Veterinary Research Communications, 26 (2002) 61^71 # 2002 Kluwer Academic Publishers.

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Pharmacokinetics of Oleandomycin in Dogs after Intravenous or Oral Administration Alone and after Pretreatment with Metamizole or Dexamethasone
A. Milanova* and L. Lashev Department of Pharmacology, Toxicology and Therapeutics, Faculty of Veterinary Medicine, Thracia University, Student Campus, 6000 Stara Zagora, Bulgaria *Correspondence
Milanova, A. and Lashev, L., 2002. Pharmacokinetics of oleandomycin in dogs after intravenous or oral administration alone and after pretreatment with metamizole or dexamethasone. Veterinary Research Communications, 26(1), 61^71 ABSTRACT The pharmacokinetics of oleandomycin (OLD) after intravenous and oral administration, both alone and after intramuscular pretreatment with metamizole or dexamethasone, were studied in healthy dogs. , volume of After intravenous injection of OLD alone (10 mg/kg as bolus), the elimination half-life (t1 2b distribution (Vd,area), body clearance (ClB) and area under the concentration^time curve (AUC) were 1.60 h, 1.11 L/kg, 7.36 (ml/kg)/min and 21.66 mg h/ml, respectively. There were no statistically signicant dierences following pretreatment with metamizole or dexamethasone. After oral adminis, maximum plasma concentrations (Cmax), time of Cmax (tmax), mean tration of OLD alone, the t1 2b absorption time (MAT) and absolute bioavailability (Fabs) were 1.68 h, 5.34 mg/ml, 1.5 h, 1.34 h and 84.29%, respectively. Pretreatment with metamizole caused a signicantly decreased value for Cmax (2.93 mg/ml) but the MAT value (2.23 h) was signicantly increased. Statistically signicant changes in the pharmacokinetic parameters of OLD following oral administration were also observed as a result of pretreatment with dexamethasone. The Cmax was increased (8.24 mg/ml) and the tmax (0.5 h) and MAT (0.45 h) were lower. Keywords: dexamethasone, dog, drug interactions, intravenous, metamizole, oleandomycin, oral, pharmacokinetics Abbreviations: AUC, area under the concentration^time curve; ClB, total body clearance; Cmax, maximum plasma levels; CV, coecient of variation; Fabs%, absolute bioavailability; Fr%, relative bioavailability; im, intramuscular; iv, intravenous; k12 and k21, the distribution rate constants for transferring the drug the from central to the peripheral compartment and back, respectively; kel, elimination rate constant from central compartment; MAT, mean absorption time; MIC, minimal inhibitory concentration in vitro; MRT, mean residence time; NSAIDs, nonsteroidal anti-inammatory , terminal elimination half-life; tmax, time of Cmax; Vd,area, Vc, Vt drugs; o, oral; OLD, oleandomycin; t1 2b and Vss, area volume of distribution, the distribution volume of the central and peripheral compartments and the steady-state volume of distribution, respectively

INTRODUCTION Macrolides are antibiotics widely used in veterinary medicine. Oleandomycin (OLD) belongs to the 14-membered ring group and exhibits the typical properties of this group. It is active against Gram-positive and some Gram-negative microorganisms
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that cause infections in animals (Carli et al., 1984; Pathanasophon et al., 1990). OLD is active against Staphylococcus aureus, Haemophilus pleuropneumoniae, Listeria monocytogenes, Streptococcus spp. (Prescott and Baggot, 1993), Bacillus spp. and Corynebacterium spp. (Le Noc et al., 1989). The pharmacokinetics of macrolides is characterized by good tissue penetration and excretion, mainly in bile, although the urinary route also plays a role in this excretion process (Nouws and Ziv, 1979; Duthu, 1985; Moutafchieva, 1992; Anadon and Reeve-Johnson, 1999). There are reported data on the pharmacokinetics of OLD in mice, rats, dogs, humans (Duthu, 1985), calves (Carli et al., 1984) and birds (Lashev et al., 1999). There are no reported data on the pharmacokinetics of OLD following oral administration in dogs. Nonsteroidal anti-inammatory drugs (NSAIDs), glucocorticoids and antibiotics, including OLD, are frequently used in combination in veterinary medicine. NSAIDs are able to inhibit in vitro metabolism of drugs (Zweers-Zeilmaker, 1997) and some NSAIDs, such as phenylbutazone and indomethacin, alter the pharmacokinetics of aminoglycosides and penicillins (Hekman et al., 1982; Zarn et al., 1985; Firth et al., 1990). Mestorino and colleagues (2000) reported that diclofenac increased the Cmax and prolonged the t1 of intramuscularly administered oxytetracycline in cattle. 2b Metamizole decreased plasma levels of cyclosporin in the rst few hours after drug intake in humans (Zylber-Katz et al., 1999). It is known that dexamethasone induces microsomal enzymes in several mammalian species and may determine the duration of action of many drugs (Anadon et al., 2000). Rollins and colleagues (1972) found that dexamethasone increased the rate of elimination of penicillin in horses. Thus, there are descriptions of changes in the pharmacokinetics of various antibacterial agents after simultaneous administration or pretreatment with anti-inammatory drugs (Scheld and Brodeur, 1983; Balakrishnarao and Narayana, 1990; Whittem et al., 1996; Carsenti-Etesse et al., 1998), but there are no data in the literature on the pharmacokinetics of OLD administered after pretreatment with NSAIDs or glucocorticoids. However, OLD is known to cause much less inhibition of cytochrome P450 activity than troleandomycin (Anadon and Reeve-Johnson, 1999). The present investigation was carried out to study the pharmacokinetics of OLD in dogs after intravenous oral administration. The pharmacokinetics of OLD was also determined in the same species after intramuscular administration of metamizole or dexamethasone. MATERIALS AND METHODS Experimental animals Six crossbred female dogs were used, 1^3 years old and ranging in body weight from 12 to 23 kg. They were shown to be clinically healthy by means of daily observation for 20 days, physical examination, total red cell count and total and dierential white cell counts. Animal care and handling were in accordance with the provisions of the European Community, as adopted by the Bulgarian Government.

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Drug administration and blood sampling The dogs were treated with a single dose of oleandomycin (oleandomycin phosphate, kindly donated by VetProm Bulgaria, 1 mg = 805 UI, as a 5% w/v aqueous solution for oral administration and as a 20% w/v aqueous solution for intravenous injection, prepared immediately before use). The dogs were used in six consecutive experiments. Each experiment was followed by a 10-day washout period. Experiment I. The dogs were treated intravenously with a single dose of OLD at a dose rate of 10 mg/kg. Experiment II. The dogs received a single intramuscular dose of 30 mg/kg metamizole (Analgin, 50% injectable solution, Sopharma, Soa, Bulgaria) and, 30 min later, a single intravenous dose of 10 mg/kg of OLD. Experiment III. The dogs were treated intramuscularly with dexamethasone (dexamethasone, 0.2% injectable solution, Veterin, Greece) given in two doses of 100 mg/kg, 24 h apart. Thirty minutes after the second dose of dexamethasone, an intravenous dose of 10 mg/kg of OLD was given. Experiment IV. The dogs were treated orally with a single dose of OLD at a dose rate of 12.5 mg/kg, after 18 h fasting. Experiment V. The dogs received a single intramuscular dose of 30 mg/kg metamizole and, 30 min later, a single oral dose of 12.5 mg/kg OLD. The dogs had been fasted for 18 h before receiving the OLD. Experiment VI. The dogs were treated intramuscularly with dexamethasone given in two doses of 100 mg/kg, 24 h apart. Thirty minutes after the second injection, an oral dose of 12.5 mg/kg OLD was given. The dogs had been fasted for 18 h before receiving the OLD. OLD was injected intravenously into the cephalic vein. Blood samples were collected from the opposite cephalic vein, using an intravenous catheter (22G, Helm Pharmaceuticals GmbH, Hamburg, Germany). They were collected before each treatment with OLD and at 0.083, 0.25, 0.5, 1, 2, 3, 4, 5, 6 and 7 h after the administration. After oral administration, blood samples were collected from the cephalic vein before each treatment with OLD and at 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10 h thereafter. Drug analysis Plasma concentrations of oleandomycin were determined using Bacillus mycoides HB2 as the test organism. The standard solutions were prepared in plasma obtained from an untreated dog. The concentrations of the standard solutions were 10, 5, 2.5, 1.25, 0.625, 0.312 and 0.15 mg/ml. Assay validation indicated a mean percentage of recovery

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of OLD of 96.99%+7.9%, with an intra-assay CV of 6.66 and an inter-assay CV of 11.06. The response of OLD was linear over the range of concentrations between 0.15 and 10 mg/ml. The relationship between the concentrations and diameters of the measured sterile zones followed the equation y = 10(0.20x^3.45). The linearity (presented as r) was 0.9985. The limit of quantication for plasma was 0.15 mg/ml. According to Lakritz and colleagues (1999), the data obtained from such microbiological assays are comparable with those of high-performance liquid chromatography assays and can provide adequate information regarding the disposition of macrolide antibiotics. Pharmacokinetic analysis The pharmacokinetic parameters were calculated using a computer program (Topt 2.0; Heinzel et al., 1993). Pharmacokinetic analysis was performed using a twocompartment model for the data obtained after intravenous administration. Initial estimates were rened by nonlinear regression and a weighting scheme was utilized for curve tting (weighting by 1/y2 was used, where y is the observed drug concentration at time t). The most appropriate model was chosen according to Akaike's information criterion (Yamaoka et al., 1978). Noncompartmental analysis based on statistical moments theory (Gibaldi and Perrier, 1982) was also performed for the data obtained after intravenous injection and was used to compute MRT, ClB and AUC. A noncompartmental model was also used for the data obtained after oral treatment, the terminal elimination rate constant (b) being computed from the slope of the curve that was linear after Cmax. The AUC was calculated by the method of trapezoids and extrapolation to innity was made. After oral administration, MAT values were calculated as the dierences between the MRT after oral administration and the MRT after intravenous administration. The intravenous maintenance dose was determined from D = Cp,min Vd,area(exp(bt) ^ 1) (1)

(Baggot, 1977), where Cp,min = minimum therapeutic plasma level; b = terminal (elimination) rate constant and t = dosage interval. The oral maintenance dose was determined from Bapp = Pmin (1 ^ exp(^bt)) / exp(^bt) (2)

where Bapp = the value of the coecient based on the terminal exponential phase used for correcting the applied dose according to the desired MIC and dosage interval and Pmin = MIC (Mercer et al., 1977). The absolute bioavailability was calculated from Fabs = (AUCoral DIV / AUCIV Doral) 6 100 (Prescott and Baggot, 1993). (3)

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The relative bioavailability was calculated from Fr = AUCoral coadministration / AUCoral single administration) 6100 (4)

(Rowland and Tozer, 1995). The doses and dose intervals were dened with respect to the desirable values of the MIC for oleandomycin, based upon its pharmacokinetic parameters. Statistical analysis Pharmacokinetic parameters were presented as the median values and range. The statistically signicant dierences between the pharmacokinetic parameters following the single administration of OLD and after pretreatment with metamizole or dexamethasone were determined using the Friedman and Wilcoxon tests, as calculated using the computer program StatisticaTM (Microsoft Corp., StatSoft Inc., USA, 1993). Values of p50.05 were considered signicant. RESULTS The concentrations of OLD in the plasma obtained between 0.083 h and 7 h after intravenous treatments are shown in Figure 1 and the pharmacokinetic parameters in Table I. After a single intravenous injection of OLD, a rapid distribution phase and a slower elimination phase were observed. From the ratio of b to kel, it can be estimated that 50.6% of the OLD was available for elimination from the central compartment in the post-distributional phase (Table I). The value of the ratio Vc/Vss was 0.59. Detectable antibiotic concentrations were still present 10 h after oral administration of OLD alone (Figure 2). When OLD was administered intravenously after pretreatment with metamizole, there were no statistically signicant dierences in the plasma concentrations compared with when antibiotic was given alone (Figure 1). The values of b/kel and Vc/Vss were 0.49 and 0.55, respectively. The pharmacokinetic parameters for OLD were not signicantly inuenced when it was given after metamizole (Table I). After oral administration of the antibiotic following metamizole, the Cmax was signicantly lower than that achieved with the other two treatments (Figure 2). The tmax and MRT values were signicantly increased in comparison to those obtained using the OLD^ dexamethasone combination and MAT values were signicantly increased compared to those obtained with the other two treatments (Table II). After pretreatment with dexamethasone, the plasma OLD levels (Figure 2) and the pharmacokinetic parameters did not dier signicantly from those obtained with intravenous administration of OLD alone or from those obtained with the combination of OLD and metamizole. The value of the ratio b/kel was 0.68 and that of Vc/Vss was 0.77. When OLD was administered orally after dexamethasone pretreatment, the Cmax value was higher than that after either of the other two treatments (p50.05) and

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Figure 1. Mean+SD plasma concentrations of oleandomycin in dogs after the intravenous administration of 10 mg/kg, alone and after intramuscular administration of metamizole (30 mg/kg) or dexamethasone (100 mg/kg)

occurred earlier. Detectable amounts of OLD were no longer present 10 h after treatment (Figure 2). The MAT values were signicantly lower than those after the other two oral administrations of OLD. The values of tmax and MRT were signicantly lower than those obtained after pretreatment with metamizole (Table II). DISCUSSION According to most authors and to our results, the behaviour of OLD after intravenous administration is best described in terms of a two-compartment open model. This model has been reported to characterize the disposition of OLD following intravenous administration in calves (Carli et al., 1984), mice, rats, dogs, humans (Duthu, 1985) and birds (Lashev et al., 1999). The elimination half-life after intravenous administration of OLD in the present study was similar to that reported by Duthu (1985) in Beagle dogs (1.53 h), but the Vss and ClB obtained by that author were higher, 1.6 L/kg and 12 (ml/kg)/min, respectively. The elimination half-life (from 2.38 h in pigeons to 4.85 h in ducks), body clearance (from 57.23 (ml/mg)/min in ducks to 86.00 (ml/kg)/ min in pigeons) and the volume of distribution (Vss, from 9.98 L/kg in chickens to 17.26 L/kg in ducks) in birds were all higher than the parameters found in mammals (Lashev et al., 1999). The data for the pharmacokinetics of OLD in dogs in this study are in accordance with that nding. The relatively high values for Vd,area and Vss

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TABLE I Pharmacokinetic parameters of oleandomycin after a single intravenous (IV) (10 mg/kg) administration alone in dogs (n = 6) and after intramuscular (IM) pretreatment with metamizole (30 mg/kg) or dexamethasone (100 mg/kg) (median values and range) Oleandomycin (IV) 30 min after metamizole (IM) 9.90 (5.63^15.06) 4.08 (1.09^7.30) 0.17 (0.09^0.64) 7.00 (0.84^9.54) 0.40 (0.19^0.48) 1.74 (1.45^3.63) 1.96+0.46 1.63 (0.29^3.47) 1.99 (0.30^3.34) 0.81 (0.69^1.01) 1.29 (0.96^3.95) 0.63 (0.48^1.2) 0.54 (0.41^1.69) 1.15 (0.89^2.89) 2.13 (1.75^2.93) 8.12 (6.54^13.9) 20.6 (12.0^25.48) Oleandomycin (IV) after 2 injections of dexamethasone (IM) 2.57 (0.02^6.54) 5.9 (4.48^15) 0.12 (0.05^0.16) 9.78 (7.75^11.43) 0.42 (0.35^0.63) 1.65 (1.1^1.98) 1.56+0.50 6.02 (1.83^9.59) 4.7 (4.4^8.65) 0.62 (0.36^5.07) 1.03 (0.85^1.20) 0.79 (0.35^1.09) 0.46 (0.22^0.77) 1.03 (0.82^1.12) 2.22 (1.55^2.76) 6.78 (6.27^9.57) 24.58 (17.4^26.57)

Parameters A (mg/ml) a (h^1) t1 (h) 2a B mg/ml) b (h^1) t1 (h) 2b t1 (h)* 2b k12 (h^1) k21 (h^1) kel (h^1) Vd,area (L/kg) Vc (L/kg) Vt (L/kg) Vss (L/kg)

Oleandomycin (IV) 8.59 (6.45^14.66) 5.45 (3.31^6.14) 0.13 (0.11^0.21) 8.43 (5.99^13.24) 0.42 (0.29^0.53) 1.60 (1.32^2.34) 1.63+0.25 1.98 (1.32^2.65) 2.89 (1.52^3.72) 0.83 (0.50^1.00) 1.11 (0.69^1.40) 0.62 (0.36^0.67) 0.42 (0.27^0.56) 1.04 (0.63^1.2)

Noncompartmental analysis MRT (h) 2.11 (1.67^3.17) 7.36 (5.41^9.17) ClB ((ml/kg)/min) AUC (mg h/ml) 21.66 (18.2^39.8)
*Harmonic mean presented as mean+SD

A, zero-time concentration intercept of the distribution curve; B, zero-time concentration intercept of the elimination curve; a, hybrid rate constant for the distribution phase; b, hybrid rate constant for the elimination phase; kel, overall rate constant for drug elimination; k12, the distribution rate constants for transferring the drug from the central to the peripheral compartment; k21, the distribution rate constants for transferring the drug from the peripheral to the central compartment; ta, distribution phase half-life , elimination phase half-life time; AUC, area under the concentration^time curve; Vd,area, Vc, Vt, time; t1 2b Vss, area volume of distribution, volume of the central and the peripheral compartment, volume of distribution at steady state respectively; MRT, mean residence time; ClB, total body clearance

suggest good distribution in the body. The values for Vc/Vss and b/kel allow us to conclude that the almost half of the OLD tends to remain within the central compartment. The elimination half-life of OLD after oral administration to dogs was close to that calculated after intravenous administration, suggesting that this parameter is not dependent on the route of administration. The same situation occurred in chickens, where t1 was 2.66 h after intravenous injection of OLD, while after oral administration 2b

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Figure 2. Mean+SD plasma concentrations of oleandomycin in dogs after the oral administration of 10 mg/kg, alone and after intramuscular administration of metamizole (30 mg/kg) or dexamethasone (100 mg/kg). *At 0.5 h statistically signicant dierences between OLD+dexamethasone and the two other groups; at 2 h statistically signicant dierences between all groups

it was 2.19 h, but in pigeons after oral administration of OLD t1 was longer (6.16 h) 2b (Lashev et al., 1999). Relatively high values for MAT and tmax indicate that absorption is not very rapid. The high value of Fabs suggests good absorption of OLD after oral administration in dogs. A lower degree of absorption of between 37.7% and 57.7% was determined in birds (Lashev et al., 1999). Following intravenous administration of OLD after metamizole, the antibiotic was distributed nearly equally in the two compartments, as shown by the values of Vc/Vss and b/kel. However, in view of the lack of signicant changes in the pharmacokinetic parameters, we conclude that metamizole did not modify behaviour of OLD. When OLD was administered orally after pretreatment with metamizole, the Cmax of the antibiotic was reduced. Metamizole causes a similar change with cylastatin (Zylber-Katz et al., 1999). The signicantly higher MAT indicates slower absorption of OLD compared to the controls. The Fr value of less than 100% and the lower AUC value suggest that metamizole decreases absorption of OLD compared to oral administration of OLD alone. When OLD was injected intravenously after pretreatment with dexamethasone, the ratios Vc/Vss and b/kel indicated that most of the antibiotic tended to remain within the central compartment. Despite that dierence, the pharmacokinetics of OLD were not changed signicantly by the dexamethasone. In contrast to our results, Rollins and

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TABLE II Pharmacokinetic parameters of oleandomycin after oral (O) (12.5 mg/kg) administration alone in dogs (n = 6) and after intramuscular (IM) pretreatment with metamizole (30 mg/kg) or dexamethasone (100 mg/kg) (median values and range) Oleandomycin (O) 30 min after metamizole (IM) 0.31 (0.20^0.36) 2.23 (1.91^3.55) 2.29+0.21 2.0 (0.5^3)c 2.93 (2.42^5.61)ac 4.13 (2.91^6.53)c 2.23 (1.86^4.43)ac 15.95 (12.27^26.2) 6.16 (4.4^12) 67.11 (50.65^98.39) 72.81 (64.68^82.01) Oleandomycin (O) after 2 injections of dexamethasone (IM) 0.40 (0.35^0.41) 1.73 (1.68^1.99) 1.78+0.13 0.5 (0.5^1)ab 8.24 (5.84^15.8)ab 2.7 (2.53^3.05)b 0.45 (0.14^1.15)ab 19.65 (16.58^46.49) 8.40 (6.33^19) 74.17 (57.62^139.9) 101.89 (79.74^135.71)

Parameters b' (h^1) t1 (h) 2b t1 (h)* b 2 tmax (h) Cmax (mg/ml) MRT (h) MAT (h) AUC (mg h/ml) C0 (mg/ml) Fabs (%) Fr (%)

Oleandomycin (O) 0.41 (0.29^0.49) 1.68 (1.43^2.32) 1.70+0.17 1.5 (1^2) 5.34 (3.9^10.6)bc 3.14 (2.71^3.58) 1.34 (0.69^1.91)bc 22.89 (17.5^37.07) 12.35 (5.37^23.6) 84.29 (45.75^92.94)

*Harmonic mean presented as mean+SD

a

Statistically signicant dierence at p50.05 level compared to OLD Statistically signicant dierence at p50.05 level compared to OLD and metamizole

b c

Statistically signicant dierence at p50.05 level compared to OLD and dexamethasone

, elimination half-life; MRT, mean residence time; MAT, mean absorption b', elimination rate constant; t1 2b time; AUC, area under the concentration^time curve; C0, extrapolated zero-time plasma concentration of the elimination phase; Cmax, peak drug concentration; tmax, time of Cmax; Fabs%, absolute bioavailability; Fr%, relative bioavailability from AUC values

colleagues (1972) found that dexamethasone increased the elimination of penicillin from horses. This suggests that there are dierences in drug interactions when dexamethasone is administered with dierent antibiotics. The lower values of tmax and MAT, and the higher value of Cmax, suggest that, in the presence of dexamethasone, OLD was absorbed faster and reached higher maximum plasma concentrations than in the other two treatments. The Fr of close to 100% indicates that dexamethasone does not change the extent of the absorption of OLD. The clinical indications for OLD include S. aureus (MIC 0.2^0.39 mg/ml), H. pleuropneumoniae (MIC 0.2 mg/ml), L. monocytogenes (MIC 1.6 mg/ml), Streptococcus spp. (MIC 0.25 mg/ml), Bacillus spp., Corynebacterium spp. (MIC 1 mg/ml) and others. Thus, the MIC eective against the above microorganisms ranges from 0.2 to 1 mg/ml (Prescott and Baggot, 1993; Le Noc et al., 1989). Because OLD is a bacteriostatic antibiotic, it is necessary to seek to exceed the MIC for the infecting organism continually when determining the dosage regimens that will provide eective treatment

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(Prescott and Baggot, 1993). The methods used to calculate the dosage regime from the pharmacokinetic parameters determined in this study allowed the conclusion that the maintenance dose following intravenous administration of OLD alone that is necessary to provide an MIC of over 1 mg/ml for 6 h is 12.7 mg/kg. The pharmacokinetic parameters determined after coadministration with metamizole or dexamethasone showed that it is not necessary to change the dosage regimen to obtain plasma levels of OLD for 6 h similar to those reached after its application alone. After oral administration of OLD, the calculated dose necessary to provide an MIC of over 1 mg/ml for 6 h was 10.84 mg/kg. The dose used by us (12.5 mg/kg) provides an MIC of over 1.15 mg/ml for the same time. Again, the pharmacokinetic parameters derived after oral administration of OLD and metamizole in dogs showed that the dose of OLD necessary to provide an MIC of over 1 mg/ml should be the same as after its administration alone, as should be the dose interval. However, the pharmacokinetic parameters after oral application of OLD and dexamethasone in dogs showed that the dose of OLD necessary to provide plasma concentrations similar to those following its application alone, and above 1 mg/ml, should be increased to 15 mg/kg. REFERENCES
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