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Biomedical subjects

R A Franklin

Publications and source records attributed to R A Franklin.

At least 19 recordsLinked to original sources
PubMed1992

Rapamycin inhibits the phosphorylation of p70 S6 kinase in IL-2 and mitogen-activated human T cells.

Phosphorylation of 40S ribosomal protein S6 is regulated in part by the mitogen-activated p70 S6 kinase (p70s6k). Following the addition of IL-2 to the IL-2 dependent human cell line Kit225, or mitogenic activation of resting human T cells, a rapid phosphorylation of p70s6k was observed by immunoblotting. Rapamycin (RAP), a potent suppressor of T-cell proliferative responses, markedly inhibited the phosphorylation of p70s6k induced by IL-2 in Kit225 cells or by the mitogens added to resting T cells. Other immunosuppressants such as cyclosporin A or an FK506 analogue were without effect. Moreover, the effect of RAP was restricted to p70s6k; it did not inhibit the phosphorylation of p90rsk, another kinase which utilizes the S6 protein as a substrate. These data indicate for the first time that RAP may target the pathway leading to p70s6k phosphorylation during human T-cell proliferation.

Amino Acid Sequence↗
PubMed1992

Monoclonal antibodies directed to different epitopes in the CD3-TCR complex induce different states of competence in resting human T cells.

After the initial stages of activation, T cells are not able to proliferate on their own but become competent to proliferate in response to exogenously added lymphokines. In the present study we compared the capacity of mAb directed to CD3 (OKT3, Leu4, UCHT1) or to common epitopes on the alpha/beta T-cell receptor (BMA 031, BMA 032) to induce competence in purified resting T cells. Stimulation with either soluble anti-CD3 or anti-alpha/beta TCR mAb rendered cells competent to progress to DNA synthesis in response to exogenous IL-2. In contrast, only soluble BMA 031 and BMA 032 were able to induce responsiveness to IL-4; anti-CD3 mAb had either to be immobilized or used in combination with anti-CD28 mAb to induce responsiveness to IL-4. Further, BMA 031-induced IL-4 responsiveness was selectively found in the CD45RA+ T cell subset. Analysis of early activation events revealed that the capacity of soluble BMA 031 and BMA 032 to induce responsiveness to IL-4 did not correlate with the ability of these mAb to increase the level of cytosolic Ca2+ or to induce detectable tyrosine phosphorylation. On the other hand, soluble Leu4 (anti-CD3) triggered an increase in both intracellular Ca2+ and tyrosine phosphorylation but was unable to induce IL-4 responsiveness. These data indicate that the induction of IL-2 and IL-4 responsiveness requires different sets of activation signals which can be induced by stimulating different epitopes in the CD3-TCR complex. This supports the concept that distinct activation pathways are coupled to the CD3-TCR complex.

Antibodies, Monoclonal↗
PubMed1992

Signal transduction by interleukin 2 in human T cells: activation of tyrosine and ribosomal S6 kinases and cell-cycle regulatory genes.

The early events of signal transduction associated with interleukin-2 (IL-2) binding to its receptor were examined using a human IL-2 dependent T-cell line, Kit225. Cell cycle analysis showed that 90% of Kit225 cells were in the G0/G1 phase after a 72-hr incubation in the absence of exogenous IL-2. At this point, stimulation of the cells with IL-2 resulted in the rapid initiation of RNA and DNA synthesis by 9 and 20 hr, respectively. Within 5 min after addition of IL-2, rapid activation of tyrosine and ribosomal S6 kinases was detected. Addition of IL-2 also increased mRNA levels for c-fos, c-myc, IL-2 receptor alpha, and IL-2 receptor beta chain. These events increased in the absence of detectable changes in free cytosolic [Ca2+]i, inositol phosphate metabolism, or the activity of several kinases including cAMP-dependent protein kinase, Ca2+/calmodulin-dependent protein kinase, or protein kinase C. These findings demonstrate that the signals triggered by IL-2 binding to its receptors are quickly transduced into the nucleus with increased mRNA transcription of activation-associated genes. Furthermore, the data indicate that tyrosine and ribosomal S6 kinases may be important for IL-2-induced cell growth.

Calcium↗
PubMed1992

Smoking.

Cigarette smoking remains a major health problem in not only the United States but the world. The dependency-producing effects of nicotine are well documented. Primary prevention, preventing the initiation of smoking, is receiving increased attention in the field of health education. Secondary prevention, smoking cessation, is showing promising results. Perhaps the goal of a smoke-free America by 2000 is not a "pipe dream" after all.

Costs and Cost Analysis↗
PubMed1990

The proliferative response of rat T cells to calcium ionophores increases with age.

Splenocytes and T cells from both old and young rats proliferate to A23187 and ionomycin, and this response increases 3- to 10-fold in aged animals. Augmented responsiveness to ionomycin occurs in the absence of any defect in Con A-induced proliferation of T lymphocytes of aged rats and is dependent upon the addition of thiol compounds to the tissue culture medium. Augmented proliferative responses to ionomycin precede the significant but much smaller decline (30 to 40%) in Con A-induced proliferative responsiveness of splenocytes, which is evident only when rats reach 24 months of age. Heightened proliferation to calcium ionophores is not caused by a greater ability of T lymphocytes from aged rats to increase [Ca2+]i in response to ionomycin. The increased proliferative response of lymphocytes from aged rats to ionomycin occurs in the absence of detectable amounts of secreted IL 2 or IL 4. The ionophore response is a much more sensitive biomarker of age than the decline in Con A-induced proliferative responses of lymphocytes and identifies an activity of T lymphocytes that increases rather than decreases during the aging process.

Aging↗
PubMed1990

Glutathione augments in vitro proliferative responses of lymphocytes to concanavalin A to a greater degree in old than in young rats.

The proliferative response of splenocytes to concanavalin A (Con A) is significantly lower in aged than in young rats. The addition of reduced (GSH) but not oxidized (GSSG) gamma-glutamylcysteinyl-glycine (glutathione) in vitro totally reverses the defective proliferative response of splenocytes from aged rats. The inhibitor of gamma-glutamylcysteine synthetase, buthionine sulfoximine, abrogates the in vitro proliferation of splenocytes from young rats activated with Con A, and this effect is significantly reversed by addition of GSH. The enhancing effects of GSH on proliferation of Con A-activated splenocytes of both young and old rats are apparent as early as 24 h and are still evident as late as 72 h in culture. Both cysteine and 2-mercaptoethanol are able to mimic the effect of GSH in causing a greater increase in Con A-induced proliferative responses of splenocytes from old rats (eightfold) as compared to young animals (threefold). Although 2-mercaptoethanol increases expression of membrane-bound transferrin receptors on both Con A-activated splenocytes and T lymphocytes, this alone does not account for the greater enhancement of Con A-induced proliferation of splenocytes from old as compared to young rats. These data are consistent with the hypothesis that the glutathione peroxidase-dependent detoxification system is defective in T lymphocytes of aged rats.

Aging↗
PubMed1989

The disposition of meptazinol after single and multiple intravenous administration to pregnant and non-pregnant women.

We have studied the disposition of the centrally-acting analgesic meptazinol in a group of age-matched non-pregnant and pregnant (36-38 weeks gestation) women. Ten non-pregnant and nine multiparous pregnant volunteers each received a single i.v. dose of meptazinol hydrochloride (equivalent to 25 mg base). A further group of 9 non-pregnant (including four of the original participants) and 10 multiparous pregnant subjects were given repeated i.v. doses of meptazinol hydrochloride (each equivalent to 10 mg base) at 30-min intervals for 2.5 h. Meptazinol plasma concentrations were determined by HPLC using fluorescence detection and the pharmacokinetic variables investigated. After single dosing there were no statistical differences in half-life, clearance, or apparent volume of distribution between the two groups, suggesting that the disposition of meptazinol was not altered by pregnancy. This was confirmed in the repeated dose study, in which no significant differences occurred in either the plasma concentrations achieved or in areas under the curves between the non-pregnant and pregnant subjects. Furthermore, the steady-state concentrations were comparable with those predicted from the single dose results. This indicates that there should be no requirement for dosage alteration of meptazinol during pregnancy.

Adult↗
PubMed1989

The systemic availability of meptazinol in man after oral and rectal doses.

We have studied the pharmacokinetics of the centrally-acting analgesic meptazinol after oral and rectal administration to 15 healthy men. Each subject took a standard 200 mg tablet orally and Witepsol H12 suppositories containing 75, 100, and 150 mg of the drug in a cross-over design. Meptazinol plasma concentrations were measured by HPLC using fluorescence detection and the pharmacokinetics determined. The tmax values for the 100 mg and 150 mg suppositories (median = 0.5 h) were statistically significantly shorter than for the tablet (median = 1.13 h), suggesting that meptazinol was more rapidly absorbed via the rectal route. Despite substantial intersubject variation in Cmax the plasma concentrations after rectal dosage were higher than after oral administration. There was a statistically significant (p less than 0.001) improvement in systemic availability for each of the suppository doses (mean approximately 15.5% compared with the oral tablet (mean approximately 4.5%).

Administration, Oral↗
PubMed1989

Pharmacokinetic interaction between indoramin and ethanol.

1. The effect of ethanol consumption (0.5 g/kg) on the pharmacokinetics of the alpha adrenoceptor antagonist indoramin, administered orally (50 mg) or intravenously (0.175 mg/kg) has been investigated in young volunteers. Sedation was also assessed using a visual analogue scale. 2. After oral indoramin administration, ethanol caused increases of 58% (P less than 0.01) in Cpmax, and 25% (P less than 0.05) in AUC. There was no effect of alcohol on elimination half-life. The combination of ethanol and indoramin was more sedative than indoramin alone. 3. Ethanol did not alter the pharmacokinetics of an intravenous dose of indoramin. However indoramin caused a small but statistically significant increase (26%) in blood ethanol concentrations during the first 1.25 h after dosing. Both indoramin and ethanol caused sedation. 4. The increased bioavailability of oral indoramin in the presence of ethanol may reflect some enhanced absorption, but it is also consistent with inhibition of first-pass metabolism of a flow-limited drug. The clinical implications are discussed.

Administration, Oral↗
PubMed1989

Quantitative aspects of the urinary excretion of meptazinol and its metabolites in human volunteers.

1. The urinary excretion of meptazinol and its metabolites has been studied in five healthy human volunteers following oral administration of 200 mg of the 3H-labelled drug. 2. Meptazinol was well absorbed, with 90% of the radioactivity excreted in the urine; elimination of drug-related material took place rapidly. 3. Metabolism was extensive, no unchanged material being detected in the urine. Following selective enzymic hydrolysis the major metabolites were identified as glucuronide and sulphate conjugates of the parent drug present in an approximate ratio of 4:1. 4. A number of minor metabolites, also present in conjugated form, were tentatively identified.

Administration, Oral↗
PubMed1989

The pharmacokinetics of pirtenidine in the rat and dog.

1. Pharmacokinetic studies on the topical antimicrobial agent, pirtenidine, have been conducted in male Sprague-Dawley rats and beagle dogs, using a validated h.p.l.c. method with u.v. detection to measure the drug in plasma. 2. Following a single i.v. bolus dose to the rat (equivalent to 1.35 mg base/kg) or dog (equivalent to 0.23 mg base/kg), the drug was extensively distributed with an apparent volume of distribution of 8.61/kg in rat and 3.31/kg in dog. Clearance was high (rat 2.71/h/kg; dog 1.51/kg) which resulted in a short terminal half-life in both species (2.2 and 1.5 h respectively). 3. Following a single oral dose to rats (equivalent to 4.5 mg base/kg) plasma pirtenidine concentrations were generally below the minimum quantifiable level of the analytical method (1 ng/ml). A maximum possible bioavailability of 0.3% was estimated. 4. After administering the same oral dose to dogs plasma concentrations rose slowly (t 1/2 abs = 1.2 h) to a peak (49.7 ng/ml) at 5.0 h post-dose. The terminal elimination half-life was 2.1 h. The absolute bioavailability was 10%.

Aminopyridines↗
PubMed1988

Intra- and inter-subject variation in the pharmacokinetics of indoramin and its 6-hydroxylated metabolite.

Intra- and inter-subject variation in the kinetics of indoramin and its active metabolite 6-hydroxyindoramin have been studied in 5 young, healthy, male volunteers administered a single oral dose of the drug on 5 separate occasions. Inter-subject variation represented the main source of variability in indoramin plasma concentrations with, for example, the between-subjects sum of squares (a measure of the contribution to the total variability) representing around 97% of the total sum of squares for Cmax and AUC (0-24). Intra-subject and inter-subject coefficients of variation (C.V.s) were circa 20% and 100% respectively for both these parameters. Variability in 6-hydroxyindoramin concentrations was much lower and was approximately equally derived from intra- and inter-subject variation, with the C.V.s being approximately 44% for both Cmax and AUC (0-24). The results imply that the kinetic behaviour of indoramin within an individual will prove relatively consistent, despite widespread inter-subject variation, once an appropriate dosage regime has been established.

Administration, Oral↗
PubMed1988

The clinical pharmacokinetics and metabolism of the analgesic meptazinol.

1. The analgesic drug meptazinol is rapidly and completely absorbed after oral, intramuscular (i.m.) and rectal dosage. However, the absolute bioavailability of the drug following oral dosage is low (4.5-8.7%). Rectal administration leads to a higher bioavailability (15.5%) while after i.m. dosage the drug is totally systemically available. 2. Meptazinol is widely distributed outside the vasculature (Vd*area 5.9 l/kg) partly due to the low degree of binding to plasma proteins (27% bound) and also the relatively high lipophilicity of the unionized species (log P = 2.7). 3. Elimination of the drug from plasma proceeds rapidly (t1/2 2 h) largely as the result of glucuronidation and sulphation of the phenolic function in the molecule. The major route of excretion is via the urine, greater than 70% of the dose appearing in the 0-24 h urine collection almost entirely as conjugated metabolites. 4. After multiple dosing, orally or parenterally, there is no accumulation above that predicted from single dose kinetics. 5. The pharmacokinetics of the drug are generally unaltered by age (neonates to geriatrics) and pregnancy. Renal disease also has no effect in this respect, although cirrhotic liver disease results in up to a 4-fold increase in oral bioavailability. 6. Only limited data are available on the pharmacokinetics of meptazinol when given with other drugs. Alcohol appears to have no effect, while general anaesthesia appears to reduce clearance of the drug.

Adult↗
PubMed1987

Induction of IL-2 and lymphokine activated killer cells in the cat.

We have described the use of a cloned murine IL-2-dependent T-cell line to directly measure feline IL-2. Concanavalin A stimulated feline peripheral blood lymphocytes produced an IL-2-rich supernatant that supported the growth of this murine IL-2-dependent T-cell line. In addition to producing IL-2, Con A stimulated killer cells in PBL were cytotoxic for the FeLV transformed tumor cell line FL74. Incubating feline PBL with a cocktail of the calcium ionophore A23187 and phorbol ester also led to the generation of cytotoxic cells as well as the production of high levels of IL-2. Finally, IL-2-rich supernatant was able to stimulate cytotoxic activity in PBL from normal cats.

Animals↗