Graft-derived CCL2 increases graft injury during antibody-mediated rejection of cardiac allografts.

The pathogenic role of macrophages in antibody-mediated rejection (AMR) remains unclear. Monocyte chemoattractant protein-1 (MCP-1/CCL2) is a potent chemotactic factor for monocytes and macrophages. The current studies used a murine model of AMR to investigate the role of graft-derived CCL2 in AMR and how macrophages may participate in antibody-mediated allograft injury. B6.CCR5−/−/CD8−/− recipients rejected MHC-mismatched WT A/J allografts with high donor-reactive antibody titers and diffuse C4d deposition in the large vessels and myocardial capillaries, features consistent with AMR. In contrast, A/J.CCL2−/− allografts induced low donor-reactive antibody titers and C4d deposition at Day 7 posttransplant. Decreased donor-reactive CD4 T cells producing interferon gamma were induced in response to A/J.CCL2−/− versus WT allografts. Consequently, A/J.CCL2−/− allograft survival was modestly but significantly longer than A/J allografts. Macrophages purified from WT allografts expressed high levels of IL-1ß and IL-12p40 and this expression and the numbers of classically activated macrophages were markedly reduced in CCL2-deficient allografts on Day 7. The results indicate that allograft-derived CCL2 plays an important role in directing classically activated macrophages into allografts during AMR and that macrophages are important contributors to the inflammatory environment mediating graft tissue injury in this pathology, suggesting CCL2 as a therapeutic target for AMR.

Endogenous memory CD8 T cells directly mediate cardiac allograft rejection.

Differences in levels of environmentally induced memory T cells that cross-react with donor MHC molecules are postulated to account for the efficacy of allograft tolerance-inducing strategies in rodents versus their failure in nonhuman primates and human transplant patients. Strategies to study the impact of donor-reactive memory T cells on allografts in rodents have relied on the pretransplant induction of memory T cells cross-reactive with donor allogeneic MHC molecules through recipient viral infection, priming directly with donor antigen or adoptive transfer of donor antigen primed memory T cells. Each approach accelerates allograft rejection and confers resistance to tolerance induction, but also biases the T cell repertoire to strong donor reactivity. The ability of endogenous memory T cells within unprimed mice to directly reject an allograft is unknown. Here, we show a direct association between increased duration of cold ischemic allograft storage and numbers and enhanced functions of early graft infiltrating endogenous CD8 memory T cells. These T cells directly mediate rejection of allografts subjected to prolonged ischemia and this rejection is resistant to costimulatory blockade. These findings recapitulate the clinically significant impact of endogenous memory T cells with donor reactivity in a mouse transplant model in the absence of prior recipient priming.

Inhibitory effect of telmisartan on the blood pressure response to angiotensin II challenge.

Telmisartan is a new angiotensin receptor antagonist possessing potent, selective, and insurmountable inhibitory activity specific to the angiotensin II type 1 (AT 1 ) receptor. The current study was performed to determine the inhibition of the angiotensin II pressor response by telmisartan in 48 healthy volunteers challenged with hypertension-inducing doses of i.v. angiotensin II. Subjects were challenged with this dose of angiotensin II at intervals between 0.25 and 48 h after double-blind single-dose oral administration of telmisartan 20 mg (n = 12), 40 mg (n = 12), or 80 mg (n = 12) or placebo (n = 12) in parallel groups. Diastolic and systolic blood pressure and pulse rate were recorded continuously using a servophotoplethysmograph. Urine samples were collected during the study for urinalysis. Tolerability of telmisartan, in comparison with placebo, was also monitored throughout the study. Telmisartan 20-80 mg dose dependently inhibited the increase in diastolic and systolic blood pressure induced by angiotensin II. Telmisartan 40 mg produced 80.1% maximum inhibition, and with 80 mg 89.6% maximum inhibition of diastolic blood pressure was achieved. Inhibition was apparent after 0.3-1.1 h and was still observed 48 h after administration for all telmisartan doses. The inhibitory effect of telmisartan 20, 40, and 80 mg, 48 h after dosing was significantly greater than that of placebo. A > 25% inhibition of the angiotensin II response on diastolic blood pressure was detected until 26.9, 35.4, and 40.5 h, respectively, after telmisartan 20 mg, 40 mg, and 80 mg. Anti-clockwise hysteresis was observed, indicating a delay and longer persistence of effect than to be expected from the plasma concentration-time course. The slow dissociation of telmisartan from the receptor probably contributed to this hysteresis. The incidence of adverse events was comparable in telmisartan-and placebo-treated subjects and was not dose dependent. In conclusion, telmisartan 40 mg provides rapid-onset, well-tolerated, and near-maximal inhibition of angiotensin II-induced hypertension, with maintenance of the inhibitory effect for 48 h.

Pharmacokinetics of orally and intravenously administered telmisartan in healthy young and elderly volunteers and in hypertensive patients.

A series of studies was conducted in healthy young males and healthy elderly males or females to evaluate the pharmacokinetic profile of telmisartan. In addition, two phase-II clinical trials assessed the pharmacokinetics and the safety of telmisartan in mild-to-moderate hypertensive patients. Telmisartan was given as a single oral (1-160 mg) or intravenous (10-160 mg) dose to young males. In another multiple-dose study, telmisartan 320 mg was administered orally once daily for 7 days to healthy young male subjects. Elderly subjects received oral telmisartan (20 and 120 mg) once daily for 7 days. Telmisartan doses of 10, 20, 40, 80, 120 and 160 mg were taken once daily by mild-to-moderate hypertensive patients for 7 days. Additionally, oral telmisartan (40, 80 or 120 mg) was administered once daily for 28 days to hypertensive subjects. Following oral dosing, median time to maximum plasma telmisartan concentration was 0.5 - 2 h, with maximum plasma concentrations increasing disproportionately with dose. By contrast, plasma concentrations were directly related to the intravenous dose. Steady state was observed after 5-7 days of once-daily administration, and there was no clinically relevant accumulation at 28 days. The plasma concentration-time profiles were similar in all study groups and were characterized by fast absorption and a rapid biexponential decline after the peak plasma concentration, with a prolonged terminal elimination phase (> 20 h in healthy and hypertensive subjects). Telmisartan was well tolerated, with a low incidence of drug-related adverse events. The most frequent event was headache, which also occurred in placebo-treated control subjects. No changes in heart rate, electrocardiograms or clinical chemistry were detected following receipt of telmisartan. The study thus shows that high systemic levels of telmisartan, which are well tolerated, can be attained in healthy adults of any age and in hypertensive subjects. The long terminal elimination half-life makes telmisartan suitable for once-daily dosing and contributes to the sustained efficacy over the full 24-h dosing interval.

Steady-state pharmacodynamics and pharmacokinetics of warfarin in the presence and absence of telmisartan in healthy male volunteers.

The effects of multiple-dose telmisartan on the steady-state pharmacodynamics and pharmacokinetics of warfarin were assessed in 12 healthy young males in an open-label, single-period study conducted over 30 days. Subjects received loading doses of oral once-daily warfarin on days 1 to 5, which were individually adjusted at days 6 and/or 9 to attain stable predose prothrombin time values (INRpre) of between 1.2 and 1.8 by the end of medication phase 1 (day 14). From days 15 to 24 (medication phase 2), subjects received oral once-daily telmisartan 120 mg in addition to individualized oral doses of once-daily warfarin. On days 25 to 31 (medication phase 3), oral once-daily warfarin was again administered alone at individualized doses. Under steady-state conditions, INRpre remained unchanged during medication phases 1, 2, and 3. The difference between phases 1 and 3 was -0.04 (95% confidence interval [CI]: -0.7 to 0.10) and between phases 2 and 1 was 0.03 (95% CI: -0.11 to 0.10). Mean trough plasma warfarin concentrations (Cpre) were stable during medication with warfarin alone but showed a small, although statistically significant, decrease during the combined-medication phase. The point estimate of the ratio of phase 2/phase 1 was 0.89 (95% CI: 0.84 to 0.95). The decrease in Cpre did not result in decreased anticoagulation. This suggests that the extent of pharmacokinetic interaction between telmisartan and warfarin is limited, and since telmisartan had no effect on INRpre and the concomitant medication was well tolerated, there is no evidence for a clinically relevant interaction between telmisartan and warfarin.

Pharmacokinetics of acetaminophen and ibuprofen when coadministered with telmisartan in healthy volunteers.

Two open-label, two-way, crossover studies were performed to assess any pharmacokinetic interaction of telmisartan with either acetaminophen or ibuprofen. Healthy male adult volunteers (n = 12) received a single oral dose of acetaminophen 1 g alone and with oral telmisartan 120 mg in one study. Oral ibuprofen 400 mg three times daily with and without oral once-daily telmisartan 120 mg was given for 7 days in the other study conducted in 6 males and 6 females. In both studies, there was a washout period of > or = 13 days between single and combination medication administration. The primary end points Cmax and AUC were compared between combination (acetaminophen or ibuprofen + telmisartan) and single-agent medication (acetaminophen or ibuprofen). Pharmacokinetic drug interaction was assessed by analysis of variance (ANOVA) and calculation of 90% confidence intervals (CI) for treatment ratios using log-transformed parameters. Bioequivalence (i.e., lack of interaction) was concluded if the 90% CI of the ratios for both Cmax and AUC were within the acceptance limit of 0.80 to 1.25. Geometric mean Cmax values for acetaminophen and R-(-)- and S-(+)-ibuprofen enantiomers were similar with and without telmisartan coadministration (12.6 micrograms/mL vs. 14.1 micrograms/mL; 17.3 micrograms/mL vs. 16.7 micrograms/mL; 19.4 micrograms/mL vs. 19.5 micrograms/mL, respectively), and values for R-(-)- as well as S-(+)-ibuprofen were bioequivalent. Geometric mean AUC values for acetaminophen and R-(-)- and S-(+)-ibuprofen were also bioequivalent with and without telmisartan. The distribution and elimination parameters of both acetaminophen and ibuprofen were comparable in the presence or absence of telmisartan. The concomitant and single-agent medications were all well tolerated. In conclusion, the long half-life and excellent safety profile of telmisartan were unaffected by concurrent acetaminophen or ibuprofen medication; thus, once-daily dosing of telmisartan can be maintained, which may help to optimize patient compliance, and patients may self-administer concomitant acetaminophen or ibuprofen.

Pharmacokinetics of repeated oral doses of amlodipine and amlodipine plus telmisartan in healthy volunteers.

This open-label, crossover study was performed to establish if there is evidence for interaction between telmisartan, an angiotensin II antagonist, and amlodipine, a class II (dihydropyridine) calcium channel antagonist, on the basis of pharmacokinetics and safety. In a two-way crossover trial, 12 healthy Caucasian males were randomized to receive once daily for 9 days oral amlodipine 10 mg with or without oral telmisartan 120 mg. After a washout period of > or = 13 days, the subjects were switched to the other medication regimen. The geometric means of the primary pharmacokinetic parameters at steady state (day 9) for amlodipine when given alone were the following: maximum plasma concentration (Cmax) 17.7 ng/mL, area under the plasma concentration-time curve (AUC) 331 ng.h/mL, and renal clearance 39.5 mL/min, with 8% of the total amlodipine dose being excreted. When concomitant telmisartan was given, the respective values were 18.7 ng/mL, 352 ng.h/mL, and 43.0 mL/min, with 9.4% of the total amlodipine dose being excreted renally. The limits of the 90% confidence intervals (CIs) for the ratios of these steady-state parameters were 0.97 to 1.14 for Cmax and 0.98 to 1.16 for AUC; both were within the predefined reference range (0.8 to 1.25) for bioequivalence. The high intersubject variability in urinary amlodipine excretion resulted in bioequivalence not being demonstrated for renal clearance. Adverse effects were few, mild to moderate in intensity, and transient whether amlodipine was given alone or with telmisartan. Vital signs, except for blood pressure, and clinical laboratory values were unaffected by either medication. The findings of this study show that concomitant telmisartan and amlodipine may be administered as there is no clinically significant variation in primary pharmacokinetic parameters of amlodipine in the presence of telmisartan, and the safety of the combination is comparable to that of amlodipine alone.

Pharmacokinetics and safety of intravenous and oral telmisartan 20 mg and 120 mg in subjects with hepatic impairment compared with healthy volunteers.

The pharmacokinetics and safety of telmisartan were assessed in subjects with hepatic impairment in a single-center, open-label study. Single oral doses of telmisartan 20 mg and 120 mg, separated by a washout period of 14 days, were given to 12 hepatically impaired subjects and 12 healthy subjects. In 5 hepatically impaired subjects who received both oral doses, a single i.v. infusion of telmisartan 120 mg was later administered. After oral dosing, the pharmacokinetic profile of telmisartan was characterized by rapid absorption and disposition kinetics and a slow terminal elimination phase with mean half-lives of 27 to 42 hours. The maximum plasma concentration and area under the telmisartan plasma concentration-time curve (AUC0-infinity) increased in hepatically impaired subjects compared with healthy volunteers 6.4-fold and 2.7-fold, respectively, for telmisartan 20 mg and 3.2-fold and 3.1-fold, respectively, for telmisartan 120 mg. Maximum plasma concentrations and AUC0-infinity after i.v. infusion were markedly elevated compared with values obtained from other studies conducted in healthy volunteers. Hepatic impairment resulted in an apparent increase in the absolute bioavailability of telmisartan, and total clearance following oral and i.v. administration was significantly reduced compared with healthy volunteers. Plasma protein binding of telmisartan was > or = 99.5% in hepatically impaired and healthy subjects and was not changed when compared to healthy subjects. Oral and i.v. telmisartan were well tolerated in both the hepatically impaired and the healthy; headache was the most common potentially telmisartan-related adverse event. Changes in vital signs and clinical laboratory parameters were transient and of no clinical relevance. The good tolerability of telmisartan in hepatically impaired patients demonstrated in this study, the proven sustained blood pressure control in hypertensive patients, and the increased exposure in patients with hepatic dysfunction suggest that effective treatment of hypertensive patients with impaired hepatic function would be achieved even with the lowest dose of telmisartan available. The increased bioavailability of telmisartan suggests that lower doses of telmisartan should be considered when the drug is administered to patients with hepatic impairment.

Pharmacokinetics of single-dose telmisartan 120 mg given during and between hemodialysis in subjects with severe renal insufficiency: comparison with healthy volunteers.

The pharmacokinetics of oral telmisartan 120 mg evaluated in subjects with severe renal insufficiency between dialyses and during hemodialysis were compared with those observed in healthy male subjects. Between dialyses and during dialysis, the plasma concentration-time curves of subjects with renal insufficiency were lower than those of healthy subjects. The mean plasma protein binding of telmisartan was 99.5% in healthy subjects, compared with mean values of 99.1% between dialyses and 98.8% during dialysis. Only very small amounts of telmisartan were removed by dialysis. Single doses of telmisartan 120 mg were well tolerated in subjects with severe renal insufficiency when administered either between dialyses or during dialysis, and no clinically relevant changes in vital signs were detected. In conclusion, the maximum plasma concentrations of telmisartan and areas under the plasma concentration-time curves in subjects with severe renal insufficiency were markedly reduced compared with healthy subjects. The fraction of telmisartan not bound to plasma proteins was increased approximately twofold. Changes in the pharmacokinetic profile in subjects with renal insufficiency did not affect the safety profile of telmisartan, which was well tolerated in these subjects.

The effect of telmisartan on the steady-state pharmacokinetics of digoxin in healthy male volunteers.

A multiple-dose, open-label, two-period, crossover randomized study was conducted in 12 healthy male volunteers to investigate the effect of multiple-dose telmisartan on the steady-state pharmacokinetics of digoxin. On day 1 of a 7-day medication period, subjects received a loading dose of digoxin 0.5 mg in the morning, followed by an evening dose of digoxin 0.25 mg, either alone or together with telmisartan 120 mg administered in the morning. On the subsequent 6 days, either digoxin 0.25 mg or digoxin 0.25 mg together with telmisartan 120 mg was administered once daily in the morning. Each 7-day medication period was separated by a washout period of > or = 14 days. A steady-state plasma concentration-time profile was assessed for digoxin during each period and for telmisartan during the period with the combined treatment. Multiple-dose telmisartan administered with digoxin resulted in higher serum digoxin concentrations than those observed after digoxin given alone. Geometric mean AUC144-168, Cmax, and Cmin values for digoxin when given in combination with telmisartan were higher by 22%, 50%, and 13%, respectively, compared with values when given alone. However, the 90% confidence interval for the geometric mean of Cmin was within the predefined 80% to 125% range of no interaction. During combination medication, digoxin tmax was shorter and Cmax/AUC144-168 increased, suggesting that the rise in digoxin Cmax may be due to more rapid drug absorption. Study medications were well tolerated, with the incidence, nature, and intensity of adverse events being similar during both medication periods. Also, no changes in vital signs or clinical laboratory tests were observed during the study. Although there was some evidence for a pharmacokinetic interaction between digoxin and telmisartan found in this study, the safety and tolerability of digoxin were unaffected by concurrent administration of telmisartan in the study population. Since any symptoms of overdose are related only to steady state and not peak concentrations and due to the fact that there was a lack of effect on serum trough levels of digoxin in this study, it is unlikely that the findings have any clinical relevance. The magnitude of increase in digoxin concentrations is comparable with increases observed with administration of calcium antagonists, carvedilol, ACE inhibitors such as captopril, and antiarrhythmic drugs such as amiodarone, quinidine, and propafenone. Monitoring of serum digoxin concentrations should be considered when patients first receive telmisartan and in the event of any changes in telmisartan dose.

Bioavailability of repaglinide, a novel antidiabetic agent, administered orally in tablet or solution form or intravenously in healthy male volunteers.

OBJECTIVE: Repaglinide is a novel prandial glucose regulator (PGR) for the treatment of type 2 diabetes. In order to investigate subject variability following oral administration of repaglinide, and to determine the relative and absolute bioavailabilities of repaglinide following oral or intravenous administration, two single-centre, open-label, randomized, crossover clinical studies were conducted. SUBJECTS AND METHODS: Study 1 was conducted in 24 healthy male subjects (aged 18 to 49 years), who received repaglinide 2 mg, as either tablet or oral solution, twice each on 4 separate occasions at least 7 days apart. Study 2 was conducted in 12 healthy male subjects (aged 18 to 45 years), who received repaglinide 2 mg, either as a tablet or as an intravenous infusion over 15 minutes, once each on 2 separate occasions, with a washout period of 7-10 days. RESULTS: In study 1 there was no significant difference between administration of repaglinide 2 mg, in either tablet or oral solution form with regard to intrasubject variation in AUC and Cmax. However, the intrasubject variation in t(max) and mean residence time (MRT) was significantly (p = 0.001) larger for the tablets than for the oral solution. Intersubject variation (CV) in AUC ranged from 44.7% to 62.1% after oral administration. The relative bioavailability of repaglinide (AUC(tablet)/AUC(oral solution)) was 110% (95% CI, 103%-117%). In study 2 the absolute bioavailability of repaglinide administered as a tablet was 62.5% (95% CI, 49.2%-79.5%) relative to an intravenous infusion of the same dose. CONCLUSION: There was no evidence from either study that the tablet formulation led to greater variation in serum profiles of repaglinide. It was concluded that repaglinide is rapidly absorbed and eliminated in healthy subjects when administered orally or intravenously under fasting conditions, and that the total availability of repaglinide is similar in the tablet and oral solution formulations, though that the rate of absorption is slower for the tablet formulation.

Lack of interaction between meloxicam and warfarin in healthy volunteers.

OBJECTIVE: The effect of multiple oral doses of meloxicam 15 mg on the pharmacodynamics and pharmacokinetics of warfarin was investigated in healthy male volunteers. Warfarin was administered in an individualized dose to achieve a stable reduction in prothrombin times calculated as International Normalized Ratio (INR) values. Then INR- and a drug concentration-time profile was determined. For the interaction phase, meloxicam was added for 7 days and then INR measurements and the warfarin drug profiles were repeated for comparison. Overall, warfarin treatment lasted for 30 days. RESULTS: Warfarin and meloxicam were well tolerated by healthy volunteers in this study. Thirteen healthy volunteers with stable INR values entered the interaction phase. Prothrombin times, expressed as mean INR values, were not significantly altered by concomitant meloxicam treatment, being 1.20 for warfarin alone and 1.27 for warfarin with meloxicam cotreatment. R- and S-warfarin pharmacokinetics were similar for both treatments. Geometric mean (% gCV) AUCss values for the more potent S-enantiomer were 5.07 mg.h.l-1 (27.5%) for warfarin alone and 5.64 mg.h.l-1 (28.1%) during the interaction phase. Respective AUCss values for R-warfarin were 7.31 mg.h.l-1 (43.8%) and 7.58 mg.h.l-1 (39.1%). CONCLUSION: The concomitant administration of the new non-steroidal anti-inflammatory drug (NSAID) meloxicam affected neither the pharmacodynamics nor the pharmacokinetics of a titrated warfarin dose. A combination of both drugs should nevertheless be avoided and, if necessary, INR monitoring is considered mandatory.

Dose-dependent uricosuric effect of ambroxol.

Ambroxol is known to promote bronchial secretion and is used as an expectorant. Previous studies had suggested that high doses of ambroxol could reduce the plasma uric acid concentration. The present study was undertaken to confirm this finding, to determine its dose-response relationship and to identify the underlying mechanism of action. Using a placebo-controlled, double-blind parallel group design, 48 healthy male volunteers were randomly allocated to receive placebo b.d. and ambroxol 125 mg b.d., 250 mg b.d. or 500 mg b.d. (12 subjects per group). The subjects were hospitalised during a dietary run-in period of 3 days (Days -3 to -1) and a treatment period of 5 days (Days 1 to 5). On Day -1 (baseline) and Days 1 to 5, all urine was collected and blood samples were taken for the analysis of uric acid, creatinine, xanthine and ambroxol. The measurements were repeated four days after treatment had closed. Steady state plasma concentrations of ambroxol (trough levels) were reached after 2 or 3 days and were linearly related to dose. Ambroxol induced a significant, dose-dependent, reduction in plasma uric acid (250 mg b.d. about 20%; and at 500 mg b.d. about 30%). The diurnally fluctuating uric acid clearance was dose dependently increased and there was no notable effect on creatinine clearance. Plasma hypoxanthine levels were not affected by ambroxol. No severe adverse events were reported and no drug induced changes in the clinical laboratory values were observed. It is concluded that ambroxol has an uricosuric action following oral administration of higher doses (250 mg-500 mg b.d.) and it is well tolerated.

Dipyridamole alone or combined with low-dose acetylsalicylic acid inhibits platelet aggregation in human whole blood ex vivo.

1. In a randomized, double-blind trial we compared the inhibition of the platelet-vessel wall interactions in whole blood ex vivo. There were four groups of 24 healthy volunteers each of whom were treated orally for 3.5 days with either 200 mg dipyridamole (sustained release preparation), 25 mg acetylsalicylic acid, both drugs combined or placebo twice daily. 2. The mean area of all platelets/aggregates was reduced by 6.2% +/- 4.2% (+/- s.e. mean) by placebo (n = 23), 19.8% +/- 6.7% by dipyridamole (n = 22), 53.7% +/- 4.9% by acetylsalicylic acid (n = 23) and 71.4% +/- 3.7% by the combination of both drugs (n = 24), when compared with total inhibition of aggregation by EGTA. Thus, low-dose acetylsalicylic acid inhibited aggregation (P less than 0.001). 3. Dipyridamole reduced the size of platelet aggregates (P less than 0.01, two-fold analysis of variance). The reduction was correlated with the individual dipyridamole plasma levels (P less than 0.05, analysis of covariance). The subgroup of large and very large thrombi being formed was also reduced by dipyridamole (P less than 0.05). 4. This ex vivo study demonstrates that dipyridamole alone inhibits formation of thrombi on subendothelial matrix and enhances the inhibitory effect of low dose acetylsalicylic acid in this model of thrombosis.

Pharmacokinetics of antigen and activity of recombinant tissue-type plasminogen activator after infusion in healthy volunteers.

Pharmacokinetics of recombinant tissue plasminogen activator (rt-PA, large-scale process) were determined based on antigen and activity after infusion of 0.25 mg/kg in 8 healthy volunteers. Plasma antigen was measured using enzyme-linked immunosorbent assay (ELISA) with and without treatment of blood at collection with D-Phe-Pro-Arg-CH2Cl (P PACK); activity was quantified in acidified plasma both on fibrin plates and in a chromogenic assay. Highest rt-PA concentrations were measured in ELISA with P PACK-treated samples, yielding the following pharmacokinetic parameters (2-compartment model, mean +/- S.D.): Cmax = 973 +/- 133 ng/ml, CL = 687 ml/min, dominant half-life t1/2 alpha = 3.3 +/- 0.4 min, t1/2 beta = 26 +/- 12 min, V1 = 3.9 +/- 0.6 l and Vss = 7.2 +/- 1.0 l. The other assays yielded lower rt-PA concentrations, which affected clearance and volume parameters but not t1/2 beta and t1/2 beta. Linear regressions of the fibrin plate and chromogenic assay results vs. ELISA yielded excellent correlations (R greater than 0.96, n = 55-57) but slopes of 0.76 and 0.64, respectively. This indicates that about 25-35% of rt-PA antigen in thawed plasma samples are not detected in activity assays, due at least partially to in vitro binding of rt-PA by proteinase inhibitors.

Clinical pharmacology of two specific bradycardiac agents.

The effect of two i.v.-infusion regimens of falipamil on atropine-induced changes of heart rate and the effect of ULFS 49 Cl in 3 different oral doses during a 7-day medication period were studied in volunteers. Both studies were double-blind, randomized and placebo controlled. Under placebo, low doses of atropine caused a 16% reduction in heart rate, a 1 mg cumulative dose increased heart rate by 23%. 100 mg falipamil was followed by a 9% reduction in heart rate. Low doses of atropine enhanced this decrease to 14%, whereas a 1 mg cumulative dose of atropine increased heart rate by only 3%. Similar results were obtained after administration of 200 mg falipamil. ULFS 49 Cl induced a constant reduction of heart rate at rest and during ergometry without changing systolic and diastolic blood pressure. Because no interrelation was found between efficacy and corresponding plasma levels of the drug, it can be concluded that the concentration of the drug in the tissue is responsible for efficacy and duration of action. The minimal effective and the therapeutic doses were 3 X 2.5 mg p.o. and 3 X 5 mg p.o. respectively. In contrast to falipamil, which increased the QT-interval by approximately 20%, ULFS 49 Cl did not change QT-time. Side-effects typical for 'specific bradycardic agents', such as coruscation were seen. Peak occurrence was between day 1 and day 4, thereafter a decreasing frequency was observed. In general, both drugs were effective and well tolerated.

Pharmacokinetics and effects on fibrinolytic and coagulation parameters of two doses of recombinant tissue-type plasminogen activator in healthy volunteers.

Pharmacokinetics and pharmacological effects of two intravenous doses of recombinant tissue-type plasminogen activator (rt-PA) (40 and 60 mg over 90 min) were determined in healthy volunteers. Mean maximum plasma concentrations were 1080 and 1560 ng/ml respectively. The steady state level during subsequent maintenance infusion of 30 mg over 6 h was 250 ng/ml. The pharmacokinetics of rt-PA showed a bi-exponential disappearance from plasma consistent with a 2-compartment model of t1/2 alpha = 5.7 min, a t1/2 beta = 1.3 h and a total clearance of 380 ml/min. Mean fibrinogen levels at the end of the infusions of 40 mg or 60 mg rt-PA over 90 min, measured in thawed plasma samples collected on citrate/aprotinin, decreased to 74% and 57% of the preinfusion values respectively. Plasminogen fell to 55% and 48%, and alpha 2-antiplasmin to 28% and 18% of initial values. No further decrease of these parameters was observed during the infusion of 30 mg rt-PA over 6 h. Only 2% of the preinfusion fibrinogen levels could be recovered as fibrinogen-fibrin degradation products. This moderate extent of systemic fibrinogenolysis is much less than that reported for therapeutic i.v. infusions of streptokinase.

[The diagnosis of medullary carcinoma of the thyroid (author's transl)]. / Diagnostik des medullären Schilddrüsenkarzinoms

The pentagastrin stimulation test was given to ten brothers and sisters of two patients who had previously undergone total thyroidectomy for medullary carcinoma of the thyroid. 5 microng pentagastrin/kg body-weight were injected as an intravenous bolus and calcitonin levels determined before and after. The test was positive in four members of the family and the presence of a medullary carcinoma was subsequently confirmed in them histologically.