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Biomedical subjects

T M Simon

Publications and source records attributed to T M Simon.

At least 37 records · Page 2Linked to original sources
PubMed1983

I. Unbound serum gold: procedure for quantitation.

The unbound fraction of many drugs appears to be the therapeutically active component. However, the major problem encountered in following unbound serum gold (UBSG) concentration during chrysotherapy has been the ability to quantitate such a small quantity of gold reliably without matrix interference. The methodology detailed here overcomes these difficulties and provides an effective means of monitoring the UBSG fraction during chrysotherapy. We have observed that the unbound fraction of gold dissipates quickly after gold sodium thiomalate administration and constitutes less than 2% of the total serum gold concentration.

Arthritis, Rheumatoid↗
PubMed1983

II. Unbound versus total serum gold concentration: pharmacological actions on cellular function.

Unbound serum gold (UBSG) has received little attention, possibly because of rapid in vivo decay and in vivo concentration below the range of existing analytical procedures. We have recently developed a methodology enabling quantitation and study of UBSG during chrysotherapy to assess effects on cellular functions. UBSG after gold administration is labile, declining rapidly after attaining peak values at which lymphocyte mitogen response and polymorphonuclear phagocytosis were observed to be suppressed. Oral gold, i.e., auranofin, 3 mg BID as compared to systemic chrysotherapy 50 mg/wk, resulted in a higher percentage of UBSG to total serum gold.

Anti-Inflammatory Agents↗
PubMed1983

Sjögren's syndrome with pseudolymphoma treated with chrysotherapy.

A 72-year-old woman presented with a 10 X 10 cm pseudolymphoma of the lung and Sjögren's syndrome. She was treated with weekly chrysotherapy for 4 years and had gradual diminution of the lung mass over this period along with normalization of her parotid gland scintiscan. In addition her rheumatoid factor titer (RF) of 1:160,000 fell to zero, IgM level became normal and lymphocyte mitogen response improved. On 5-year followup the patient remains stable with a negative RF, normal IgM and stable chest radiographs.

Aged↗
PubMed1981

Assessment of immune response during chrysotherapy. Comparison of gold sodium thiomalate vs. auranofin.

Auranofin (AF) differs significantly from gold sodium thiomalate (GST) in formulation, i.e., aurous gold is stabilized by dual sulfur and phosphorus ligands, has hydrophobic rather than hydrophilic characteristics, and lacks ionic charge. These attributes facilitate: oral absorption of AF, plasma membrane penetration, increase in intracellular lymphocyte gold concentration and perhaps thereby influence lymphocyte function. AF therapy was observed to affect primarily T rather than B lymphocyte function in 16 RA subjects receiving 6 mg of AF per day for an average of 45 weeks (range 20-74 weeks) compared with GST-treated RA subjects. Lymphocytes from AF-treated subjects manifested prompt and sharp declines in mitogen-induced lymphoproliferative response (LPR); suppressed response to skin testing with dinitrochlorobenzene (DNCB); and blebbing of lymphocyte membranes as shown by scanning electron microscopy. Suppression of LPR with AF was approximately 60% after the first week and 80% after 20 weeks of therapy, contrasting with 0% and 30% for the respective intervals in GST-treated subjects. DNCB skin testing of AF patients, indicated 11 of 14, failed to respond, whereas all GST patients responded. Local or systemic fungal, bacterial and/or opportunistic infections were not encountered. The effect of AF on B cell effector function, e.g., suppression of immunoglobulins and rheumatoid factor titer, was less marked when contrasted with GST therapy in RA subjects, as previously reported.

Arthritis, Rheumatoid↗
PubMed1981

Screening trial with the coordinated gold compound auranofin using mouse lymphocyte leukemia P388.

The coordinated gold compound, 2,3,4,6-tetra-O-acetyl-1-thio-beta-D-glucopyranosato-S-triethylphosphine-gold (auranofin) was found to be effective in increasing the life span of C57BL x DBA/2 F1 mice inoculated with the lymphocytic leukemia P388. A number of dose schedules were used, the lowest dose being 6 mg/kg every fourth day and the highest dose being 6.0 mg/kg twice daily for 9 days; the lowest and highest doses produced treated versus control ratios of 140 and 220%, respectively. All treatment groups achieved the minimum treated versus control ratio of 125%. Animal weights remained stable at twice-daily and high-dose-daily regimens. Increased life span and weight changes were both found to correlate with drug concentration and/or dose frequency.

Animals↗
PubMed1979

Inhibitory effects of a new oral gold compound on HeLa cells.

Auranofin (AF), a recently introduced oral antirheumatic coordinated gold compound, was investigated for its antitumor potential. Due to certain similarities with the antitumor-coordinated compound, cis-Diamminedichloroplatinum II, we studied the effects of AF on cell proliferation. These studies included assessing DNA, RNA, and protein synthesis as measured by incorporation of 3H-thymidine, 3H-uridine, and 3H-leucine, respectively, into HeLa cells. AF was shown to exert a dose-dependent inhibition on DNA synthesis and to inhibit 3H-thymidine uptake more rapidly and persistently than 3H-uridine or 3H-leucine uptake at a gold concentration of 75--100 micrograms/dl. These three parameters were inhibited with a 24-hour exposure to 100 micrograms/dl. The inhibition of 3H-thymidine uptake in HeLa pretreated for 6 hours with 50 or 100 micrograms/dl of gold was found to be irreversible. No change in tracer uptake was observed in the acid-soluble pool or in the uptake of 3H-2-deoxy-D-glucose in these cells. Furthermore, HeLa cells demonstrated marked reductions in viability and oxygen uptake after exposure to AF. Dose-dependent surface morphological changes, e.g., blebbing, pitting, were noted in these cells after a brief treatment period. These results suggest this coordinated gold compount exerts a significant inhibitory effect on essential biological processes and functions.

Aurothioglucose↗
PubMed1979

Effect of chrysotherapy on parameters of immune response.

Thirty-nine subjects with classical or definite rheumatoid arthritis received weekly intramuscular gold sodium thiomalate (GST) to sustain gold blood levels of more than 320 microgram/dl. Statistical analysis revealed significant declines from pre-treatment values for IgM, IgG, and IaA. Rheumatoid factor titer decreased in 29 of 39 subjects, 15 becoming seronegative. Circulating lymphocytes decreased by 27%. The maximal suppressive effect on IgM was not achieved until the 3rd and 4th years of GST administration. Auranofin (AF) 6 mg/day was administered to 15 patients for an average interval of 45 weeks. In vitro and in vivo suppression of lymphocyte mitogen response with AF was more rapid in onset and significantly greater than with GST. Suppression of dinitrochlorobenzene skin sensitization was observed in AF patients. The clinical response in GST treated subjects correlated with suppression of immunoglobulins, rheumatoid factor titer, and circulating lymphocytes. A significant decline in these variables was not achieved for a corresponding interval with AF treatment. It is suggested that chrysotherapy may be applied more widely to immunologically-mediated disorders and perhaps be used to affect selectively B versus T mediated dysfunction.

Antibody Formation↗
PubMed1979

Cellular antiproliferative action exerted by auranofin.

Auranofin (AF) is a new orally absorbed coordinated gold compound currently undergoing Phase I studies for its use in the treatment of rheumatoid arthritis. Our investigations with RAJI lymphoma, HeLa carcinoma, and EBV-transformed cells indicate AF exerts an inhibitory effect on DNA, RNA, and protein synthesis as assessed by 3H-thymidine, 3H-uridine, and 3H-leucine uptake, respectively. A rapid and persistent dose dependent inhibition of 3H-thymidine uptake was observed at gold concentrations of 50-100 microgram/dl while all parameters were inhibited after a 24 hr exposure to 100 microgram/dl. Reductions in viability and surface morphological changes were also observed. These results suggest AF exerts a significant inhibitory effect on essential biological processes and functions.

Aurothioglucose↗
PubMed1975

Chrysotherapy: pharmacological and clinical correlates.

Relationships between gold administration and serum gold content were observed in 56 RA subjects receiving up to five years of weekly chrysotherapy. Wide fluctuations in serum gold responses to standard 50 mg IM injections were noted. Individual adjustments to dosage schedules were made as dictated by patient serum gold responses. Enhanced clinical and laboratory response was prolonged with higher sustained serum gold concentration greater than 300 mug per cent. Maintaining serum levels greater than 300 mug per cent is postulated to facilitate access of gold to "effector sites" within the deeper compartments by providing higher sustained gradients between superficial (blood) and deeper body compartments. The complexity of the system of effector sites responsive to gold and their divergent location within the body likely affects the accessibility of the agent for these sites; hence, affecting the correlation between gold levels and therapeutic response. The application of pharmacokinetic principles in chrysotherapy, nevertheless, provides the basis for optimizing accessibility of the agent and the therapeutic response. (J Rheumatol 2: 401-410, 1975).

Arthritis, Rheumatoid↗
PubMedDate not supplied

Freeze dried anterior cruciate ligament allografts. Preliminary studies in a goat model.

One ACL in each of 11 mature goats was replaced with a freeze dried bone-ACL-bone allograft. One year following implantation the goats had their knees evaluated biomechanically and for microvascularity and histologic changes. The reconstructed knees had a significantly greater total AP laxity (3.8 +/- 0.6 mm) (mean and SEM) than the controls (1.0 +/- 0.1 mm). Differences in primary AP laxity were responsible for 81% of the difference in total laxity, with only a 0.4 mm difference in secondary laxity. Neutral stiffness in the reconstructive knee was 17% of control, while stiffness at 30 newtons (N) of anterior force was approximately 50% of controls. Ligament stiffness in the linear region for the ACL allograft was 35% of the control value of 686 N/mm. The maximum load of the allografts was 571 +/- 45 N, or 25% of the contralateral ACL control strength (2301 +/- 155 N). Five of the seven allografts failed at the femoral insertion. Both elongation (83%) and energy (21%) to maximum load were less for allografts than controls. Histologic evaluation of the allografts revealed the presence of a regular oriented dense connective tissue which resembled a normal ligament. Microangiography revealed a periligamentous and endoligamentous vascular pattern reminiscent of a normal ACL and complete revascularization of the bone plugs.

Animals↗
PubMedDate not supplied

Cruciate reconstruction using freeze dried anterior cruciate ligament allograft and a ligament augmentation device (LAD). An experimental study in a goat model.

One ACL in each of 11 mature goats was replaced with a freeze dried bone-ACL-bone allograft and a ligament augmentation device (LAD). The LAD was released from its tibial fixation at 3 months postoperation. Biomechanical, microvascular, and histological changes were evaluated 1 year following implantation. The reconstructed knees had a significantly greater total AP translation (3.1 +/- 0.5 mm) (mean and SEM) than the contralateral controls (1.0 +/- 0.1 mm). Differences in primary AP translation were responsible for 59% of the difference in total translation, with only a 0.6 mm difference in secondary translation. Neutral stiffness in the reconstructive knee was 22% of control, while stiffness at 30 N of anterior force was approximately 35% of controls. Ligament stiffness in the linear region for the ACL allograft/LAD was 53% of the control value of 691 N/mm. The maximum load of the allograft/LADs was 1,052 +/- 145 N, or 43% of the contralateral ACL control strength (2,448 +/- 144 N). Five of the six allografts failed at the femoral insertion. Energy (39%) to maximum load was less for allograft/LADs than controls but elongation to maximum load was the same as control. Histologic evaluation of the allograft/LADs revealed soft tissue cellular ingrowth into the LAD in the extraarticular portions. No bony growth into the LAD was observed. The collagen fibers of the graft appear to be arranged in a longitudinal orientation although some areas show chaotic collagen fibers. Microangiography revealed a periligamentous and endoligamentous vascular pattern reminiscent of a normal ACL and complete revascularization of the bone plugs.

Animals↗
PubMedDate not supplied

The effects of processing techniques on the mechanical properties of bone-anterior cruciate ligament-bone allografts. An experimental study in goats.

There has been a growing interest in the use of allografts as ACL substitutes. Allografts are often freeze dried to increase shelf storage time and sterilized with ethylene oxide. This study was conducted to determine the effect of a specific ethylene oxide sterilization procedure and freeze drying process on the initial mechanical properties of femur-ACL-tibia preparations. Twelve knees (stifle joints) from six mature goats were divided into two groups (one knee of pair to each group). Knees were cleaned of all soft tissue except for the anterior cruciate, posterior cruciate, and collateral ligaments. Group 1 was sterilized with ethylene oxide (simulating clean procurement) then freeze dried. Group 2 was freeze dried only (simulating sterile procurement). The knees were rehydrated and then tested in tension to failure to determine their structural mechanical properties. The ethylene oxide-freeze dried specimens (Group 1) had a mean maximum load before failure of 2059 +/- 273 newtons (N) (+/- SE) which was not statistically different than the maximum load of the freeze dried specimens (Group 2) of 2023 +/- 214 N. The average strength of Group 1 and 2 combined was not significantly different than a third group of 12 normal femur-ACL-tibia controls which had an average maximum force of 2403 +/- 133 N. No significant differences between the groups were observed for stiffness, energy to maximum strength, or elongation to maximum force. It appears the freeze dry processing, with or without ethylene oxide sterilization, using the procedure we used, has, at most, a small effect on the initial mechanical properties of the preparations.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMedDate not supplied

Intraarticular reaction associated with the use of freeze-dried, ethylene oxide-sterilized bone-patella tendon-bone allografts in the reconstruction of the anterior cruciate ligament.

One hundred nine patients over a 3 year period underwent reconstruction for chronic ACL ruptures using a freeze-dried, ethylene oxide-sterilized bone-patella tendon-bone allograft. Seven patients (6.4%) developed a characteristic persistent intraarticular reaction. This reaction was characterized by persistent synovial effusion with collagenous particulates and cellular inflammatory response. Synovial biopsies in all cases showed a similar chronic inflammatory process, characterized by fibrin, collagen, and phagocytic cells. The intraarticular white cells were predominantly lymphocytes. Removal of the allograft resulted in resolution of the reaction in all of the patients. Three of the seven patients showed HLA conversion. Gas chromatography demonstrated detectable levels of ethylene chlorohydrin, a toxic reaction product of ethylene oxide, within the allograft and synovium 14 months following implantation of one graft. These seven cases presented strongly suggest a nonspecific or immune mediated response that must be further delineated. The use of freeze-dried, ethylene oxide-sterilized allografts using standard techniques cannot be recommended for reconstruction of the ACL.

Adolescent↗
PubMedDate not supplied

Meniscal transplantation using fresh and cryopreserved allografts. An experimental study in goats.

A comparative study of three subgroups of meniscal transplants was undertaken in the goat model: Group 1 (autograft) involved removal and immediate reimplantation of the meniscus; Group 2, fresh meniscal allografts; and Group 3, cryopreserved (30 days) meniscal allografts. Six months after surgery, tissues were evaluated for gross degenerative changes, proteoglycan concentration (as assessed by uronic acid), water content, vascularity, histology, and cell viability. The contralateral knee served as control for all comparisons. There was no statistical difference in the amount of arthritis present and all transplants demonstrated an essentially normal peripheral vascularity compared to controls. Sections revealed reduced numbers of cells in the central portions of the transplanted menisci and these viable cells demonstrated different behavior in multiplication in tissue culture compared to contralateral controls. Grossly and microscopically, the implanted menisci differed little from the controls. The measurement of proteoglycan concentration and water content of the transplanted meniscal cartilage suggest alterations that may affect the long-term mechanical properties. The autograft specimens showed the water content was very slightly increased (3% to 6%), while the proteoglycan concentration was increased (42% in terms of uronic acid). In contrast, the water content of the fresh allograft group and the cryopreserved group was increased 12% to 24%. Proteoglycan concentration in these groups was decreased up to 56% in portions of some menisci compared to controls. Fresh and cryopreserved meniscal allografts showed peripheral healing, revascularization, cellularity, and incorporation, and grossly appeared good at 6 months in the goat model. The biochemical changes in the extracellular matrix at 6 months raises questions on the long-term function of these transplanted menisci.

Animals↗
PubMedDate not supplied

A comparison of patellar tendon autograft and allograft used for anterior cruciate ligament reconstruction in the goat model.

Similar-sized patellar tendon autografts and fresh-frozen allografts were used to reconstruct the anterior cruciate ligament of one knee in 40 female goats. Evaluations of the reconstructions and contralateral controls at the 6-week and 6-month postoperative periods included anterior-posterior translation, mechanical properties determined during tensile failure tests, measurement of cross-sectional area, histology, collagen fibril size and area distribution, and associated articular cartilage degenerative changes. Six months after anterior cruciate ligament reconstruction, the autografts demonstrated a smaller increase in anterior-posterior displacement, values of maximum force to failure two times greater, a significant increase in cross-sectional area, a more rapid loss of large-diameter collagen fibrils, and an increased density and number of small-diameter collagen fibrils compared to the allografts. Clinical significance. More surgeons are allowing their patients to return to running and sports 6 months after anterior cruciate ligament reconstruction. While the structural and material properties of autografts and allografts at time zero are similar, in the goat model during the first 6 months they differ. The allografts demonstrate a greater decrease in their implantation structural properties, a slower rate of biologic incorporation, and the prolonged presence of an inflammatory response. At 6 months the autograft demonstrates a more robust biologic response, improved stability, and increased strength to failure values.

Animals↗
PubMedDate not supplied

Cell survival after transplantation of fresh meniscal allografts. DNA probe analysis in a goat model.

UNLABELLED: Fibrochondrocytes synthesize and maintain the extracellular matrix responsible for the distinctive material and structural properties of a normal meniscus. Viable meniscal cells are believed to be necessary for the long-term maintenance of these properties in meniscal allografts. The purpose of this study was to determine if the donor cells (fibrochondrocytes) survive after a fresh meniscal allograft transplantation. A DNA probe technique was used to clearly distinguish the DNA patterns in donor cells from the host cells in the Spanish goat. No remaining donor DNA could be demonstrated at 4 weeks in transplanted meniscal tissue; it was all of host origin. The host DNA content at 4 weeks approached or exceeded the amount present in the contralateral control meniscus. CLINICAL SIGNIFICANCE: The results of this study demonstrate that viable cells in medial meniscal allografts transplanted from one animal to another do not survive. Host cells rapidly repopulate the transplanted meniscus. There is no evidence these new cells will maintain on a long-term basis the extracellular matrix of the meniscus. The evidence in this paper, that the fibrochondrocytes do not survive transplantation, suggests further justification is necessary for using grafts with living cells. Allografts with living cells have an increased expense, more complicated surgical logistics, and have a higher potential risk of disease transmission.

Animals↗