Adverse effects of a single dose of (+)-sotalol in patients with mild stable asthma

Aims To investigate the effect of (+)-sotalol, which is not thought to possess clinically significant β-adrenoceptor blocking activity, on airway responsiveness in subjects with mild asthma.
Methods A placebo controlled, double-blind, single dose, cross over study, evaluating the effects of oral (+)-sotalol 300  mg and oral (±)-sotalol 240  mg, on airway responsiveness, FEV₁, and heart rate in 18 asthmatic volunteers with quantifiable levels of airway responsiveness.
Results Compared with placebo, (+)-sotalol induced a significant increase in airway responsiveness, and a significant decrease in FEV₁, but there was no significant change in heart rate. Following (±)-sotalol there was no significant effect on airway responsiveness, but there were significant decreases in FEV₁ and heart rate. In one subject both (+)-sotalol and (±)-sotalol provoked a 49% decrement in FEV₁, and in another there were decrements of 20% and 18%, respectively.
Conclusions Despite theoretical considerations, it cannot be assumed that (+)-sotalol is safe in patients with asthma.     

Erythropoietin production in healthy volunteers subjected to controlled haemorrhage: evidence against a major role for adenosine

1 This study was carried out to assess the role of adenosine in the regulation of human erythropoietin (EPO) production. To this end we investigated in healthy volunteers whether the nonspecific adenosine antagonist theophylline increases and the adenosine uptake inhibitor dipyridamole decreases EPO production in response to an haemorrhage of 750  ml.
2 Healthy male nonsmokers received i.v. in a parallel, randomized, single-blind trial theophylline (loading dose 5  mg  kg⁻¹ over 20  min, followed by 0.5  mg  kg⁻¹ min⁻¹), dipyridamole (0.21  mg  kg⁻¹ h⁻¹) or placebo (0.9% NaCl) for 6  h following the phlebotomy. EPO concentrations were followed up to 72  h after phlebotomy.
3 Following blood loss EPO concentrations increased during all treatments. The AUC_EPO (0,72  h) were not statistically significantly different (theophylline: 398±30, dipyridamole: 301±15, placebo: 332±57 [mu  ml⁻¹ h]). Creatinine clearance and urinary cAMP excretion were unaltered by any treatment. Urinary excretion of adenosine was significantly increased during infusion of dipyridamole. Plasma renin activitiy was significantly increased during theophylline infusion.
4 In our model of controlled, physiological stimulation of EPO production by haemorrhage, adenosine appears unlikely to play a major role as a mediator of renal EPO production.     

Effect of intravenous magnesium sulphate on airway calibre and airway reactivity to histamine in asthmatic subjects

In a randomized, double-blind, placebo controlled cross-over study we have investigated the effect of intravenous magnesium on airway calibre and airway reactivity to histamine in 20 subjects with mild to moderate asthma. After baseline measurements of forced expiratory volume in one second (FEV₁), subjects received 100 ml normal saline with or without 2 g of magnesium sulphate by infusion over 20 min. Measurements of FEV₁ were repeated at 5 min intervals throughout the infusion, and the provocative dose of histamine required to drop the FEV₁ by 20% from baseline ( PD ₂₀FEV₁) was determined at 20 min. The area under the curve (AUC) in litre minutes for change from baseline in FEV₁ between 0 and 20 min was significantly higher on the magnesium study day (mean difference in AUC (95% CI) 1.71 (0.02-3.4), P = 0.049). The increase in FEV₁ from baseline with magnesium relative to saline was maximal at 20 min (mean difference (95% CI) 0.13 (0.02-0.23) 1, P = 0.01). Log P D ₂₀FEV₁ to histamine was not significantly different after magnesium and saline (mean difference in log P D ₂₀FEV₁ (95% CI) 0.04 (-0.19 to 0.27), P = 0.7). We conclude that intravenous magnesium is a weak bronchodilator but does not alter airway reactivity at this dose in stable asthmatic subjects.     

Benazepril, an angiotensin converting enzyme inhibitor: drug interaction with salbutamol and bronchial response to histamine in normal subjects

Aims To investigate the effect of the angiotensin converting enzyme inhibitor, benazepril, on pulmonary function.
Methods We investigated the influence of benazepril, on lung function and the interaction with inhaled salbutamol (0.1 to 6.6  mg) and histamine (0.03 to 30.69  g  l⁻¹ ) in normal subjects. Benazepril 20  mg, salbutamol 8  mg, propranolol 160  mg, and placebo were given orally once daily over 10 days.
Results On day 8, there was no difference in the area under the salbutamol dose-response curves between benazepril, placebo and oral salbutamol ( P >0.05), propranolol shifted the curves to the right ( P <0.05). On day 10, histamine challenge resulted in following P D ₃₅sGaw values (geometric mean and 95% CI): with placebo 1.02 (0.95–1.09)  g  l⁻¹ , benazepril 1.04 (0.99–1.08), salbutamol 1.19 (1.13–1.25), propranolol 0.57 (0.50–0.65).
Conclusions Benazepril had no influence on baseline lung function, caused no interaction with inhaled salbutamol and the bronchial response to histamine was similar to placebo. However, our findings in normal subjects cannot be extrapolated automatically to asthmatics.     

Cyclosporin pharmacokinetics following administration of capsules and Neoral in paediatric patients with lupus nephritis

Aims Neoral is a new microemulsion form of cyclosporin. Pharmacokinetic reports in children are scarce. Therefore, we performed a pharmacokinetic study between Cyclosporin A (CsA) capsules and Neoral in paediatric patients with lupus nephritis.
Methods A single 5  mg  kg⁻¹ dose orally of either CsA capsules or Neoral was given to 10 paediatric patients (serum creatinine<1.5  mg dl⁻¹ ). CsA whole blood levels were measured for 24  h post-dose by h.p.l.c.
Results Neoral had a higher C _max and AUC( C _max: 943±176  ng  ml⁻¹; AUC: 4612±785  ng  ml⁻¹  h) than those of the CsA capsules ( C _max: 697±187  ng  ml⁻¹; AUC: 3483±873  ng  ml⁻¹  h; P <0.05). There was no difference in t _max and t _1/2,z between the two groups.
Conclusions CsA Neoral had improved absorption and bioavailability, which is similar to what is reported in adults. However, interpatient variability still existed. Careful drug monitoring and dose adjustment should be performed during treatment to avoid nephrotoxicity, especially in lupus nephritis.     

The effects of ziprasidone on steady‐state lithium levels and renal clearance of lithium

Aims   To assess the potential of ziprasidone to alter the renal clearance and steady‐state serum levels of lithium.
Methods  Healthy subjects who had stable serum lithium levels during the first 7 days of treatment with lithium 900 mg day^{− 1}, given as two divided daily doses, were randomized to receive concomitant treatment with either ziprasidone, 40 mg day^{− 1}, given as two divided daily doses, on days 9–11 followed by 80 mg day^{− 1}, given as two divided daily doses on days 12–15 ( n  = 12), or placebo twice daily ( n  = 13). Ziprasidone or placebo was administered 2 h before each dose of lithium.
Results   Ziprasidone administration was associated with a 0.07 mmol l^{− 1} (13%) mean increase in steady‐state serum lithium levels compared with a mean increase of 0.06 mmol l^{− 1} (10%) with placebo. Mean renal clearance of lithium decreased by 0.09 l h^{− 1} (5%) in the ziprasidone group and by 0.14 l h^{− 1} (9%) in the placebo group. None of these differences between the two groups was statistically or clinically significant.
Conclusions   Ziprasidone does not alter steady‐state serum lithium concentrations or renal clearance of lithium.     

Pharmacokinetics and tolerance of intravenous and intramuscular phylloquinone(vitamin K1) mixed micelles formulation

1 The pharmacokinetics and tolerance of phylloquinone(vitamin K₁) mixed micelles formulation (Konakion^® MM) were evaluated, in normal human adult volunteers ( n =30) using an open randomized crossover design protocol following a 10  mg intravenous or intramuscular injection.
2 Blood samples were collected for up to 12  h after the intravenous and up to 72  h after the intramuscular injections and the phylloquinone(vitamin K₁) levels determined by reversed phase h.p.l.c. with fluorometric detection after post-column electrochemical reduction.
3 Konakion^® MM was well tolerated after either route of administration. Pharmacokinetic analysis of plasma phylloquinone(vitamin K₁) concentration vs time profiles revealed that in one-fifth of the subjects systemic availability of intramuscular phylloquinone(vitamin K₁) was below 65%.
4 Our data suggest that due to sustained, but irregular and unpredictable absorption of the phylloquinone(vitamin K₁) from the depot site, the intramuscular route of Konakion^® MM administration is not suitable and thus not recommended.
5 Konakion^® MM i.v. is indicated to be well tolerated and effective in antagonizing coumarin-type-anticoagulants like Marcoumar^®     

Stimulatory as well as inhibitory effects of ethinyloestradiol on the metabolic clearances of propranolol in young women

1   The metabolism of a single 80  mg oral dose of propranolol was determined in nine young women before and after administration of ethinyloestradiol alone (EE₂) or in combination with norethindrone (OC).
2   Whereas the total clearance of propranolol (2713±404  ml min⁻¹ (mean±s.e.mean)) was not significantly altered by either EE₂ (3365±347  ml min⁻¹) or the combined OC (2905±345  ml min⁻¹), significant changes in all three primary metabolic pathways were observed.
3   The clearance through side-chain oxidation decreased from 345±55  ml min⁻¹ to 262±33  ml min⁻¹ after EE₂ ( P <0.05). A similar reduction of cytochrome P450 metabolism by EE₂ has been observed for other drugs.
4   The clearance through glucuronidation increased from 364±61  ml min⁻¹ to 625±117  ml min⁻¹ after EE₂ ( P <0.01). Similar stimulation of glucuronic acid conjugation by EE₂ has also been observed for other drugs.
5   The clearance through ring oxidation increased from 697±109  ml min⁻¹ to 1280±162  ml min⁻¹ after EE₂ ( P <0.01). This observation appears to be a novel finding with EE₂ and cytochrome P450 metabolism.
6   The treatment with OC produced changes in propranolol's metabolic clearances which were qualitatively similar to those generated by EE₂.     

1-Methylxanthine derived from caffeine as a pharmacodynamic probe of oxypurinol effect

Aims In the present study we have investigated the use of caffeine, administered in the form of instant coffee, as a prodrug for 1MX to validate the use of the 1MU:1MX ratio following caffeine administration as a pharmacodynamic measure of oxypurinol effect on xanthine oxidase.
Methods Five healthy volunteers took caffeine 75  mg 8 hourly administered as instant coffee over a 7 day period. They were given allopurinol 600  mg on day 4. Urine was collected in 8  h aliquots from day 1–day 7. The ratio of 1-methyluric acid (1MU) to 1-methylxanthuric (1MX) was determined.
Results The relationship between the plasma oxypurinol (the active metabolite of allopurinol) concentration at the midpoint of each caffeine dosage interval and the decrement in the urinary 1MX to 1MU ratio fitted well by a sigmoid E_max model. Mean (±s.d.) values of the oxypurinol E C ₅₀(3.9±1.4  mg  l^{− 1} ), E C ₉₀(8.7±1.8  mg  l^{− 1} ) and the exponent, n (3.0±1.2) were similar to those obtained previously following either the direct administration of 1MX or the use of theophylline as a prodrug for 1MX.
Conclusions These data indicate that the use of caffeine as a source of 1MX could provide a simple and ethically acceptable method for monitoring oxypurinol effect in patients taking allopurinol for the treatment of gout.     

The effects of ketoconazole on ziprasidone pharmacokinetics —a placebo‐controlled crossover study in healthy volunteers

Aims   To assess the effects of multiple oral doses of ketoconazole on the single‐dose pharmacokinetics of oral ziprasidone HCl.
Methods   This was a 14‐day, open‐label, randomized, crossover study in 14 healthy subjects aged 18–31 years. Group 1 received oral ketoconazole 400 mg once daily for 6 days, followed by a 2 day wash‐out period and 6 days of placebo administration. Group 2 received placebo followed by ketoconazole. Single oral doses of ziprasidone HCl 40 mg were administered on days 5 and 13 in both groups. Ziprasidone pharmacokinetic parameters were compared between placebo and ketoconazole administration periods.
Results   Co‐administration of ziprasidone with ketoconazole was associated with a modest increase in ziprasidone exposure; mean ziprasidone AUC(0,∞) increased by 33%, from 899 ng ml^{− 1} h with placebo to 1199 ng ml^{− 1} h with ketoconazole. Mean C _max increased by 34%, from 89 ng ml^{− 1} to 119 ng ml^{− 1}, respectively. The treatment effect on both of these parameters was statistically significant ( P < 0.02). Most adverse events were of mild intensity. There were no serious adverse events, laboratory abnormalities, abnormal ECGs, or clinically significant alterations in vital signs throughout the study.
Conclusions   The concurrent administration of ketoconazole and ziprasidone led to modest, statistically significant increases in ziprasidone exposure, although the changes seen were not considered clinically relevant. This suggests that other inhibitors of CYP3A4 are unlikely to significantly affect the pharmacokinetics of ziprasidone.     

Pharmacokinetics of recombinant human interleukin-2 in advanced renal cell carcinoma patients following subcutaneous application

Aims The aim of the study was to investigate the pharmacokinetics of recombinant human interleukin-2 (rhIL-2) in patients with metastatic renal cell carcinoma following different subcutaneous (s.c.) administration regimens.
Methods RhIL-2 was administered subcutaneously to 10 patients according to two different dosing regimens: group A received 20×10⁶  IU  m⁻² once daily and group B 10×10⁶ IU  m⁻² twice daily (every 12  h). Additionally, in all patients the influence of soluble interleukin-2 receptor (sIL-2R) on the pharmacokinetics of rhIL-2 was investigated.
Results The mean area under the serum concentration-time curve to 24  h (AUC(0,24  h)) was 627  IU  ml⁻¹  h in treatment group A and 1130  IU  ml⁻¹  h ( P =0.029) in treatment group B. In both study groups C _max and AUC(0,12  h) were not significantly different. Seventy-two  hours after the beginning of s.c. rhIL-2 therapy the sIL-2R increased significantly ( P =0.016), and sIL-2R levels over 1200  pmol  l⁻¹ seemed to reduce the AUC.
Conclusions In patients with metastatic renal cell cancer administration of 20×10⁶  IU  m⁻² of rhIL-2  s.c. in two daily doses (10×10⁶  IU  m⁻² every 12  h) provides better bioavailability and is preferable to the single dose administration.     

Nitric oxide: an important role in the maintenance of systemic and pulmonary vascular tone in man

Aims The aim of this study was to examine whether nitric oxide (NO) has an important role in maintaining basal vascular tone in normal man by examining the effects of nitric oxide inhibition using N ^G-monomethyl-l-arginine (l-NMMA) on systemic and pulmonary haemodynamics.
Methods Ten normal male volunteers 26±1.6 years were studied on two separate occasions in a double-blind, placebo controlled crossover study. They were randomised to receive either a continuous infusion of l-NMMA (4  mg  kg⁻¹  h⁻¹ ) with a front loaded bolus (4  mg  kg⁻¹ ) or volume matched placebo. Pulsed wave Doppler echocardiography was used to measure cardiac output (CO), mean pulmonary artery pressure (MPAP) and hence systemic vascular resistance (SVR) and total pulmonary vascular resistance (TPR). Measurements were made prior to infusion ( t ₀ ) and after 4, 8, and 12  min ( t ₁, t ₂ and t ₃ ).
Results Infusion of l-NMMA significantly increased mean arterial blood pressure (MAP), SVR and TPR and significantly reduced heart rate (HR), stroke volume (SV) and CO compared to placebo. These effects were observed at t ₁ and persisted during the entire infusion period.
Conclusions These results are consistent with a role for basal nitric oxide generation in the maintenance of basal systemic and pulmonary vascular tone in normal man.     

The induction effect of rifampicin on activity of mephenytoin 4''-hydroxylase related to M1 mutation of CYP2C19 and gene dose

Aims To determine the induction effect of rifampicin on the activity of 4'-hydroxylase in poor metabolizers (PMs) with m₁ mutation of S-mephenytoin 4'-hydroxylation and the relationship of the effect with gene dose.
Methods Seven extensive metabolizers (EMs) of S-mephenytoin 4'-hydroxylation and five PMs with m₁ mutation were chosen to take rifampicin 300  mg day⁻¹ orally for 22 days. Prior to and after rifampicin treatment, each subject was given racemic mephenytoin 100  mg. The 4'-hydroxymephenytoin (4'-OH-MP) excreted in the 0–24  h urine and mephenytoin S/R ratio in the 0–8  h urine were determined by h.p.l.c. and GC, respectively.
Results In all EMs, the excretion of 4'-OH-MP in the 0–24  h urine was increased by 146.4±17.9%, 0–8  h urinary mephenytoin S/R ratio was decreased by 77.3±8.8%, the percentage increase in the 0–24  h excretion of 4'-OH-MP in those CYP2C19 homozygous (wt/wt) was greater than that in those heterozygous (wt/m₁ and wt/m₂ ) (203.9±42.5% vs 69.6±4.1%). 0–8  h urinary mephenytoin S/R ratio of those PMs with m₁ mutation was decreased by 9.6%, the amount of 4'-OH-MP excreted in the 0–24  h urine was increased by 80.1±48.0%.
Conclusions The activity of 4'-hydroxylase of PMs with m₁ mutation of S-mephenytoin 4'-hydroxylation can be induced by rifampicin and the inducing effect of rifampicin on 4'-hydroxylase is gene dependent.     

A comparative population pharmacokinetic analysis for methylprednisolone following multiple dosing of two prodrugs in patients with acute asthma

Aims To conduct a randomized, parallel group comparison of the population pharmacokinetics of the two methylprednisolone (MP) prodrugs Promedrol (MP suleptanate) and Solu-Medrol (MP succinate) in patients hospitalized with acute asthma.
Methods Ninety volunteers were included in the pharmacokinetic analysis. Each volunteer received a dosage regimen of 40  mg (MP equivalents) i.v. 6 hourly for 48  h. The bio-conversion and disposition of a 40  mg (MP equivalent) i.v. dose of either MP suleptanate or MP succinate to MP was modelled as a first order input, and a mono-exponential elimination phase.
Results Population modelling indicated that the only difference in MP pharmacokinetics between MP suleptanate and MP succinate was in the input rate constant (66.0  h⁻¹ vs 5.5  h⁻¹ respectively). Based on individual Bayesian estimates, the exposure of patients to MP was marginally lower for MP suleptanate although the parameter estimates were not significantly different for half-life (2.7  h vs 3.0  h), steady-state AUC (2007.0  ng  ml⁻¹  h vs 2321.0  ng  ml⁻¹  h) and steady-state C _max (698.4  ng  ml⁻¹ vs 647.8  ng  ml⁻¹ ) for MP suleptanate and MP succinate respectively.
Conclusions It was concluded that for the multiple dosage regimen used in patients with acute asthma the systemic exposure to MP following dosing with MP suleptanate is similar to that arising from MP succinate. In addition the differences in the pharmacokinetics for the prodrugs resulted in only a small difference in the relative bioavailability of MP for MP suleptanate (0.94) compared with MP succinate.     

Pharmacodynamics of oxypurinol after administration of allopurinol to healthy subjects

1   Eight healthy subjects received 50, 100, 300, 600 and 900  mg allopurinol daily for 1 week each, in random order with 1 week separating each treatment period. The pre-dose plasma concentration of oxypurinol, the extent of inhibition of xanthine oxidase, plasma urate concentration and urine urate excretion rate were assessed on the last 2 days of each treatment week.
2   The ratio of 1-methyluric acid (1MU) over 1-methylxanthine (1MX) in the urine, following a dose of 50  mg 1MX infused intravenously over 20  min, was used to measure the inhibition of xanthine oxidase.
3   The steady-state plasma concentration of oxypurinol increased linearly with increasing dose of allopurinol between 50  mg to 600  mg day⁻¹, with a weak indication of saturation at the higher 900  mg day⁻¹ dose rate.
4   The relationships between plasma oxypurinol concentration and xanthine oxidase inhibition (1MU/1MX ratio), plasma urate concentration and urine urate excretion rate were fitted to an inhibition sigmoid E_max model and the C ₅₀ values for oxypurinol were 26.38±4.87, (mean±s.d.) 36.58±8.36 and 24.61±9.08  μm, respectively.
5   1MU/1MX ratio appeared to be a reliable index of xanthine oxidase activity in vivo as the C ₅₀ for oxypurinol observed for 1MU/1MX ratio, plasma urate concentration and urine urate excretion rate were similar.
6   The concentration of oxypurinol required for inhibition of xanthine oxidase, as indicated by C ₅₀, was lower than those often observed in clinical practice.     

Pharmacokinetics of intravenous fluticasone propionate in healthy subjects

1 Fluticasone propionate (FP) is a potent glucocorticoid used in the treatment of asthma. Prior to reporting the pharmacokinetics following the inhaled and oral routes, the pharmacokinetics need to be established following intravenous dosing. The present study determines the intravenous pharmacokinetics of FP, using non-compartmental analysis, in healthy male subjects over the 250 to 1000μg dose range.
2 The pharmacokinetics of FP can be regarded as being linear over this dosing range. FP was extensively distributed within the body ( V _ss 318  l), rapidly cleared (CL 1.1 l min⁻¹) with a terminal elimination half-life of 7.8  h and a mean residence time of 4.9  h.
3 In order that future pharmacokinetic/pharmacodynamic and other modelling can be carried out, the plasma concentration-time profiles were parameterized using a model based on sums of exponentials, the appropriateness of this model was justified as the secondary kinetic parameters from the model were similar to those obtained using non-compartmental analysis.     

Single dose and steady state pharmacokinetics and pharmacodynamics of the ACE-inhibitor imidapril in hypertensive patients

Aims To investigate the pharmacokinetic profile of the ACE-inhibitor imidapril in 10 hypertensive patients after a first single dose (10  mg) and after 28 days therapy with imidapril 10  mg once daily.
Methods C _max, t _max, t _1/2 and AUC of imidapril and imidaprilat were obtained. ACE-activity and arterial blood pressure during imidapril were corrected by a preceding placebo-investigation.
Results The AUC of imidapril was 140 (43  s.d.)  ng  ml⁻¹ h after the first dose and 123 (34  s.d.)  ng  ml⁻¹ h at steady state. AUC of the active moiety imidaprilat averaged 211 (101  s.d.)  ng  ml⁻¹ h after the first dose and 240 (55  s.d.)  ng  ml⁻¹ h at the steady state investigation. Maximal ACE-inhibition was 75% after the single dose as well as at steady state. ACE inhibition before drug intake at day 28 (i.e. trough) was 50%. The (placebo-corrected) maximal drop in diastolic blood pressure after imidapril was 22  mmHg after the first dose and 25  mmHg at steady state. Exploratory analysis of imidaprilat plasma concentration vs effect profiles suggests a hyperbolic concentration effect relationship where data of the single dose contribute to the ascending part of an E_max-curve, whereas the plateau around E_max is maintained at steady state.
Conclusions In this group of hypertensive patients, the pharmacokinetic profile and the drop in ACE-activity as well as in blood pressure seen after a single dose of imidapril and at steady state were similar. The initial response to a test dose might therefore predict the response during chronic dosing.     

Single dose pharmacokinetics of lamivudine in subjects with impaired renal function and the effect of haemodialysis

Aims The purpose of this study was to investigate the pharmacokinetics of a single oral dose of lamivudine administered to subjects with renal impairment and to determine whether lamivudine was dialysable in subjects with severe renal impairment undergoing haemodialysis.
Methods Twenty-nine subjects were enrolled, nine with normal renal function (creatinine clearance (CL_CR ) 82–117  ml  min⁻¹ ), eight with moderately impaired renal function (CL_CR 25–49  ml  min⁻¹ ), six with severe impairment (CL_CR 13–19  ml  min⁻¹ ) and six with severe impairment who were also receiving haemodialysis. After an overnight fast, nondialysis subjects received a single oral dose of lamivudine. Subjects on haemodialysis were given two doses on separate occasions (intra and interdialysis). Blood was obtained before lamivudine administration and at regular intervals to 48  h post dose. Timed urine collections were performed for subjects able to produce urine. Pharmacokinetic parameters were calculated by using standard non compartmental techniques.
Results Decreasing renal function was associated with reduced lamivudine clearance in a proportional and apparently linear relationship. Lamivudine was well dialysed with an extraction ratio in the order of 50%. However, because lamivudine has a large volume of distribution (≈100  l), a haemodialysis session of 4  h did not affect overall exposure to a clinically significant degree in most subjects.
Conclusions Impaired renal function does require lamivudine dose modification according to the degree of impairment, but no further modification of dose is required for subjects undergoing regular haemodialysis.     

Absorption kinetics of oral sotalol combined with cisapride and sublingual sotalol in healthy subjects

Aims To study the absorption kinetics of sotalol following administration of different formulations. A formulation which results in fast absorption might be useful in the episodic treatment of paroxysmal supraventricular tachycardia (SVT), atrial fibrillation (Afib) or atrial flutter (Afl).
Methods In an open randomized crossover study seven healthy male volunteers were given an intravenous infusion of 20  mg sotalol, for assessing the absolute bioavailability, an oral solution containing 80  mg sotalol, an oral solution containing both 80  mg sotalol and 20  mg cisapride and an 80  mg sotalol tablet, which was taken sublingually.
Results The addition of cisapride decreased the time at which maximum serum concentrations were reached ( t _max ) from 2.79 (1.85–4.34) h to 1.16 (0.68–2.30) h ( P =0.009) [95% CI: -2.59, −0.55] and increased the absorption rate constant ( k _a ) from 0.49 (0.31–0.69) h⁻¹ to 1.26 (0.52–5.61) h⁻¹ ( P =0.017). The absolute bioavailability of sotalol was reduced by cisapride from 1.00±0.15 to 0.70±0.26 ( P =0.006), while maximum serum concentrations of both oral solutions were not significantly different. Compared with the sublingually administered tablet with a median t _max of 2.12 (0.89–3.28) h, the sotalol/cisapride oral solution gave a smaller t _max (p=0.009) [95% CI: −1.64, −0.36]. The k _a of the sotalol/cisapride solution was significanty ( P =0.010) larger than the k _a of 0.56 (0.33–0.75) h⁻¹ found after sublingual administration of the tablet.
Conclusions The sotalol/cisapride oral solution might be suitable for the episodic treatment of SVT, Afib or Afl.