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Induction of systemic TH1-like innate immunity in normal volunteers following subcutaneous but not intravenous administration of CPG 7909, a synthetic B-class CpG oligodeoxynucleotide TLR9 agonist.

Subcutaneous injection of normal human volunteers with a B-class CpG oligodeoxynucleotide (ODN) TLR9 agonist, CPG 7909, induced a TH1-like pattern of systemic innate immune activation manifested by expression of IL-6, IL-12p40, IFN-alpha, and IFN-inducible chemokines. Serum IP-10 was found to be the most sensitive assay for subcutaneous CPG 7909 stimulation; its level was significantly increased in all subjects at all dose levels, including the lowest tested dose of just 0.0025 mg/kg. This pattern of chemokine and cytokine induction was markedly different from that previously reported to be induced by TLR9 stimulation in rodents, most likely reflecting species-specific differences in the cell types expressing TLR9. Subcutaneous CPG 7909 injection induced transient shifts in blood neutrophils, lymphocytes, and monocytes, consistent with the increased chemokine expression. Levels of acute phase reactants such as C-reactive protein were also increased. A second subcutaneous CPG 7909 injection administered 2 weeks after the first elicited similar immune responses, showing little or no tolerance to the effects of repeated in vivo TLR9 stimulation. Subjects developed dose-dependent transient injection site reactions and flu-like symptoms but otherwise tolerated injection well, with no evidence of organ toxicity or systemic autoimmunity. The activation of innate immunity was dependent on the route of ODN administration, since intravenous injection caused no such effects. These studies indicate that in vivo activation of TLR9 by subcutaneous administration of CPG 7909 could be a well-tolerated immunotherapeutic approach for induction of TH1 innate immune activation.

Autoimmunity↗

Pharmacokinetics of phenylethylmalonamide (PEMA) after oral and intravenous administration.

The pharmacokinetics of phenylethylmalonamide (PEMA), one of the major metabolites of the antiepileptic drug primidone, have been studied in 6 healthy volunteers after administration of single 500mg intravenous and oral doses. Following intravenous administration, after a very short distributive phase (t1/2 = 0.23-0.53h), the decline of the log-PEMA concentration with respect to time appeared linear. The pharmacokinetic parameters, calculated according to a 1-compartment open model, showed the following values (mean +/- SD): terminal half-life, 15.7 +/- 3.4h; apparent volume of distribution, 0.69 +/- 0.10 L/kg; total serum clearance, 31.3 +/- 6.6 ml/h/kg. After oral administration, peak serum concentrations occurred at 0.5 to 4 hours and the oral bioavailability was 86.4 to 95.9%.

Administration, Oral↗

Subcutaneous administration of amifostine (ethyol) is equivalent to intravenous administration in a rat mucositis model.

PURPOSE: Amifostine (Ethyol) is currently approved for intravenous (IV) administration to prevent xerostomia in patients receiving radiotherapy for head-and-neck cancer. Recently, subcutaneous (SC) administration has been explored as an alternative route. To determine whether SC administration was equivalent to IV administration, we used models to follow pharmacokinetics and oral mucosal protection in rats. METHODS: Amifostine was administered to rats at doses of 200, 100, or 50 mg/kg (1300, 650, or 325 mg/m(2)) IV or SC at various times before radiation at 15.3 Gy (protection studies) or harvest of blood and tissues for analysis by HPLC (pharmacokinetic studies). RESULTS: Amifostine administered IV or SC 1 h before radiation protected rats from mucositis, but the protective effect was more prolonged when amifostine was administered SC. Tissue levels of the active metabolite (WR-1065) were equivalent after SC administration. The correlation between tissue levels of WR-1065 and protection was strong, but that between blood levels of WR-1065 and protection was only weak. CONCLUSION: These data demonstrate that, in a rat model, SC administration of amifostine was at least as effective as that by IV.

Amifostine↗

Improvement in human decay accelerating factor transgenic porcine kidney xenograft rejection with intravenous administration of gas914, a polymeric form of alphaGAL.

BACKGROUND: The present study was undertaken to determine whether intravenous administration of GAS914, a polymeric form of alphaGal, would minimize porcine kidney xenograft rejection in baboons. Human decay accelerating factor renal xenografts were transplanted into 16 baboon recipients. METHODS: Baseline immunosuppression for all groups included cyclosporine A, cyclophosphamide, SDZ-RAD, and methylprednisolone. Group 1 received only baseline immunosuppression; group 2 animals received low-dose GAS914 with baseline immunosuppression; group 3 animals received high dose GAS914 with high-dose baseline immunosuppression; and animals from group 4 received high-dose GAS914 and low-dose baseline immunosuppression. RESULTS: None of the animals in this study developed hyperacute rejection. Intravenous administration of GAS914 significantly reduced xenoreactive antibodies as measured by antiporcine hemolytic assays and anti-Gal (immunoglobulin [Ig] G and IgM) antibody assays. Rejection was less severe in the GAS914-treated group. Only 25% (3 of 12) of GAS914-treated animals were killed as a result of rejection, whereas 75% (three of four) of non-GAS914-treated animals were killed because of terminal rejection (P<0.01). Protocol biopsies demonstrated that the degree of acute humoral xenograft rejection (AHXR) was reduced in the GAS914-treated animals compared with non-GAS914-treated animals. CONCLUSION: The intravenous administration of GAS914 reduces xenoreactive antibody levels and reduces the degree of porcine kidney xenograft rejection, but does not improve survival. AHXR and drug toxicity remain major barriers to the long-term success of xenotransplantation.

Adrenal Cortex Hormones↗

Plasma concentrations after intravenous administration of phylloquinone (vitamin K(1)) in preterm and sick neonates.

Vitamin K prophylaxis usually is administered orally or intramuscularly, but in neonatal intensive care oral administration might not be feasible and intramuscular administration is not general practice in very small infants. No data are available about plasma levels after intravenous administration of vitamin K to neonates. Therefore, we investigated plasma levels in 18 infants: 14 preterms with a birthweight of 1785+/-648 g and 4 sick newborns with a birth-weight of 3167+/-510 g after administration of a single dose of 0.3+/-0.1 mg/kg phylloquinone (vitamin K(1)) (Konakion MM((R)), Roche) intravenously after birth. Blood was collected 22.9+/-18.4 hours after intravenous administration of vitamin K(1). In 10 neonates a second sample was obtained 111.8+/-49.1 hours after the first vitamin K(1) administration. Gas chromatography-mass spectrometry (GC-MS) was used as the method for determination of vitamin K(1). The measured plasma concentration after intravenous administration of vitamin K(1) was 191.3+/-102.6 ng vitamin K in the first sample /mL in the first sample and 98.7+/-75.2 ng vitamin K(1)/mL in the second samples. These results are similar to those described in newborns after oral administration of 3 mg vitamin K(1) and after intramuscular administration of 1.5 mg vitamin K(1). In conclusion, the recommendation of the producer to give 0.4 mg/kg of vitamin K intravenously to neonates, in whom oral or intramuscular administration is not feasible, seems to be rational.

Female↗

Ocular and serum disposition kinetics of cloxacillin after topical administration of benzathine cloxacillin and intravenous administration of sodium cloxacillin to calves.

Disposition kinetics of cloxacillin were examined in calves after topical administration of benzathine cloxacillin and single IV administration of sodium cloxacillin, and the susceptibility of 17 field isolates of Moraxella bovis was measured. For the IV pharmacokinetic phase, sodium cloxacillin was administered at dosage of 10 mg/kg of body weight to male Holstein calves (n = 6, weighing 146 to 170 kg), and serum concentration of cloxacillin was measured thereafter for 10 hours. For the ocular pharmacokinetic phase, 6 calves were given either of 4 benzathine cloxacillin topical formulations consisting of 50-, 125-, 250-, or 375-mg doses. Treatment was repeated every 10 days until all 4 benzathine cloxacillin dosages were tested in the same 6 calves. Blood and tears were collected for 72 hours after each benzathine cloxacillin formulation was administered, and the concentration of cloxacillin in each specimen was measured, using a bioassay. The minimal inhibitory concentration of cloxacillin for 17 field isolates of M bovis was determined by use of an agar pour-plate dilution assay. After single IV administration of sodium cloxacillin, its half-life, body clearance, and volume of distribution were 19.5 +/- 12.8 minutes, 18.3 +/- 2.2 ml/min.kg, and 496 +/- 290 ml/kg, respectively. After topical administration of benzathine cloxacillin, cloxacillin concentration in lacrimal fluid peaked between 30 and 45 minutes and ranged between 963 micrograms/ml and 3,256 micrograms/ml for the 125- and 375-mg doses, respectively. There was no detectable cloxacillin activity in the lacrimal fluid of any calf by 36 hours after topical administration of benzathine cloxacillin, and cloxacillin was not detected in the serum at any time.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Topical↗

Metabolism and disposition of naltrexone in man after oral and intravenous administration.

The metabolism and elimination of [15, 16,-3H2]naltrexone was studied in man after oral and intravenous administration. The same metabolites, although in varying proportions, were observed in both cases; conjugated naltrexone and conjugated and unconjugated 6 beta-naltrexol were the major metabolites observed in plasma, urine, and feces. 2-Hydroxy-3-O-methyl-6 beta-naltrexol was found in minor quantities. Naltrexone was almost completely absorbed after oral administration. After oral and intravenous administration of naltrexone, about 60% of the dose was recovered in the urine in 48 and 72 hr, respectively. The route of administration did not significantly affect urinary clearance values obtained for unconjugated or conjugated naltrexone and 6 beta-naltrexol. The route of administration significantly affected terminal plasma half-life values obtained for unconjugated naltrexone (2.7 hr, iv; 8.9 hr, oral), but had little effect on comparable values obtained for total drug, conjugated naltrexone, and unconjugated and conjugated 6 beta-naltrexol. Combined gas chromatography-mass spectrometry was used to validate the presence of naltrexone, 6 beta-naltrexol, and 2-hydroxy-3-O-methyl-6 beta-naltrexol in urine.

Administration, Oral↗

Metabolic coronary-flow regulation and exogenous nitric oxide in human coronary artery disease: assessment by intravenous administration of nitroglycerin.

We sought to evaluate the effect of intravenous administration of the nitric oxide--donor substance nitroglycerin (NTG) on metabolic coronary-flow regulation in patients with coronary artery disease (CAD). In 12 patients with stable CAD, we measured coronary sinus blood flow and myocardial oxygen supply and consumption (MVO2) at sinus rhythm and during atrial pacing (30 beats/min above sinus rate), both at control and during infusion of NTG, 1 microg/kg/min, and NTG, 2 microg/kg/min. To study metabolic coronary vasodilation, changes in myocardial oxygen supply were related to pacing-induced changes in MVO2, by using standard regression analysis. The myocardial oxygen supply/consumption ratio (i.e., the slope of the regression line at control, characterizing physiological metabolic coronary flow regulation) was compared with the ratios obtained during infusion of NTG. Compared with control measurements, NTG, 1 microg/kg/min, and NTG, 2 microg/kg/min, attenuated pacing-induced increases in MVO2 by 29 and 60%, respectively, whereas coronary blood flow during pacing remained unchanged. At control, normal metabolic coronary-flow regulation resulted in a myocardial oxygen supply/demand ratio of 1.39 (95% CI, 1.29-1.49). This ratio did not change during NTG, 1 microg/kg/min: 1.44 (95% CI, 1.33-1.56). However, during NTG, 2 microg/kg/min, this ratio significantly increased to 1.84 (95% CI, 1.63-2.05; p<0.01). Intravenous administration of high-dose NTG, a donor of exogenous NO, blunts pacing-induced increases in MVO2 and may increase metabolic coronary vasodilation in patients with CAD.

Aged↗

Reduction of Myocardial Necrosis After Glycosaminoglycan Administration: Effects of a Single Intravenous Administration of Heparin or N-Acetylheparin 2 Hours Before Regional Ischemia and Reperfusion.

BACKGROUND: We determined if a single administration of heparin or nonanticoagulant N-acetylheparin could reduce myocardial injury resulting from a 90-minute occlusion of the left circumflex coronary artery (LCX) and 6 hours of reperfusion in the anesthetized canine. METHODS AND RESULTS: Heparin (2 mg/kg), N-acetylheparin (2 mg/kg), or vehicle, 0.9% sodium chloride (control), was administered intravenously to separate groups of animals 2 hours before LCX occlusion. To ensure parity of LCX ischemia, only animals with ischemic zone regional blood flow < 0.16 mL/min/g tissue were included in the final analysis. Hemodynamics did not differ among the three study groups. Infarct size as a percentage of the left ventricular area at risk was obtained for each group. Myocardial infarct size was 43.0 +/- 3.9% in the vehicle, 28.8 +/- 5.8% in the heparin (P <.05 vs vehicle) and 24.7 +/- 4.6% (P <.05 vs vehicle) in the N-acetylheparin-treated animals. CONCLUSIONS: Pretreatment with heparin or its nonanticoagulant derivative, N-acetylheparin, provides significant protection to the regionally ischemic and reperfused canine myocardium independent of either plasma glycosaminoglycan concentration or alterations in the coagulation system.

Journal Article↗

Perfluoroctylbromide. Acute hemodynamic effects, in pigs, of intravenous administration compared with the standard ionic contrast media.

Perfluoroctylbromide (PFOB) is a relatively new noniodinated contrast media that, after intravenous administration, produces prolonged opacification of the blood pool and subsequently selectively enhances the liver and spleen on computed tomography. There has been concern regarding the hemodynamic effect of this agent but little actual knowledge exists in this regard. Accordingly, the acute transient hemodynamic effects of PFOB emulsion were evaluated in five pigs and compared with the standard ionic contrast agent meglumine sodium diatrizoate (Renografin-76). Left ventricular (LV) pressure, internal diameter, and wall thickness were monitored during the alternate intravenous administration of 930 mg/ml PFOB and 370 mg/ml R-76 at a rate of 20 mls/second for a total volume of 1 ml/kg body weight. Renografin-76 caused a significant decrease in LV pressure and dp/dt (rate of change of LV pressure), and an increase in LV end-systolic diameter and a decrease in LV end-diastolic wall thickness. PFOB caused no change in LV pressure and dimensions. Thus, rapid intravenous administration of PFOB does not induce significant acute alterations in left ventricular pressure, dp/dt, dimension, or wall thickness.

Animals↗

Pharmacokinetics of nicardipine following oral and intravenous administration in man.

The pharmacokinetics of nicardipine have been studied following oral and intravenous administration in man and the effects of food on nicardipine kinetics investigated. Following intravenous administration of nicardipine as an infusion plasma levels declined in a biphasic manner and plasma clearance values were of the same order as hepatic plasma flow. Following oral administration in the starved state nicardipine was rapidly absorbed but subject to presystemic elimination. Maximal plasma concentrations were achieved typically between 20 minutes and 2 hours after administration. The oral bioavailability of nicardipine determined by reference to a co-administered intravenous radiolabelled dose was found to be non-linearly related to dose. Bioavailability ranged from 15-45% approximately over the dose range 10-40 mg. Administration of nicardipine following a meal reduced the bioavailability of nicardipine.

Administration, Oral↗

Pulmonary edema and emphysema in cattle after intraruminal and intravenous administration of 3-methylindole.

Intraruminal and intravenous administration of 3-methylindole (3MI; skatole) caused interstitial pulmonary edema and emphysema in cattle. In 3 adult heifers given the intraruminal dose of 0.2 g of 3 MI per kilogram of body weight, clinical signs of respiratory disease appeared between 6 and 12 hours after dosing, and death due to pulmonary edema and emphysema occurred at 33, 69, and 72 hours. The mean plasma concentration of 3MI became maximal (18.5 mug/ml) at 3 hours and then decreased to low concentrations by 48 hours. In 2 heifers given an intraruminal dose of 0.1 g of 3MI/kg, clinical signs developed, but they did not die during the 96-hour experiment. The mean plasma concentration of 3 MI became maximal (16.8 mug/ml) at 3 hours and decreased to 1.6 and 0.4 mug/ml at 12 and 36 hours, respectively. At necropsy of the heifers, the lung were large, firm, dark red, and heavier than normal. Diffuse pulmonary edema was the predominant change in cattle which died early, and interstitial emphysema was more severe at later stages of the disease. During the early stages, alveoli were overdistended, and a few more ruptured. Most alveolar spaces were filled with proteinaceous residue, but the alveolar septums were smooth and of normal thickness. At later stages, proliferation of alveolar cells was observed, and alveolar septums were thickened. In 3 cows given 0.06 g of 3MI/kg by jugular infusion, clinical signs appeared in all cows, and 1 cow died of pulmonary edema and emphysema 56 hours after the infusion was started. Severe pulmonary lesions seen in all of the cows given a 3MI infusion were similar to those in the cows given an intraruminal dose of 3MI. The mean plasma concentration of 3MI increased to 10.7 mug/ml at 9 hours after starting the infusion and decreased to 0.5 mug/ml at 18 hours. The results indicate that 3MI, a product of ruminal tryptophan fermentation, can cause pulmonary edema and interstitial emphysema in cattle and support the hypothesis that 3MI is the causative agent in tryptophan-induced pulmonary disease.

Administration, Oral↗

[Liver concentration of CPT-11, SN-38 and SN-38 GLU in intraperitoneal and intravenous administration of CPT-11].

Our previous mouse experiment showed intraperitoneal administration of CPT-11 was more effective not only for peritoneal seeding but for liver metastases than intravenous administration of CPT-11. We studied tissue concentrations of the liver when CPT-11 was administered intraperitoneally or intravenously for ICR mice. Mice liver was resected at 15 min, 1, 2, 4, 8 and 26 hours after intraperitoneal or intravenous administration of 40 mg/kg CPT-11. CPT-11, SN-38 and SN-38 GLU were measured with HPLC. The liver concentration of CPT-11 at 15 min after intravenous administration was higher than after intraperitoneal administration. A higher liver CPT-11 concentration was prolonged in the intraperitoneal administration group. No differences were demonstrated in the concentrations of SN-38 and SN-38 GLU between i.p. and i.v. groups.

Animals↗