Route In Man Research Articles

Pharmacokinetics of Susalimod, a Highly Biliary‐excreted Sulphasalazine Analogue, in Various Species. Nonpredictable Human Clearance by Allometric Scaling

The pharmacokinetics of susalimod (2-hydroxy-5-((4-((3-methyl-2-pyridinylamino)sulphonyl)phenyl)-ethynyl)-benzoic acid) were investigated in various animal species and in man after intravenous administration. Plasma clearance was expected to correlate mainly to biliary clearance, since susalimod is excreted approximately 90% unchanged in bile. Biliary excretion was also the main route in man, based on a high recovery in faeces. Susalimod was rapidly eliminated from plasma in all animal species (t½ < 0.5 h) but was much slower in man (t½ = 16 h). Allometric scaling of the preclinical clearance showed a very good correlation (r = 0.947) between the different animal species. However, the predicted human clearance was 20-times higher than the observed clearance. Susalimod is an example of a biliary-excreted compound exhibiting a much slower elimination rate in man compared with animals, resulting in nonpredictable human clearance by allometric scaling of preclinical data.

Anticoagulant effects and tissue factor pathway inhibitor after intrapulmonary low-molecular-weight heparin.

The present study was designed to investigate the anticoagulant action of inhaled low-molecular-weight (LMW) heparin on the release of tissue factor pathway inhibitor (TFPI) and on antifactor Xa activity, Heptest, activated partial thromboplastin time (APTT) and thrombin clotting time (TCT) in healthy volunteers. 3000 IU (group 1), 9000 IU (group 2), 27,000 IU (group 3) or 54,000 IU (group 4) LMW-heparin were given to 20 healthy volunteers each at 4 weeks intervals by inhalation. For safety reasons a dose escalating design was chosen. APTT and TCT did not change after inhalation of any dose of LMW-heparin as well as all parameters in group 1. In group 2, Heptest coagulation times were prolonged from 18.7 +/- 2.0 s before to 26.1 +/- 5.2 s 6 h and 20.5 +/- 1.9 s 24 h after inhalation and the other parameters remained uneffected. In group 3, S2222 method and the protamine assay increased from 0.01 to about 0.1 IU/ml 6 h after inhalation and returned to normal values after 24 h. TFPI antigen increased from 74.1 +/- 13.9 to 80.5 +/- 14.2 ng/ml 3 h after inhalation. TFPI activity remained unchanged. Heptest coagulation values were prolonged to 42 +/- 7.6 s after 6 h and returned to normal within 72 h after inhalation. In group 4, the following changes were observed: antifactor Xa activity increased to 0.343 +/- 0.196 U/ml after 6 h and normalized after 72 h. The protamine assay detected 0.2 +/- 0.18 U LMWH/ml after 6 h, TFPI antigen increased to 103 +/- 17.9 ng/ml and TFPI activity to 1.14 +/- 0.23 U 3 h after inhalation. All tests were normal after 24 h. Heptest coagulation values increased to 77.5 +/- 11.8 s 6 h after inhalation and normalized after 144 h. The area under the activity time curve of the S2222 method and of the Heptest assay increased with increasing doses (r = 0.677 and r = 0.571), respectively. The calculated elimination half-life of the aXa-effect was 7.5 h using S2222-, Heptest- and protamine assays. The data demonstrate a resorption of LMW-heparin by intrapulmonary route in man. The dose to produce antifactor Xa levels, prolongations of Heptest coagulation values and in releasing TFPI is about ten-fold higher than after subcutaneous administration.

Yersinia enterocolitica serotype O:3 is arthritogenic for mice

It is shown, for the first time, that Yersinia enterocolitica serotype O:3 is experimentally arthritogenic. Moreover, it is arthritogenic for the mouse, an optimal model for human yersiniosis. This arthritis can be induced by the oral route, the most common route in man. The pattern of joint disease closely parallels that of human reactive arthritis associated with this pathogen.

Absorption, disposition and preliminary metabolic pathway of 14C-rifabutin in animals and man

14C-Rifabutin was given orally to rats, rabbits and monkeys at a dose of 25 mg/kg and to healthy volunteers at a dose of 270 mg. Radioactivity was eliminated by both the renal and faecal routes in all species, with a predominance of the renal route in man and monkeys (50.19% and 46.73% of the dose, respectively, in urine at 96 h), whereas in rats and rabbits a slight predominance of faecal excretion was observed (48.09% and 45.01% of the dose, respectively, at 96 h in faeces; 42.22% and 36.37% in urine). Radioactivity as expired 14CO2 was detected in the rat and accounted for less than 0.5% of the dose within 96 h. The drug was rapidly absorbed and peak plasma radioactivity levels were reached from 1 to 4 h after dosing. Rifabutin was the predominant compound circulating in plasma at the first sampling times, but significant levels of 31-OH rifabutin were detected up to 8-24 h in all species studied. 25-O-deacetyl rifabutin was detected only in rat and man. Polar metabolites were also present, particularly at the later sampling times. The urinary metabolism was studied by radio-HPLC. Rifabutin accounted for 8.5% and 4.6% of the dose in 0-24 h urine of rats and man respectively, whereas in rabbit and monkey urine only traces of this compound were detected. The main known metabolite in all animal species was 31-OH rifabutin; 25-O-deacetyl rifabutin was detected only in rat and man. The remaining urinary radioactivity was mainly due to polar compounds.

Assessing risks from data on other exposure routes: Possibilities and limitations of using toxicity data derived from one exposure route in assessing risks from other exposure routes

There is no simple and generally applicable way in which toxicity data derived from one route of exposure can be used to evaluate the effects of exposure by another route in the same species of animal or for risk assessment of another exposure route in man. Reliable predictions may be made in some cases where substances act systemically and have relatively long half-lives and where there are adequate data on toxicity by one route and on pharmacokinetics and metabolism by both routes. Extrapolation may also be possible where it can be shown that the nature and degree of toxicity are directly related to blood or tissue concentrations. The occurrence of toxic effects at the point of exposure (local toxicity) increases the uncertainties associated with extrapolation, usually making it not feasible. The use of safety factors to allow for uncertainties inherent in extrapolating between routes of exposure where data are inadequate is not advocated. Whether an extrapolation of data is justified in an individual case should be decided on a case-by-case basis; generalizations cannot be made.

Misonidazole protects mouse tumour and normal tissues from the toxicity of oral CCNU

Because the nitrosourea CCNU is given exclusively by the oral route in man, we have carried out studies in mice on the antitumour activity, acute toxicity and pharmacokinetics of oral CCNU, either alone or in combination with the chemosensitizer misonidazole. In both plasma and KHT tumour the peak concentration and "early" AUC for total nitrosoureas were about 1.4-1.5 fold greater for the oral compared to the i.p. route. These differences were reflected in the roughly twofold greater antitumour activity for the oral route. In contrast, acute toxicity tests showed that oral CCNU was 1.45 times less toxic to normal tissue, although the dose-limiting organ may be different for the two routes. Misonidazole reduced the antitumour activity of oral CCNU by dose modifying factors (DMF) of 0.58-0.71. Similarly, the acute toxicity was also diminished by a DMF of 0.74. Misonidazole has a complex effect on oral CCNU pharmacokinetics. The plasma and tumour total nitrosourea peak concentrations were reduced by 1.5 and 1.7 fold respectively. Misonidazole also reduced the "early" nitrosourea AUC, with the extent of the reduction depending on the minimum effective concentration (MEC) chosen. For example, the plasma nitrosourea AUC was reduced by factors of 1.05 and 9.6 for MEC values of 1 and 2 micrograms ml-1 respectively. We propose these pharmacokinetic changes to be the underlying mechanism for the reduction of oral CCNU cytotoxicity by misonidazole. Clinical trials of such combinations should be accompanied by detailed pharmacokinetic evaluation.

Benzene disposition in the rat after exposure by inhalation

Little information is available on benzene disposition after exposure by inhalation despite the importance of this route in man. Benzene metabolites as a group have been measured in bone marrow, but quantitation of individual metabolites in this target tissue has not been reported. Male Fischer-344 rats were exposed to 500 ppm benzene in air and the uptake and elimination was followed in several tissues. Concentrations of free phenol, catechol, and hydroquinone in blood and bone marrow were also measured. Steady-state concentrations of benzene (11.5, 37.0, and 164.0 μg/g in blood, bone marrow, and fat, respectively) were achieved within 6 hr in all tissues studied. Benzene half-lives during the first 9 hr were similar in all tissues (0.8 hr). A plot of amount of benzene remaining to be excreted in the expired air was biphasic with t 1 2 values for the α and β phases of 0.7 and 13.1 hr, respectively. Phenol was the main metabolite in bone marrow at early times (peak concentration, 19.4 μg/g). Catechol and hydroquinone predominated later (peak concentrations, 13.0 and 70.4 μg/g, respectively). Concentrations of these two metabolites declined very slowly during the first 9 hr. These data indicate that free catechol and hydroquinone persist in bone marrow longer than benzene or free phenol.

Thyrotropin and Prolactin Response to Intraspinal TRH Administration in Man

The effect of intraspinal (i.s.) TRH administration of Prolactin (Prl) and thyrotropin stimulating hormone (TSH) serum levels was studied in order to verify the existence of a ventricular route in man for releasing factor delivery to the anterior pituitary, which has been previously reported in rats. Ten young male subjects were given 200 microgram thyrotropin releasing hormone (TRH) i.s. injections and Prl and TSH were measured by radioimmunoassay (RIA) before and at various times after TRH administration. In the same subjects, an i.v. TRH test was also performed. After i.s. TRH, a prompt Prl increase (peak values at 10-30 min and return to baseline within 150 min) and a delayed increase (3-5 h following TRH injection) were observed in 7 and 5 subjects respectively, while an early elevation in serum TSH occurred in 6 subjects and a late one in other 6. In two subjects, a biphasic response of both tropins was present. Prl and TSH response to i.v. TRH was within the normal range in all cases; no late rise of the 2 hormones was observed. A kinetic experiment with 125I-TRH was also carried out to elucidate the mode of i.s. vs i.v. TRH action. These results confirm in man data reported in animals which suggest that TRH can be transported from the cerebrospinal fluid (CSF) to the portal system and the hypophysis.

Comparison of the beta2‐adrenoceptor selectivity of rimiterol, salbutamol and isoprenaline by the intravenous route in man.

1 The bronchodilating efficacy and the degree of beta2-adrenoceptor selectivity of rimiterol, salbutamol and isoprenaline were determined in seven subjects who exhibited histamine-induced bronchoconstriction. 2 Rimiterol, 0.5 (high dose) and 0.05 (low dose) mug kg-1 min-1, salbutamol, 0.3 and 0.03 mug kg-1 min-1, isoprenaline, 0.05 and 0.005 mug kg-1 min-1 and placebo were administered by a single intravenous injection over 6 min, and the protection against histamine-induced bronchoconstriction, changes in heart rate, pulse pressure and skeletal muscle tremor were measured. 3 Rimiterol (98%), salbutamol (96%) and isoprenaline (69%) protected against histamine-induced bronchoconstriction. For these ventilatory responses, there was a heart rate increase of 31.9, 24.7 and 44.3 beats/min for rimiterol, salbutamol and isoprenaline respectively. The three drugs produced similar increases in pulse pressure and tremor. 4 Significant dose-responses were obtained for all the parameters with each drug. 5 Isoprenaline was approximately 7 and 5 times as potent as rimiterol and salbutamol respectively in bronchodilator action when equimolar doses were compared. Similarly, isoprenaline was approximately 14 and 10 times as potent in increasing the heart rate as rimiterol and salbutamol respectively. 6 Rimiterol, a new beta-adrenoceptor stimulating drug, is an effective bronchodilator and has similar beta2-adrenoceptor selectivity to salbutamol when administered intravenously. The relative potencies and degrees of beta2-adrenoceptor selectivity of these drugs depend partly on their route of administration.

Study of the cervical veins by the translingual route in man

Sublingual venography, as described in the experimental study of Jennings et al., has been used for studying the venous circulation of the neck in eighteen patients, in fifteen of them successfully. The method used in this preliminary study proved to be simple and free from serious hazards. It afforded clear outlines of the internal jugular veins, except for the uppermost portion, of the thyrolinguofacial segment and of the thyroid veins.

Development of antibodies against perorally and rectally administered streptokinase in man.

Abstract Considerable controversy exists concerning the possible benefits of buccally administered streptokinase in experimentally induced inflammatory states and in clinical posttraumatic edema and inflammation, particularly since it has not been demonstrated clearly that streptokinase is absorbed by this route in man. Since streptokinase is highly antigenic in man, absorption of even small amounts of streptokinase should induce rises of the anti-streptokinase titer. We have, therefore, studied 2 groups of 11 patients each receiving streptokinase bucally or rectally over a period of 8 days in the form of Varidase and have determined anti-streptokinase titers in weekly intervals thereafter. Statistically significant rises (P

Studies on Japanese B Encephalitis Virus Vaccines from Tissue Culture

Summary A lot of experimental live attenuated Japanese B encephalitis virus vaccine for human trial was prepared in 199 medium plus 2% human albumin by making a pool of repeated harvests from virus inoculated HKC monolayers at brief intervals. The titer was 7.7 log TCD50 before and 6.6 following filtration. The vaccine was free from bacteria and other detectable viral agents by all the usual safety tests. In weanling mice by the i.c. route and in suckling mice by the s.c. route the vaccine titered less than 100. Frozen at about -70°C it has remained stable for at least 18 months. It had a conspicuous T marker, failing to grow detectably at 40°C, and also had what appeared to be a characteristic plaque form which distinguished it from wild strains. Only one monkey of those given undiluted virus i.c. died. This occurred on the 18th day. Virus isolated from the brain had partially altered characteristics. All surviving monkeys given undiluted virus by the i.c. route developed detectable neutralizing antibodies. HAI antibody response was equivocal and CF negative. Six monkeys and two chimpanzees inoculated s.c. with 1 ml of the vaccine failed to develop either fever, viremia or neutralizing antibodies. One of three of these monkeys given a second injection after 60 days developed antibodies which persisted 171 days and another responded after a third injection. Three others not given a booster were tested for viremia following an s.c. challenge with virulent virus. The viremia response appeared to be less than that of the controls. Weanling mice with reduced body temperatures proved to be somewhat more susceptible to i.c. inoculation of this virus than were those with higher temperatures and survivors were more resistant to subsequent i.c. challenge inoculation. It is concluded that this experimental vaccine lot has all the characteristics of earlier lots made with lactalbumin hydrolysate and calf serum and that other characterization beyond that to which other lots were subjected supports further its suitability for cautious testing by the peripheral route in man. Safety appears reasonably assured.

Preparation of a water emulsion of alpha-tocopherylhydroquinone suitable for intravenous administration in animals.

SummaryA relatively stable emulsion of α-tocopherylhydroquinone in propylene glycol and water can be formed. Best results were obtained when propylene glycol solutions containing 100 mg/cc of the hydroquinone were used and the concentration of propylene glycol in the emulsion was 10%. Such emulsions contained 90% of the added hydroquinone and were relatively stable. The emulsion was useful for intravenous administration in rabbits and produced no significant local reaction in the blood vessels. The emulsion has not been administered parenterally in patients; its injection by the intravenous route in man must await further investigation, and the development of satisfactory methods of sterilization.