airway generation. This methodology has been used to study the intrapulmonary deposition patterns of two formulations of a metered dose inhaler and two nebulizers in control subjects. The nebulizer study has also been stimulated using a computer model of deposition. The comparison between derived experimental results and those from computer modeling shows areas of agreement, although there are also areas of discrepancy. The new methodology has considerable potential value in the fields of inhalation therapy and deposition modeling, although more detailed validation is still required.

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Aerosols of nedocromil sodium labelled with 99Tcm were delivered on 20 separate occasions to healthy male volunteers. Planar and single photon emission computerized tomography (SPECT) gamma scintigraphy were immediately performed to assess the pulmonary regional distribution of delivered aerosol. On a separate occasion volunteers were imaged using X-ray computed tomography (CT). Alignment of SPECT and CT images was performed using marked anatomical features and the anterior and lateral skin outlines. CT images provided data for attenuation correction and were used to define the anatomical lung volume. Central to peripheral (CP) ratios of deposited activity were calculated from volumes of interest in coronal and transverse sections of the right lung. These were compared with CP ratios obtained from planar images obtained immediately following aerosol inhalation. Volumetric CP ratio correlated significantly with immediate planar CP ratio (p < 0.001). Analysis of deposition in the whole right lung was performed by separating the SPECT lung data into a series of thin concentric shells centred on the entry of the right main bronchus. Measures were defined for describing the variation of deposition density and cumulative total deposition with distance from the lung centre. These showed significant correlation with planar CP ratio (p < 0.001). SPECT analysis using CT is consistent with planar measures of aerosol deposition but offers a more complete quantification of aerosol penetration and absolute deposited activity within the whole lung. It is a valuable new tool for aerosol analysis.

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A syndrome consisting of an absent or faint second heart sound, prominent cardiac impulse and non-regurgitant or forward collapse of the pulse is described. There was, moreover, no second sound or flow murmur audible in either the aortic or the pulmonary area even though the impulse and collapsing pulse suggested a hyperdynamic circulation; the upstroke was sharp but without the full waterhammer knock. It is argued that the dominant cause of the collapsing pulse will usually be vasodilation, that absence or faintness of the second sound is due to a narrow angle of divergence between the ventricular and arterial pressure decay curves, and that in marked contrast to aortic regurgitation the quality of the impulse derives from rapid systole of lightly loaded ventricles. Although they described its separate elements, pre-homeostatic era clinicians may have overlooked the syndrome in the belief that the heart regulated a largely passive circulation, regarding only primary intracardiac events and the first heart sound as important. Sir William Stokes nevertheless foresaw that alterations in the second sound might be due to changes in vascular tone as well as in elasticity. Wider recognition, deeper understanding and appropriate correction of this syndrome may prove both useful and enlightening.

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1 Labetalol, a new hypotensive drug combining alpha- and beta-adrenoreceptor antagonist properties, has been compared with propranolol in the treatment of severe hypertension (blood pressure 190/115-249/139 mmHg) in a double-blind trial lasting 14 weeks. Additional diuretic therapy was given to both groups of patients. 2 Both drugs caused an effective reduction in blood pressure, bbut labetalol caused a greater fall in pressure in the standing position and after exercise. Two groups of nine patients have each completed the trial so far. Group average pressures for the last 3 weeks of treatment were: for labetalol 137/87 supine, 121/84 standing, and 117/78 mmHg after exercise; and for propranolol, 138/87 supine, 132/93 standing, and 133/94 mmHg after exercise. 3 Group average heart rates were lower in all three positions for those patients treated with propranolol compared with labetalol. 4 The average final dose ratio for labetalol: propranolol was 1.44:1 (w/w). 5 Labetalol initially induced a number of side-effects, predominantly related to alpha-adrenoreceptor blockade, which disappeared by the end of the trial. 6 Labetalol, in conjunction with diuretic therapy, was at least as effective as propranolol in lowering blood pressure in patients with severe hypertension.

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