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T J Smith

Publications and source records attributed to T J Smith.

At least 19 recordsLinked to original sources
PubMed1992

Expression of murine beta 7, alpha 4, and beta 1 integrin genes by rodent mast cells.

The screening of a rat mast cell cDNA library with a probe selected to recognize those genes preferentially or exclusively expressed by mast cells identified a rat gene sequence, RF-17, that shared homology with the beta-integrins. This integrin was expressed in rat tissues enriched for mast cells and T cells. The rat RF-17 sequence was used to isolate the murine homologue from a spleen cDNA library. The murine gene encodes a protein of 806 amino acids that is the probable homologue to the human beta 7 chain. Transcripts specific for the murine gene are found in the thymus, spleen, and lung. To attempt to identify the gene product for this new integrin chain, we examined the murine T cell line TK-1, which expresses a novel integrin heterodimer, lymphocyte Peyer's patch high endothelial venule adhesion molecule (LPAM-1), of a known alpha 4 chain and an unknown beta P chain, for expression of murine beta 7 (RF-17). This cell line expresses high levels of RF-17 transcripts, suggesting that beta P is encoded by the beta 7 gene. Bone marrow cells induced to differentiate into mast cells via IL-3 express the beta 7 gene as well as the genes encoding the murine integrin alpha 4 and beta 1 proteins. Surface staining analysis indicates that these cells express an alpha 4-containing integrin complex throughout the differentiation process. These data suggest that the Peyer's patch homing LPAM-1 receptor expressed by a subset of T cells consists of the beta 7 gene product and the alpha 4 chain, and that this integrin chain complex is also found on the surface of maturing mast cells. The presence of beta 1 transcripts also suggests that these maturing mast cells possess the LPAM-2 integrin complex (alpha 4/beta 1) as well. The experimental strategy described in this manuscript has, thus, identified a novel murine beta-integrin chain that is expressed by rodent T cells and mast cells.

Amino Acid Sequence↗
PubMed1992

Modulation of the levels of cytochromes P450 in rat liver and lung by dietary lipid.

This study was undertaken to investigate the effect of dietary lipid on the regulation of several constitutive P450 isozymes. Male Sprague-Dawley rats with body weights of 130-140 g were fed either a 20% corn oil (CO) diet or a fat-free (FF) diet for 4 days following 2 days of fasting. Using liver microsomes, the catalytic activities and immunochemically detectable protein levels of P450s 1A1 and 2, 2A1, 2B1 and 2, 2C11, 2E1, and 3A were determined. The microsomes from rats fed the 20% CO diet exhibited 2-fold higher levels in N-nitrosodimethylamine demethylase activity and P450 2E1 protein than those from rats fed the FF diet. The CO group also showed 2.5-fold higher levels in 6 beta-hydroxylation of testosterone and P450 3A protein than the FF group. In contrast, the CO diet did not affect the immunodetectable level of P450 2C11 protein and its catalytic activities such as benzphetamine demethylase activity and 2 alpha-hydroxylation of testosterone. P450 1A1 was not detectable in either group, but 1A2 was 2.5-fold higher in the CO group than in the FF group. In the liver, the P450 2B1 level was very low in both groups as measured by pentoxyresorufin dealkylase activity and the protein level, whereas 2B2 was 2.5-fold higher in the CO diet group. In lung microsomes from rats fed different amounts of CO, an inverse relationship was observed between the P450 2B1 level and the dietary CO level. The results suggest that the constitutive levels of P450 isozymes are modulated by dietary lipid in a selective manner; the levels of hepatic P450s 1A2, 2B2, 2E1, and 3A were regulated positively but the level of pulmonary P450 2B1 was suppressed by dietary lipid.

Animals↗
PubMed1992

Stereochemical requirements for the modulation by retinoic acid of thyroid hormone activation of Ca(2+)-ATPase and binding at the human erythrocyte membrane.

Physiological concentrations of retinoic acid can block the activation of human erythrocyte Ca(2+)-ATPase in vitro by thyroid hormone [Smith, Davis & Davis (1989) J. Biol. Chem. 264, 687-689]. The present studies were undertaken to ascertain the nature of this blockade. Two binding sites for L-thyroxine (T4) were demonstrated on washed erythrocyte membranes; the high-affinity site had a Kd value of 2.7 x 10(-10)M and a Bmax. of 76 fmol/mg of protein. The lower-affinity site possessed a Kd of 1 x 10(-8) M. Retinoic acid was as potent a displacer of radiolabelled T4 as was the unlabelled hormone. Certain retinoic acid analogues with either ring or fatty acid side chain modifications retained some ability to displace [125I]T4 binding and to block iodothyronine activation of Ca(2+)-ATPase. The side chain terminal carboxyl group was essential for full activity of the retinoic acid molecule. Its absence or replacement with an ethylsulphone group rendered the molecule considerably less active in the ATPase model. Retinol, 13-cis-retinoic acid, benzene-substituted all-trans-retinoic acid and polyprenoic acid all failed to influence iodothyronine binding or to block activation of Ca(2+)-ATPase by T4. There was good agreement between the ability of an analogue to displace [125I]iodothyronine binding and its ability to inhibit the T4-dependent activation of the Ca(2+)-ATPase. It would appear from these observations that retinoic acid can modulate the activation of erythrocyte membrane Ca(2+)-ATPase by thyroid hormone through a mechanism which involves displacement of iodothyronine from binding sites. These activities apparently derive from both the ring structure and the fatty acid side chain of the retinoic acid molecule.

Calcium-Transporting ATPases↗
PubMed1992

n-butyrate reduces the expression of beta-galactoside alpha 2,6-sialyltransferase in Hep G2 cells.

n-Butyrate, a short chain fatty acid that is produced by colonic bacterial fermentation, is detectable in portal blood and induces differentiation in various human neoplastic cell lines. Earlier reports indicated approximately 20-fold induction in vitro by n-butyrate of the sialyltransferase that catalyzes terminal glycosylation of GM3 ganglioside in HeLa and colon cancer cells. We previously isolated a 1.3-kilobase cDNA for a human beta-galactoside alpha 2,6-sialyltransferase, for which N-linked glycoproteins are the acceptors. We report here that treatment of Hep G2 cells with 5 mM n-butyrate for 24 h reduced beta-galactoside alpha 2,6-sialyltransferase mRNA levels by approximately 90%. Reductions in mRNA level were followed by approximately 75 and approximately 90% reductions, respectively, in specific beta-galactoside alpha 2,6-sialyltransferase enzyme activity after treatment for 24 and 36 h with 5 mM n-butyrate. However, in contrast with earlier reports of enhanced ganglioside synthesis in response to n-butyrate treatment, incubation of Hep G2 cells with n-butyrate did not alter the ganglioside pattern as assessed by thin layer chromatography of lipids extracted from treated cells. Nuclear run-on reactions indicated that the rate of transcription of beta-galactoside, alpha 2,6-sialyltransferase was not altered by treatment with 5 mM n-butyrate for 24 h, but the effects of this treatment on cytoplasmic levels of beta-galactoside alpha 2,6-sialyltransferase mRNA were largely negated by co-treatment with actinomycin D or cycloheximide. Therefore, our results show that n-butyrate reduces expression of mature beta-galactoside alpha 2,6-sialyltransferase mRNA by post-transcriptional mechanisms.

Antigens, CD↗
PubMed1992

Interaction of an alpha-melanocyte-stimulating hormone-diphtheria toxin fusion protein with melanotropin receptors in human melanoma metastases.

A hybrid toxin targeted to melanotropin receptors and selectively cytotoxic to melanoma cell lines in vitro has recently been developed. The toxin, a recombinant fusion protein (designated DAB389-MSH), contains the peptide sequences of alpha-melanocyte-stimulating hormone (alpha-MSH) and the catalytic (cytotoxic; Fragment A) and lipophilic (part of Fragment B) domains of diphtheria toxin. In the present study, binding of DAB389-MSH to melanotropin receptors in biopsy specimens of human and mouse melanoma metastases was assessed by measuring its ability to inhibit binding of a radiolabeled, superpotent analogue of alpha-MSH (125I-[Nle4,D-Phe7]-alpha-MSH; 125I-NDP-MSH) and comparing its potency in this system with those of the established ligands NDP-MSH and alpha-MSH. Radioligand binding to tissue sections in vitro was localized and quantified by autoradiography and image analysis. DAB389-MSH inhibited binding of 125I-NDP-MSH to experimental murine B16-F1C23 melanoma metastasis tissue and to melanoma metastases of three patients. In both mouse and human melanoma tissues, concentration-response relationships for DAB389-MSH-mediated inhibition of 125I-NDP-MSH binding were parallel, and its maximal effects were comparable in magnitude, to those of NDP-MSH and alpha-MSH. Half-maximal peptide concentrations for inhibition of 125I-NDP-MSH binding to mouse melanoma tissue sections were: NDP-MSH, 0.63 nM; alpha-MSH, 3.14 nM; and DAB389-MSH, 10.1 nM. In human melanoma tissues, the respective half-maximal peptide concentrations for inhibition of 125I-NDP-MSH binding to mouse melanoma tissue sections were: NDP-MSH, 1.80 nM; alpha-MSH, 2.43 nM; and DAB389-MSH, 11.9 nM. Taken together, these results suggest that NDP-MSH, alpha-MSH, and DAB389-MSH bind to a common melanotropin receptor in human metastatic melanoma cells. Since previous work has shown that melanotropin receptors are detectable in melanoma metastases of about 80% of human patients, malignant melanoma cells of many patients may be susceptible to killing by the melanotropin receptor-targeted cytotoxin DAB389-MSH.

Animals↗
PubMed1992

Efficacy and cost-effectiveness of autologous bone marrow transplantation in metastatic breast cancer. Estimates using decision analysis while awaiting clinical trial results.

OBJECTIVE: To assess the efficacy and cost-effectiveness of standard chemotherapy and high-dose chemotherapy with autologous bone marrow transplantation (ABMT) in metastatic breast cancer. DESIGN: Decision analysis model using a Markov process. SETTING: Response and recurrence rates from the published literature for standard therapy and from case series of ABMT. Costs were based on local charges and on adjusted Medicare data. PATIENTS: Hypothetical cohorts of women with metastatic breast cancer who had no bone marrow involvement and no comorbid illness. INTERVENTION: The standard chemotherapy cohort received cyclophosphamide, doxorubicin, and fluorouracil. The ABMT cohort was treated with intense induction chemotherapy, then additional high-dose chemotherapy following a remission, with ABMT support. MAIN OUTCOME MEASURES: Anticipated survival, incremental cost per year of life, and incremental cost per quality-adjusted year of life gained using a 5-year time horizon. Rigorous sensitivity analyses were done, including assessing a benefit "tail" of normal life expectancy for those free of disease after 5 years. RESULTS: ABMT was the preferred approach under almost all assumptions, but the size of the benefit varied greatly. ABMT had a survival benefit of 6.0 months at 5 years at an incremental cost of $115,800 per year of life saved. If patients who were free of disease after 5 years had normal survival, the benefit was 18.1 months at an incremental cost of $28,600 per year. The benefit of ABMT was primarily dependent on whether the recurrence risk was constant or decreases after a finite period of time. CONCLUSION: Using reasonable assumptions, ABMT provided a substantial benefit but at a cost that may be untenable. Decision analysis highlights the limitations in the currently available data and the assumptions made for the emotional question of using ABMT in metastatic breast cancer. The model supports the need for randomized clinical trials.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1992

Metabolism of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone in human lung and liver microsomes and cytochromes P-450 expressed in hepatoma cells.

4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a potent tobacco-specific carcinogen in animals, has been linked to tobacco-related cancers in humans. The cytochrome(s) P-450 (P-450) responsible for the metabolic activation of NNK in humans has not been identified. The present work investigated the ability of human lung and liver microsomes and 12 forms of human P-450, expressed in Hep G2 (hepatoma) cells, to metabolize NNK. Of the 12 P-450 forms, P-450 1A2 had the highest activity in catalyzing the conversion of NNK to the keto alcohol, 4-hydroxy-1-(3-pyridyl)-1-butanone. P-450s 2A6, 2B7, 2E1, 2F1, and 3A5 also had measurable activities in the formation of keto alcohol. The apparent Km and Vmax for the formation of keto alcohol in the P-450 1A2-expressed Hep G2 cell lysate were 309 microM and 55 pmol/min/mg protein, respectively. 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol, a reductive product, was the major metabolite formed, whereas the formation of keto alcohol and its aldehyde and acid derivatives (all alpha-hydroxylation products) constituted approximately 1% of the initial amount of NNK in P450-expressed Hep G2 cell lysate. A similar metabolite pattern was observed with human lung or liver microsomes. In human lung microsomes, the apparent Kms for the formation of 4-hydroxy-4-(3-pyridyl)butyric acid, 4-oxo-1-(3-pyridyl)-1-butanone, NNK-N-oxide, and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol were 526, 653, 531, and 573 microM, respectively; the formation of keto alcohol was not observed. For human lung microsomes, there was no sex-related difference in NNK metabolism. Carbon monoxide (90% atmosphere) significantly inhibited the metabolism of NNK in human lung and liver microsomes. 7,8-Benzoflavone, an inhibitor of P-450s 1A1 and 1A2, had no effect on NNK metabolism in human lung microsomes but decreased the formation of keto alcohol by 47% in human liver microsomes. Similarly, antibodies against human P-450s 1A2 and 2E1 decreased keto alcohol formation by 42% and 53%, respectively, in human liver microsomes but did not affect NNK metabolism in lung microsomes. Inhibitory antibodies against P-450s 2A1, 2C8, 2D1, or 3A4 had little or no effect on the metabolism of NNK in human liver or lung microsomes.(ABSTRACT TRUNCATED AT 400 WORDS)

Antibodies↗
PubMed1992

Intravitreal sustained-release ganciclovir.

Current treatment of cytomegalovirus retinitis in patients with acquired immunodeficiency syndrome involves frequent intravenous administration of sodium ganciclovir that often results in unacceptable side effects. We have developed devices that release ganciclovir at rates of 2 micrograms/h and 5 micrograms/h in vitro. When implanted into the vitreous of rabbit eyes, mean intravitreal ganciclovir levels of 9 mg/L and 16 mg/L were maintained for more than 80 and 42 days, respectively. Devices were well tolerated, with no toxic effects attributable to the polymers used in the devices. This investigation indicates that these devices can maintain therapeutic levels of drug for extended periods and are well tolerated in the rabbit eye. They may prove useful in the clinical management of cytomegalovirus retinitis in patients with acquired immunodeficiency syndrome.

Animals↗
PubMed1992

Occupational exposure and dose over time: limitations of cumulative exposure.

Cumulative exposure (average intensity times duration) is one of the most common summary measures for exposure used in occupational epidemiology. Its utility for describing quantitative exposure-effect relationships is based on several interlocking assumptions about the processes relating exposure to tissue dose, and tissue dose to adverse effects. The pharmacokinetic relationship between cumulative exposure and tissue dose was examined with models for two common exposures: inhalation of insoluble, respirable particles, and toxic metabolites of a nonpolar organic solvent. It was found that the assumption of a linear relationship between cumulative exposure and tissue dose was violated for typical exposure intensity for both substances. This caused strong nonlinear exposure-tissue dose relationships and variability in the relationship. The findings provide a possible explanation for the common observation of a disproportionately high risk of pulmonary effects for workers with relatively short, intense dust exposures, and for the finding that workers exposed to metabolically activated organic agents have a risk that is related to years of exposure but not to intensity.

Air Pollutants↗
PubMed1992

Mortality studies of machining fluid exposure in the automobile industry I: A standardized mortality ratio analysis.

Machining fluids are widely used in a variety of common industrial metalworking operations to lubricate and cool both the tool and the working surfaces. Previous studies have suggested elevated respiratory, digestive, and skin cancers in exposed populations. This cohort study was initiated to assess whether long-term exposure to machining fluids in the course of machining, grinding, and other cutting operations is associated with excess cancer mortality. The cohort includes more than 45,000 automobile production workers from 3 plants, almost 1 million years of follow-up, over 10,000 deaths, and an extensive exposure assessment component. Standardized mortality ratios (SMRs) have been estimated for each of the 3 plants, using both U.S. as well as local populations as reference. Relative risks of 1.2-3.1 have been observed for several specific respiratory and digestive cancers of a priori interest, including cancer of the stomach, large intestine, pancreas, lung, and larynx. In addition, elevated risks for leukemia and asthma were noted. Future exposure-response analyses will provide the opportunity to identify relatively modest excesses in cause-specific mortality risk associated with exposure to specific types (straight, soluble, or synthetic), additives, or components of machining fluids.

Automobiles↗
PubMed1992

An extended phase II trial of ifosfamide plus mesna in malignant mesothelioma.

Forty three patients with histologically confirmed malignant mesothelioma were entered onto an Eastern Cooperative Oncology Group phase II study of ifosfamide given with mesna. Eligibility criteria included adequate performance status, hemogram and renal functions. Ifosfamide was given at 1.5 g/m2 in 200 ml of normal saline over 30 minutes by intravenous infusion on days 1 to 5 of each 21 day cycle. Mesna was given at 300 mg/m2 on each day of ifosfamide at 0, 4 and 8 hours. Two patients were cancelled and one patient was ineligible. The most common toxicity was haematologic. More than 50% of the patients had at least one episode of severe or life threatening toxicity and 2 patients had lethal toxicity (1 renal and 1 pulmonary oedema attributed to treatment), and an additional 4 patients died while on study (2 of cardiac and 2 of cerebral vascular disease not considered directly related to treatment). Of the 40 eligible patients one was unevaluable for response, and one patient had a partial response lasting 6.3 months. Twenty four patients had a no change status with a median duration of 5 months. The median time to treatment failure for all eligible patients was 2.5 months. The median overall survival time (from registration) for all eligible patients was 6.9 months. In multi variable models, factors that predicted for a statistically significant poorer survival were age > or = 62, stage > or = 3, performance status poorer than 0 to 1 and prior surgery (i.e.: more than biopsy).(ABSTRACT TRUNCATED AT 250 WORDS)

Drug Administration Schedule↗
PubMed1992

Should women with node-negative breast cancer receive adjuvant chemotherapy?--Insights from a decision analysis model.

The use of adjuvant chemotherapy in women with node-negative breast cancer has been controversial and actively debated since the 1988 National Cancer Institute Clinical Alert. We developed a decision analysis model that used the results of available randomized controlled trials to assess the potential clinical and financial effects of using adjuvant chemotherapy for groups of 45-year-old and 60-year-old women. Using the baseline assumptions, we found that chemotherapy increases quality adjusted life expectancy and survival by a substantial amount at a cost comparable to most accepted medical interventions. The model highlights the uncertainties in duration of benefit from therapy, the need for refinements in risk stratification, the importance of patient preferences about toxicity and benefit, and the need for accurate cost-accounting for oncologic therapies. Decision analysis complements other methods for information gathering, analysis, and synthesis used in clinical research. With the increasing focus on the effectiveness of medical interventions, decision analysis will be an important tool for oncologists to understand.

Breast Neoplasms↗
PubMed1992

Metabolism of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone by inducible and constitutive cytochrome P450 enzymes in rats.

The tobacco-specific nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) induces tumor formation in the liver, lung, nasal cavity, and pancreas of rats. Metabolic activation is required for the tumorigenicity of this compound. The involvement of cytochrome P450 enzymes in NNK bioactivation was investigated in rats by studies with chemical inducers and antibodies against P450s. Liver microsomal enzymes catalyzed the formation of 4-oxo-1-(3-pyridyl)-1-butanone (keto aldehyde), 4-hydroxy-1-(3-pyridyl)-1-butanone (keto alcohol), 4-(methylnitrosamino)-1-(3-pyridyl-N-oxide)-1-butanone (NNK-N-oxide), and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) from NNK. When the activity was expressed on a per nanomole P450 basis, treatments of rats with 3-methylcholanthrene (MC), phenobarbital (PB), pregnenolone 16-alpha-carbonitrile (PCN), Aroclor 1254 (AR), safrole (SA), and isosafrole (ISA) increased the keto aldehyde formation in liver microsomes 2.0-, 2.4-, 3.8-, 2.5-, 2.1-, and 1.8-fold, respectively; PB, AR, SA, and ISA increased the keto alcohol formation 1.7-, 1.3-, 2.0-, and 1.3-fold, respectively. The extents of induction were more pronounced when expressed on a per milligram protein basis, due to the higher microsomal P450 contents in the induced microsomes. The formation of NNK-N-oxide was markedly increased by PB and PCN and slightly increased by AR, SA, and ISA. However, the formation of NNAL, the major metabolite due to carbonyl reduction, was not increased by the treatments but was decreased by AR, ISA, and acetone (AC). The kinetic parameters of NNK metabolism by control, MC-, PB-, and PCN-induced liver microsomes were obtained. A panel of monoclonal (anti-1A1, -2B1, -2C11, and -2E1) and polyclonal (anti-1A2, -2A1, and -3A) antibodies were used to assess the involvement of constitutive hepatic P450 enzymes in NNK metabolism. Keto aldehyde formation was inhibited by anti-1A2 and anti-3A (about 15%) but not by others; the formation of keto alcohol was inhibited by anti-1A2, anti-2A1, and anti-3A (by 13-26%). In incubations with lung microsomes, the formation of keto aldehyde, keto alcohol, NNK-N-oxide, and NNAL were observed. With nasal mucosa microsomes, however, only keto aldehyde and keto alcohol formation were appreciable. SA and AC significantly decreased NNK metabolism in lung and nasal mucosa microsomes.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1992

Purification and crystallization of intact human rhinovirus complexed with a neutralizing Fab.

We report the first crystallization of an intact virion, human rhinovirus 14, complexed with the Fab fragment from a neutralizing antibody. These crystals diffract to at least 6.0A resolution. It has been suggested that Fab's and mAb's can induce large conformational changes in the capsid upon binding. The structure of this complex should enable us to detect the existence and role of such changes.

Antibodies, Monoclonal↗
PubMed1992

Urinary mutagenic activity in workers exposed to diesel exhaust.

We measured postshift urinary mutagenicity (mutu; n = 306 samples) on a population of railroad workers (n = 87) with a range of diesel exhaust exposures. Postshift urinary mutagenicity was determined by a sensitive microsuspension procedure using Salmonella strain TA98 +/- S9. Number of cigarettes smoked on the study day and urinary cotinine were highly correlated with postshift urinary mutagenicity. Diesel exhaust exposure was measured over the work shift by constant-flow personal sampling pumps. Respirable particle concentrations were adjusted for the contribution of environmental tobacco smoke, as estimated from nicotine concentration on treated filters. The relative ranking of jobs by this adjusted respirable particle concentration (ARP) was correlated with relative contact the job groups have with operating diesel locomotives. After adjustment for cigarette smoking (active and passive) in multiple regressions, there was no independent association of diesel exhaust exposure, as estimated by ARP, with postshift urinary mutagenicity among smokers or nonsmokers. An important finding is the detection of "baseline" mutagenicity in most of the nonsmoking workers. Despite the use of individual measurements of diesel exhaust exposure, the absence of a significant association in this study may be due to the low levels of diesel exposure, the lack of a specific marker for diesel exhaust exposure, and/or urinary mutagenicity levels from diesel exposure below the limit of sensitivity for the mutagenicity assay.

Adult↗
PubMed1992

Comparative effects of thyroxine and/or retinoic acid treatment in vivo on growth hormone synthesis and release by pituitaries from thyroidectomized rats.

Thyroid hormones and retinoic acid (RA) coregulate growth hormone (GH) synthesis and release from cultured pituitary tumor cells by interacting with nuclear receptors that activate GH gene transcription. Whether these two compounds share overlapping GH regulatory activities in vivo is unclear. Therefore we compared the effects of in vivo replacement therapy with thyroxine (T4) and/or retinoic acid (RA) on GH synthesis and release in pituitaries from hypothyroid rats. Three weeks after thyroidectomy, male rats (100-150 grams, body weight) received 7 days of intraperitoneal T4 (20 ug/kg/day) and/or RA (500 ug/kg/day) or vehicle. Isolated pituitary fragments were incubated for 3 h with [14C]leucine followed by 2 h with [3H]leucine and 3 nM rat growth hormone-releasing hormone (GHRH). Basal synthesis, GHRH-induced release of stored [14C]GH, and GHRH-stimulated release of newly synthesized [3H]GH were assessed by specific immunopercipitation of media and tissue homogenates. T4 increased the synthesis of GH in the absence and presence of GHRH. T4, but not RA, increased the absolute amount of stored and newly synthesized GH released by GHRH. Neither T4 nor RA altered the percent of stored GH released by GHRH, however, both independently or additively decreased the percent of newly synthesized GH released by GHRH. In summary, treatment of hypothyroidism with T4 increased GH synthesis and absolute release. Interestingly the fractional release of GH was unchanged or decreased by T4 treatment. RA treatment had no effect on GH synthesis or absolute release, but like T4 it decreased the fractional release of newly synthesized GH. Thus T4 and RA did not share similar regulatory effects on GH synthesis and stored GH release but did have similar effects on the fractional release of newly synthesized GH in pituitaries from thyroidectomized male rats.

Analysis of Variance↗
PubMed1992

Intravitreal ganciclovir pharmacokinetics in rabbits and man.

Cytomegalovirus (CMV) retinitis occurs in immunocompromised patients and can be treated by repeated intravenous or intravitreal injections of ganciclovir (GCV) or foscarnet. Due to toxicity and complications these modalities are not ideal. The development of alternative administration routes is hindered by a lack of pharmacokinetic data. Devices giving pseudo zero order release of GCV were implanted intravitreally first in rabbits and then in patients with AIDS associated CMV retinitis as part of a Phase I clinical trial. Steady state intravitreal GCV levels were obtained immediately after death and the elimination rate constants were calculated assuming first order pharmacokinetics. Normalizing for retinal surface area, distribution volume and anatomic volume, the retinal elimination rate constants were calculated. These were found to be 0.017 cm-2hr-1 in rabbits and 0.015 cm-2hr-1 in man. This indicates that the rabbit eye is a good model for studying intravitreal pharmacokinetics of ganciclovir and suggests a common elimination mechanism which may be trans-retinal.

Animals↗