Acrylic microspheres in vivo VI: antitumor effect of microparticles with immobilized L-asparaginase against 6C3HED lymphoma

The antitumor effect of immobilized L-asparaginase was tested against lymphoid leukemia in mice with concomitant scanning of the L-asparagine level in serum. L-Asparaginase was immobilized in microspheres of polyacrylamide or polyacryldextran. These particles were used in C3H mice bearing the L-asparagine-dependent lymphoma (6C3HED). The tumor was maintained as an ascites tumor, 1 X 10(6) cells were injected intraperitoneally and on day 4 after inoculation, L-asparaginase was injected intramuscularly or intraperitoneally in microparticles. After injection of 5.0 IU ip of L-asparaginase in microparticles, partial remission was induced, generally, however, the cancer relapsed and killed the mice within 2-3 weeks. To obtain complete regression, it was necessary to inject 20 IU of L-asparaginase in microparticles intraperitoneally. The best therapeutic effect was obtained when the particles were administered intramuscularly. After injection of 5 IU the survival time was prolonged, but complete regression was not achieved. The best effect was obtained when the particles were given intramuscularly in two small doses (2.5 IU) at a 3-day interval. Such treatment induced complete regression; 10 out of 12 treated mice were completely cured and lived for several months. It is concluded that the L-asparagine level in serum has to be depressed to less than 20% of the normal level for at least 6-7 days to obtain complete regression of the tumor.     

Influence of administration route and treatment duration on the glucoregulatory effects of sex steroids in female mice

Glucose tolerance and plasma insulin concentrations were determined in intact female mice treated orally, subcutaneously and intramuscularly for 4 and 24 days with estradiol-17 beta (5 micrograms/kg/day), ethinyl estradiol (5 micrograms/kg/day) and progesterone (1 mg/kg/day). Estradiol-17 beta improved glucose tolerance and raised plasma insulin concentrations. These effects were generally greater after the longer treatment period and the s.c. administration route produced the greatest improvement in glucose tolerance with the smallest increase in plasma insulin. Ethinyl estradiol produced qualitatively similar effects to estradiol-17 beta, but quantitatively smaller. Progesterone raised plasma insulin concentrations after the longer treatment period, notably with oral and intramuscular administration, although glucose tolerance was not significantly altered. The results demonstrate the important influence of administration route and treatment duration on the changes in glucose homeostasis induced by sex steroids.     

Antimicrobial properties of mannopeptins.

Mannopeptins show in vitro antimicrobial activity against gram-positive and some gram-negative bacteria. The antimicrobial activity is unaffected by the addition of serum, and potentiated by alkaline pH or decrease in inoculum size. The antibiotics exert bectericidal effect at doses twice as high as the minimum inhibitory concentration. When the antibiotics were injected into mice through either intravenous, intraperitoneal, intramuscular or subcutaneous routes, the antimicrobial activity appeared within 15 minutes in the serum of mice and was slowly excreted in the urine. However, the antibiotics were poorly absorbed by the oral route. The antibiotics were capable of protecting mice from lethal infection produced by the intravenous injection of Staphylococcus aureus, Streptococcus pyogenes and the intraperitoneal injection of Shigella sp. and Escherichia coli, but ineffective against Salmonella typhosa.     

The parenteral controlled release of liposome encapsulated chloroquine in mice

Free (0.6 mg), and liposome encapsulated chloroquine (0.6, 3 mg), were injected intraperitoneally, intramuscularly and subcutaneously in mice. Intraperitoneal administration of liposome-encapsulated chloroquine resulted in high and long lasting concentrations of chloroquine in the blood compared with intraperitoneal administration of free chloroquine. After administration of the liposome-encapsulated chloroquine the concentrations in the spleen were also higher, indicating that chloroquine liposomes reached the blood compartment intact after intraperitoneal administration. After intramuscular and subcutaneous administration the chloroquine liposomes acted as a local depot, giving a slower release from the subcutaneous fat layer than from the muscle depot. After the 0.6 mg dose a burst effect was found at about 7 h in most of the animals; this was not found after the 3 mg dose. This finding and the slower release after the 3 mg dose than after the 0.6 mg dose could be explained by the formation of aggregates after the injection.     

Pharmacokinetics of recombinant human erythropoietin in chronic haemodialysis patients

Single dose intravenous and subcutaneous pharmacokinetics of recombinant human erythropoietin (rhEPO) has been determined in 6 chronic haemodialysis patients. Four patients, all on maintenance therapy with rhEPO, were consecutively treated both intravenously and subcutaneously with injections of rhEPO in a dose of 50 U/kg. Two previously untreated patients received 150 U/kg of rhEPO intravenously and subcutaneously. After intravenous injection of 50 U/kg of rhEPO a mean serum half-life value of 5.4 +/- 0.9 hr was found. The corresponding half-life after injection of 150 U/kg was 7.6 hr. The peak concentration of serum EPO after subcutaneous injection was 12.5-20 times lower than the corresponding intravenous Cmax. After administration of 150 U/kg subcutaneously the absorption of EPO was monitored to completion at 120 hr. The complete bioavailability of subcutaneous rhEPO after injection of 150 U/kg was 31.7%. Whether this low and protracted subcutaneous absorption of rhEPO is accounted for by either impeded absorption or partial skin degradation of rhEPO is not known.     

几种药物不同部位与不同途径给药对动物LD50的影响

盐酸普魯卡因与硫酸阿託品注射于小白鼠前肢腕部內側正中线深部时其LD₅₀值显著低于同一药物后肢肌內或背部皮下注射.氰化钾注射于小白鼠或大白鼠的上述部位其毒性显著低于后肢肌内注射与背部皮下注射.亚硝酸钠LD₅₀值于小白鼠中未見有上述的差别。实驗論証上述毒性差別主要不是因药物自注射部位吸收差別所致。盐酸普魯卡因不論肌內或腕內侧正中线深部注射都能有效地減低氰化鉀的毒性。大白鼠一側臂神經纵切除后一周,再注射氰化鉀于此側的腕內侧正中线深部,其毒性即显著低于正常动物同部位的給药組,故认为氰化鉀毒性的发生可能与神經机制有关。     

COMPARATIVE HAEMODYNAMIC EFFECTS OF CLONIDINE ADMINISTERED INTRAMUSCULARLY OR INTRAVENOUSLY TO ANAESTHETIZED RATS

1. The acute haemodynamic effects of clonidine, 0.001-1.0 mg/kg, administered intramuscularly or intravenously, were studied in anaesthetized rats. 2. The direct pressor potency of clonidine was 100-fold greater following intravenous administration than after intramuscular injection, but hypotensive efficacy was equal by either route.     

Pharmacokinetics of clodronate after single intravenous, intramuscular and subcutaneous injections in rats.

The pharmacokinetics of clodronate was studied in rats after single intravenous, intramuscular and subcutaneous doses of a mixture of unlabelled and 14C-labelled disodium clodronate (25 mg/5 muCi/kg). The peak clodronate concentration in plasma was reached within 5 min., and the drug was eliminated with a half-life of about 1.5 hr regardless of administration route. Bioavailabilities after intramuscular and subcutaneous administration were 105% and 89%, respectively. During the 72 hr collection period, the mean share of clodronate recovered from the urine was about 53% of the dose regardless of administration route. Most of the drug was excreted during the first 24 hr. The amount of clodronate in bone (femur) was 186 micrograms/g tissue at 2 hr after intravenous administration, 188 micrograms/g after intramuscular administration and 157 micrograms/g after subcutaneous administration. It is concluded that absorption of clodronate after intramuscular and subcutaneous administration is rapid and good, and that the concentrations of the drug in bone after 2 hr are about the same as after intravenous administration.     

Pharmacokinetics of Clodronate after Single Intravenous,Intramuscular and Subcutaneous Injections in Rats

Abstract: The pharmacokinetics of clodronate was studied in rats after single intravenous, intramuscular and subcutaneous doses of a mixture of unlabelled and ¹⁴C-labelled disodium clodronate (25 mg/5 μCi/kg). The peak clodronate concentration in plasma was reached within 5 min., and the drug was eliminated with a half-life of about 1.5 hr regardless of administration route. Bioavailabilities after intramuscular and subcutaneous administration were 105% and 89%, respectively. During the 72 hr collection period, the mean share of clodronate recovered from the urine was about 53% of the dose regardless of administration route. Most of the drug was excreted during the first 24 hr. The amount of clodronate in bone (femur) was 186 μg/g tissue at 2 hr after intravenous administration, 188 μg/g after intramuscular administration and 157 μg/g after subcutaneous administration. It is concluded that absorption of clodronate after intramuscular and subcutaneous administration is rapid and good, and that the concentrations of the drug in bone after 2 hr are about the same as after intravenous administration.     

The pharmacokinetics of intravenous,intramuscular, and subcutaneous nalbuphine in healthy subjects

Summary The pharmacokinetics of intravenously, intramuscularly, and subcutaneously administered nalbuphine were studied in three parallel groups of 12 healthy volunteers each. The subjects received single doses of 10 mg and 20 mg of nalbuphine separated by a one week washout period. Blood specimens were obtained up to 15 h after dosing for determination of nalbuphine.Mean plasma nalbuphine concentrations 5 min after intravenous administration of 10 or 20 mg were 39 and 73 ng/ml, respectively. The mean maximum plasma concentrations (C_max) after intramuscular or subcutaneous administration of nalbuphine 10 mg were 29 and 31 ng/ml, respectively. Mean C_max values after 20 mg doses were 60 and 56 ng/ml. Mean C_max occurred 30 to 40 min after nalbuphine administration. The mean elimination half-lives of parenterally administered nalbuphine ranged between 2.2 and 2.6 h, regardless of dose given or route administered. The mean absolute bioavailability was 81% and 83% for the 10 and 20 mg intramuscular doses, respectively, and 79% and 76% following 10 and 20 mg of subcutaneous nalbuphine. The mean volumes of distribution (V_ss) of the intravenously administered drug were 290 and 274 l and the mean systemic clearances were 1.6 and 1.5 l/min following administration of 10 and 20 mg doses, respectively.Intramuscular and subcutaneous nalbuphine appear to be interchangeable based on the similarities in C_max, mean times until maximum concentration, mean AUC data, and absolute bioavailabilities.     

A phase I study on intravenous drip infusion of astromicin

A phase I study on intravenous drip infusion of astromicin (ASTM, KW-1070), an aminoglycoside antibiotic, was performed on 9 healthy adult male volunteers to investigate the safety and pharmacokinetics of this drug. ASTM 200 mg was dissolved in 250 ml of saline and given to each of 6 volunteers by drip infusion in 1 hour. For comparison, 200 mg of ASTM in 1 ml of saline was injected intramuscularly. No subjective and objective reactions were found, and laboratory test value did not show any change possibly caused by ASTM. In a single administration study, Cmax was 10.8 micrograms/ml by intramuscular injection and 12.0 micrograms/ml by intravenous drip infusion. The areas under the time-serum concentration curve were 35.6 micrograms X hr/ml and 34.9 micrograms X hr/ml, respectively; that is, the serum levels of ASTM after one-hour intravenous drip infusion changed almost identically to those after intramuscular injection. In a multiple administration study, the change in serum levels of ASTM after the ninth administration was approximately the same as that after the first one. This means that no accumulation of ASTM in serum occurred. Recovery rates of ASTM in urine up to 8 hours after a single intramuscular injection and a single intravenous drip infusion were 85.4% and 87.5%, respectively. These results also support the conclusion that there is no accumulation of ASTM in the body by repeated administrations.     

Evidence based route of administration of vaccines

Vaccination is a proven public health initiative, however it is imperative in the context of increasing concerns about vaccine induced adverse reactions and a decreasing incidence of diseases they prevent that the optimal route for their administration is defined. Traditionally all vaccines were given by subcutaneous injection until it was recognized that adjuvanted vaccines given via this route induced an unacceptable rate of injection site reaction. Evidence-based medicine has been championed as a way of improving the quality of patient care. Application of this methodology to the route of administration of vaccines demonstrates that vaccines should be given by intramuscular injection in preference to subcutaneous injection as the intramuscular route is associated with better immune response and a lower rate of injection site reaction. The basis of this superiority is discussed.     

Epinephrine absorption after different routes of administration in an animal model

BACKGROUND: The administration of epinephrine is the most important initial treatment in systemic anaphylaxis. PURPOSE: We wanted to determine the relationship between the route of epinephrine administration and the rate and extent of epinephrine absorption. METHODS: In a prospective, randomized, five-way crossover study in rabbits, we measured plasma epinephrine concentrations before, and at intervals up to 180 min after epinephrine administration by intramuscular or subcutaneous injection, or by inhalation, with intravenous epinephrine and intramuscular saline as the positive and negative controls, respectively. RESULTS: Maximum plasma epinephrine concentrations were higher, and occurred more rapidly, after intramuscular injection than after subcutaneous injection or inhalation, and were 7719+/-3943 (S.E.M.) pg/mL at 32.5+/-6.6 min, 2692+/-863 pg/mL at 111.7+/-30.8 min and 1196+/-369 pg/mL at 45. 8+/-19.2 min, respectively. Intravenous injection of epinephrine resulted in a plasma concentration of 3544+/-422 pg/mL at 5 min, and an elimination half-life (t(1/2)) of 11.0+/-2.5 min. In the saline control study, the endogenous epinephrine concentration peaked at 518+/-142 pg/mL. CONCLUSION: In this model, absorption of epinephrine was significantly faster after intramuscular injection than after subcutaneous injection or inhalation. The extent of absorption was satisfactory after both intramuscular and subcutaneous injections. Neither the rate nor the extent of absorption was satisfactory after administration by inhalation.     

Toxicological studies on cefuroxime sodium.

The intravenous LD50 of cefuroxime sodium for mice was 10.4 g/kg. The maximum dosage administered in other acute toxicity tests was well tolerated by mice (10 g/kg, subcutaneous), by rats (4 g/kg, intravenous, 5 g/kg, subcutaneous) and by cats, dogs and monkeys (2 g/kg, intramuscularly). Cefuroxime sodium was administered subcutaneously (s.c.) or intramuscularly (i.m.) for 3 months to rats (100, 300 or 900 mg/kg/day) followed by a recovery period, and also for 6 months to rats and dogs (50, 150 or 450 mg/kg/day) and for 1 month to monkeys (150 or 450 mg/kg/day). In all these tests there were no serious toxic effects. Minor haematological changes were attributable in part if not entirely to haemorrhage and tissue reaction at the site of injection of large doses. In rats large doses caused some increase in urine volume and electrolyte excretion, and slightly aggravated an age related nephropathy. Administration to rats intravenously (i.v.) for1 month of up to 400 mg/kg/day had no toxic effects. In reproduction studies on mice and rabbits there were no adverse effects on fertility, organogenesis or the rearing of young.     

Pharmacokinetics of leucovorin calcium after intravenous, intramuscular, and oral administration

The pharmacokinetics of leucovorin was evaluated after intravenous, intramuscular, and oral administration in a randomized crossover study of 37 healthy men. A single 25-mg dose of leucovorin calcium was administered intravenously, intramuscularly, or orally to the subjects. Blood samples were obtained immediately before and at 13 time points up to 24 hours after the leucovorin dose. The three treatment phases were separated by one-week intervals. Bioavailability was assessed by measuring over 24 hours the blood concentrations of total folates, the parent compound 5-formyltetrahydrofolate, and the metabolite 5-methyltetrahydrofolate, using differential microbiologic assays with Lactobacillus casei and Streptococcus faecalis. Both intravenous and intramuscular administration produced rapid increases in serum concentrations of biologically active folates; these rises were sustained over time and were still detectable at 24 hours after drug administration. The bioavailability of intravenous and intramuscular doses was comparable based on area under the serum concentration-time curve, although for intramuscular administration, the peak concentration was lower and the time to peak concentration was longer. The initial rise in serum folate with intravenous and intramuscular dosing represented 5-formyltetrahydrofolate; this fell concomitantly with the appearance of 5-methyltetrahydrofolate. Oral leucovorin was 92% bioavailable compared with intravenous administration and produced a predictably different pattern of circulating folates, 5-methyltetrahydrofolate being the predominant form. Terminal elimination half-life, apparent volume of distribution, and clearance of total folate were not significantly different among the three treatments.(ABSTRACT TRUNCATED AT 250 WORDS)     

Antitumor activity of Klebsiella 03 lipopolysaccharide in mice

The antitumor activity of Klebsiella 03 lipopolysaccharide (KO3 LPS) isolated from the culture supernatant against S180 sarcoma, Ehrlich carcinoma, MM2 mammary carcinoma and Meth A fibrosarcoma in mice was investigated. KO3 LPS significantly prolonged the lifespan of S180-bearing ddY mice and MM2-bearing C3H/He mice by intraperitoneal pre- or postmedication at doses ranging from 0.1 to 1.0 mg/kg. The LPS also inhibited the growth of subcutaneously inoculated Ehrlich carcinoma in ddY mice and Meth A sarcoma in BALB/c mice by intraperitoneal, intravenous or intratumoral administration. The intratumoral injection of KO3 LPS was most effective and results by the intravenous and the intraperitoneal administrations followed in effectiveness, but the administration through the subcutaneous route was hardly effective. Thus, KO3 LPS was shown to have antitumor activity on both allogeneic tumors and syngeneic tumors. It was also indicated in this study that the lifeprolonging effect of KO3 LPS on S180 ascites type tumor-bearing mice was significantly minimized by pretreatment of cyclophosphamide and that the LPS did not influence the cell viability of HeLa cells, Ehrlich cells and MM2 cells in vitro. These results suggest that the antitumor activity of KO3 LPS is provided by host-mediated actions.     

Acute toxicity studies of miporamicin and its degradation products and metabolites in the mouse and rat

Acute toxicity studies of miporamicin and its trace ingredients, degradations and metabolites were conducted in mice and rats. 1. Following oral administration of miporamicin (MPM), none died among mice or rats even at the highest dosage levels. Therefore, its LD50 values were estimated to be greater than 2,500 mg/kg for mice and greater than 2,000 mg/kg for rats. The LD50 value of MPM was the highest by oral route, followed, in order, by subcutaneous route and intravenous route. There was no difference in this respect between sexes of animals studied. 2. No signs of abnormalities were observed among mice or rats following oral administration of MPM. In animals dosed with MPM by subcutaneous route, such inflammatory reactions as swelling, subcutaneous hyperemia and hemorrhage, and loss of hair incrustation at the site of injection were noted. Animals among those given MPM by intravenous injection developed postdosing depression of motor activity, respiratory depression or arrest, tremor and convulsion. 3. Deaths from administration of MPM were estimated to be due to paralysis of respiratory function inasmuch as fatally affected animals exhibited respiratory depression and cyanosis and, subsequently, respiratory arrest was followed by cardiac arrest. 4. Trace ingredients, metabolites and degradation products of MPM proved to be essentially the same as MPM in acute toxicities.     

(+)-Methamphetamine-induced spontaneous behavior in rats depends on route of (+)METH administration

These studies examined the role of (+)-methamphetamine ((+)METH) administration route on spontaneous behavioral activity vs. time relationships, and pharmacokinetic mechanisms for differences in effects. Male Sprague-Dawley rats (n=6 per administration route) received saline and three doses (0.3, 1.0 and 3.0 mg/kg) of (+)METH in a mixed-sequence design by intravenous (iv), subcutaneous (sc) or intraperitoneal (ip) administration. Locomotion and stereotypy were quantified by video-tracking analysis. The effects of (+)METH on spontaneous behavior were dose- and route-dependent. In particular, total locomotor activity was greatest following 3.0 mg/kg intraperitoneally (P<0.05) and stereotypy ratings were greatest following 3.0 mg/kg subcutaneously (P<0.05). In addition, the duration of locomotor effects was greatest after 3.0 mg/kg subcutaneously (P<0.05). Serum pharmacokinetic parameters were determined in separate rats given 3.0 mg/kg by subcutaneous and intraperitoneal administration (n=4 per administration route). The (+)METH elimination half-life was not different between the routes, but the (+)METH AUC was greater (P<0.05), and the (+)METH and (+)-amphetamine (AMP) maximum concentrations occurred later following subcutaneous than after intraperitoneal dosing (P<0.05), increasing and prolonging drug exposure. In conclusion, the overall pattern of (+)METH effects on locomotor activity depend on dose and the route of administration, which affects serum concentration and the time course of behavioral effects.     

Recombinant Murine Growth Hormone Particles are More Immunogenic with Intravenous than Subcutaneous Administration

Evaluation and mitigation of the risk of immunogenicity to protein aggregates and particles in therapeutic protein products remains a primary concern for drug developers and regulatory agencies. To investigate how the presence of protein particles and the route of administration influence the immunogenicity of a model therapeutic protein, we measured the immune response in mice to injections of formulations of recombinant murine growth hormone (rmGH) that contained controlled levels of protein particles. Mice were injected twice over 6 weeks with rmGH formulations via the subcutaneous, intraperitoneal, or intravenous (i.v.) routes. In addition to soluble, monomeric rmGH, the samples prepared contained either nanoparticles of rmGH or both nano- and microparticles of rmGH. The appearance of anti‐rmGH IgG1, IgG2a, IgG2b, IgG2c, and IgG3 titers following the second injection of both preparations implies that multiple mechanisms contributed to the immune response. No dependence of the immune response on particle size and distribution was observed. The immune response measured after the second injection was most pronounced when i.v. administration was used. Despite producing high anti‐rmGH titers mice appeared to retain the ability to properly regulate and use endogenous growth hormone. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:128–139, 2014     

Pharmacokinetics of ceftizoxime suppository in experimental animals

Ceftizoxime suppository (CZX-S) was administered rectally to mice, rats and dogs, and the pharmacokinetics were studied in comparison with those after intravenous, intramuscular and subcutaneous administration of ceftizoxime (CZX). Absorption of CZX given rectally was rapid in all animals, similar to intramuscular or subcutaneous administration. The peak serum levels of CZX in mice, rats and dogs when administered rectally at a dose of 25 mg/kg were 23.1 micrograms/ml at 7.5 minutes, 23.5 micrograms/ml at 15 minutes and 25.2 micrograms/ml at 15 minutes, respectively. These values were about 76%, 68% and 42% of the values for subcutaneous or intramuscular administration in mice, rats and dogs at the same respective doses. Urinary recoveries of CZX after rectal administration of 25 mg/kg were 44.2% (0-12 12 hours) in rats and 27.7% (0-6 hours) in dogs, and 2.7% (0-6 hours) of the dose was excreted into bile fluid in rats. Organ distribution of CZX when administered rectally to rats was similar in distribution pattern to that of muscular administration, although its concentrations in various organs were slightly lower than those for intramuscular administration, as was the case for serum concentration. Serum concentrations of CZX were proportionately elevated with dose when dogs were rectally administered CZX-S in doses of 12.5, 25 and 50 mg/kg. In the case of multiple administrations (t.i.d. for 10 days) of CZX-S to dogs, no remarkable difference was found in serum concentrations of CZX in comparison with single doses, and no accumulation of CZX was demonstrated.(ABSTRACT TRUNCATED AT 250 WORDS)