Anti-alpha1(IV) collagen autoantibodies associated with lung adenocarcinoma presenting as the Goodpasture syndrome.
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Adenocarcinoma↗
Biomedical subjects
J E Tomaszewski
Publications and source records attributed to J E Tomaszewski.
Epstein-Barr virus-associated hepatic smooth muscle neoplasm in a cardiac transplant recipient.
Host immunosuppression is increasingly recognized as a significant risk factor for the development of a primary neoplasm. Chronic immunosuppressive therapy, as used in organ transplantation, may perturb the immunosurveillance ability of the host, making the patient more susceptible to virus-associated malignancies. We have taken care of a care of a child who received an orthotopic heart transplant and who then developed both a generalized lymphoproliferative disorder and a leiomyoma of the liver a year later. Epstein-Barr virus DNA was detected in a lymph node initially and the hepatic tumor cells subsequently. The former responded to a reduction in the immunosuppressive medications and the latter responded to surgical resection. This is the first report of a hepatic smooth cell neoplasm occurring following cardiac transplant and the development of two sequential Epstein-Barr virus-associated disorders in an immunosuppressed patient.
Child↗
Cytopathology of retrograde renal pelvis brush specimens: an analysis of 40 cases with emphasis on collecting duct carcinoma and low-intermediate grade transitional cell carcinoma.
We report our experience with 40 retrograde renal brush samples of pelvic-calyceal lesions with confirmatory tissue studies. On-site cytopathologic evaluation was performed in 38 of these specimens. The final histologic diagnoses included 24 cases of transitional cell carcinoma (TCC), 17 of which were low-intermediate grade tumors. All 24 cases were diagnosed cytologically as TCC (22), or as suspicious for TCC (2). Three cases classified as collecting duct carcinomas were resected; the cytologic specimens in 2 of these cases were interpreted as TCC, and one as reactive change. There were three renal cell carcinomas (RCC); cytologically, one was considered a papillary neoplasm, one suspicious for malignancy, and one as reactive. Two cases of atypical renal cysts were reported as suspicious for malignancy in both cytologic and histologic material. There was one case of metastatic colon carcinoma identified in the brush specimen. Finally, tissue studies in the remaining 7 cases showed reactive/inflammatory changes; however, four of the corresponding pelvic brush specimens were considered abnormal. A review of the above cases is reported with the objective of presenting the cytologic features seen in collecting duct carcinoma, low-intermediate grade TCC, and diagnostically difficult cases with cyto/histomorphologic discrepancies. The contribution of on-site assessment to diagnostic accuracy is also discussed.
Carcinoma↗
Reversal of acute renal allograft rejection by extracorporeal photopheresis: a case presentation and review of the literature.
There is a clear need for well-tolerated immunomodulatory agents that can aid in the prevention of acute solid organ rejection. Extracorporeal photopherosis is an apheresis-based therapy that is currently available at many medical centers worldwide. Preliminary studies utilizing photopheresis with standard immunosuppressives have shown this therapy to successfully reverse acute cellular rejection of cardiac allografts with minimal toxicity. No formal evaluation of the role of extracorporeal photopheresis had been performed in renal transplantation. In this report, photopheresis was successfully utilized to treat acute cellular rejection in a patient with a renal allograft. This lends further support to the existing literature suggesting that photopheresis may be useful for the reversal of acute solid organ rejection. Although our experience with this patient is anecdotal, photopheresis merits further study as treatment for severe renal allograft rejection.
Acute Disease↗
Myelotoxic effects of the bifunctional alkylating agent bizelesin on human, canine and murine myeloid progenitor cells.
Bizelesin is a potent synthetic derivative of the anticancer agent CC-1065 that preferentially alkylates and binds the minor grove of DNA. Preclinical animal studies have found bizelesin to be more toxic to beagle dogs than to rodents and that myelosuppression was the dose-limiting toxicity. This toxicity was dose- and time-dependent in all species. Due to the significant difference in the in vivo myelotoxicity between species, it was important to determine which one most closely resembles humans on a pharmacodynamic basis. Therefore, hematopoietic clonal assays were utilized to evaluate the effects of bizelesin on granulocyte-macrophage (CFU-gm) colony formation. Marrow cells were exposed in vitro to bizelesin (0.001-1000 nM) for 1 or 8 h and then assayed for colony formation. There was a 3-log difference in drug concentration at which 100% colony inhibition occurred (1 or 8 h) for murine CFU-gm versus human or canine CFU-gm. The IC70 value after an 8-h bizelesin exposure for human CFU-gm (0.006 +/- 0.002 nM) was 2220-times lower than for murine CFU-gm (13.32 +/- 8.31 nM). At any given concentration, an 8 h drug exposure resulted in greater colony inhibition than a 1 h exposure for all species (P < 0.05). Increasing exposure time from 1 to 8 h increased toxicity to human and canine CFU-gm much more than to murine CFU-gm. The clinically formulated drug solution was a more potent inhibitor of human colony formation than drug dissolved in DMSO. The IC70 value after a 1-h exposure was 1.7 times lower for human CFU-gm with formulated bizelesin (0.106 +/- 0.105 nM) than bulk drug in DMSO (0.184 +/- 0.044 nM). The results of these in vitro clonal assays were qualitatively consistent with those seen in whole animal studies, suggesting that bizelesin will be a potent myelosuppressive agent in the clinic. Since the dose-limiting toxicity in preclinical models is myelosuppression and the in vitro sensitivity of human and canine CFU-gm is similar, the canine maximum tolerated dose (MTD) is better than the murine MTD to determine a safe starting dose for phase I clinical trials.
Animals↗
Analysis of Epstein-Barr virus-associated posttransplantation lymphoproliferative disorder after lung transplantation.
BACKGROUND: Epstein-Barr virus (EBV)-associated posttransplantation lymphoproliferative disorder (PTLD) is a serious complication of lung transplantation. Besides immunosuppression the risk factors for PTLD development are largely unknown. METHODS: The incidence of PTLD was ascertained in a lung transplant population consisting of 45 patients. Nine patients (20%) experienced PTLD. The clinical, histologic, and human leukocyte antigen (HLA) data were collected on all patients. The incidence of EBV infection in lymphoid tissue taken at the time of engraftment was studied by using EBV in situ hybridization. RESULTS: All patients with PTLD had polymorphous lymphoproliferations, seven of which were polymorphous B-cell hyperplasias and two of which were polymorphous B-cell lymphomas. EBV was identified in all lesions. All patients with polymorphous B-cell hyperplasias had clinically unsuspected disease, five of which were identified at autopsy. The two polymorphous B-cell lymphoma lesions were monoclonal and regressed with immunosuppression reduction. EBV in situ hybridization on donor or recipient lymph nodes obtained at engraftment from the 45 transplant recipients showed no difference in the number of EBV positive cells in patients with and without PTLD. Cyclosporine and PTLD and azathioprine dosages and cyclosporine levels were similar between patients with and without PTLD. PTLD was seen in patients with high cumulative doses of antilymphocyte globulin. Analysis of HLA status showed a predominance of HLA A2 and DR7 in the donors of the patients with PTLD, whereas donor HLA B7 was more common in patients without PTLD> CONCLUSIONS: Detailed studies are necessary to further elucidate the risk factors for PTLD development in the lung transplant population.
Adult↗
An analysis of the time course of postoperative prostate-specific antigen failure in patients with positive surgical margins: implications on the use of adjuvant therapy.
OBJECTIVES: The role of adjuvant therapy in the postprostatectomy setting for positive margin patients is an unresolved issue. The purpose of this study is to provide the rationale for patient selection in Phase III trials that test the impact of adjuvant therapy on survival in positive margin prostate cancer patients. METHODS: Early (12 months or less) and delayed (more than 12 months) postoperative prostate-specific antigen (PSA) failure have been correlated with distant and local failure, respectively, as the site of first failure. In this study, a Cox regression multivariate analysis was used to determine the significant independent clinical and pathologic predictors of early and delayed postoperative PSA failure in 143 margin-positive prostate cancer patients. RESULTS: Margin-positive patients with positive pelvic lymph nodes, seminal vesicle invasion, or prostatectomy Gleason sum 8 or higher were excluded. For the remaining patients, a prostatectomy Gleason sum of 7, preoperative PSA more than 20 ng/mL, and an endorectal coil magnetic resonance imaging (erMRI) scan showing extensive disease were significant independent predictors of early postoperative PSA failure. Conversely, a prostatectomy Gleason sum of 6 or less, preoperative PSA 20 ng/mL or less, and an erMRI showing limited disease predicted delayed PSA failure. CONCLUSIONS: Preliminary data suggest that the pattern of first failure can be predicted by the time course of rise in the postoperative PSA. The preliminary results of this study suggest that patient selection for clinical trials examining the efficacy of postoperative adjuvant therapy in the positive margin patient may be determined on the basis of the clinical and pathologic characteristics that predict early versus delayed postoperative PSA failure.
Clinical Trials, Phase III as Topic↗
Inhibition of vein graft intimal and medial thickening by periadventitial application of a sulfated carbohydrate polymer.
PURPOSE: The purpose of this study was to determine whether the wall thickening observed in vein grafts after they were placed into the arterial circulation could be inhibited by periadventitial delivery of an insoluble sulfated polymer of beta-cyclodextrin (P-CDS) capable of tightly binding heparin binding growth factors. METHODS: Thirty-four New Zealand white rabbits underwent implantation of reversed autologous jugular vein interposition grafts in the common carotid artery and were randomized to receive either 20 mg P-CDS (n = 18) topically around the graft or no additional therapy (n = 16). Before being killed at 28 days, animals were given bromodeoxyuridine to assess smooth muscle cell proliferation. Histomorphometric analyses were performed after perfusion fixation. RESULTS: Compared to controls, treatment with P-CDS was associated with reduced mean intimal thickness (24 +/- 3 vs 38 +/- 4 microns; mean SEM, p < 0.01) and intimal area (0.25 +/- 0.03 vs 0.54 +/- 0.09 mm2; p < 0.01). There was also significantly less medial thickness in the P-CDS group (45 +/- 3 vs 63 +/-3, p < 0.001). There was no significant difference in intimal or medial smooth muscle cell proliferation between P-CDS-treated and control vein grafts at 28 days. The polymer persisted in the adventitia with a mild foreign body reaction. CONCLUSION: Periadventitial placement of P-CDS, a novel, insoluble, sulfated carbohydrate polymer, inhibits intimal and medial thickening of vein bypass grafts in this model of vein grafting. The persistence of P-CDS in vivo for prolonged periods, and the ease of topical application of P-CDS during vascular bypasses may have important implications for its future use in vascular surgery.
Administration, Topical↗
The role of the Sertoli cell in active immunosuppression in the human testis.
OBJECTIVE: To define the involvement of Sertoli cells in immune suppression within the testis by identifying surface receptor molecules that describe or communicate with cells of the immune system. MATERIALS AND METHODS: Ten pairs of human testes obtained from orchidectomy were stained immunohistochemically with established monoclonal antibodies that identify common cells of the immune system. RESULTS: Patterns of staining were similar in all testes. Class I major histocompatibility complex (MHC) antigen, important for self/non-self recognition, was found on Sertoli cells. Class II MHC antigen, important for immune cell interaction and limited to immune cells, was absent. Leu M3, characteristically found on macrophages, was also seen on Sertoli cells but no receptor antigens defining basic T cell types (CD4, CD8), B cells (Leu 12) or natural killer cells (Leu 11) were seen on Sertoli cells. CONCLUSIONS: The Sertoli cell membrane lacks lymphocyte-cell surface markers but harbours somatic cell and macrophage markers. This suggests that immunosuppression within the testis is not maintained through classic lymphocyte receptors. The presence of a macrophage marker is consistent with the known phagocytic activity of the Sertoli cell.
Adult↗
Critical analysis of the ability of the endorectal coil magnetic resonance imaging scan to predict pathologic stage, margin status, and postoperative prostate-specific antigen failure in patients with clinically organ-confined prostate cancer.
PURPOSE: To determine whether there is a role for endorectal coil magnetic resonance imaging (erMRI) in the prediction of pathologic stage, margin status, and/or postoperative prostate-specific antigen (PSA) failure in patients with clinically organ-confined prostate cancer. PATIENTS AND METHODS: Using erMRI, the radiologic-pathologic correlation of extracapsular extension (ECE) and seminal vesicle invasion (SVI) was evaluated in 445 surgically managed patients. Logistic regression multivariable analysis was applied to the clinical stage, PSA, biopsy Gleason grade, and erMRI findings to assess the outcomes of ECE, SVI, positive surgical margins (PSM), and postoperative PSA failure. RESULTS: The accuracy of erMRI to predict for ECE and SVI numerically decreased with both increasing PSA and biopsy Gleason score because of the increasing false-negative scans in cases of microscopic transcapsular or seminal vesicle disease. Of patients who could not be categorized into low or high risk for postoperative PSA failure on the basis of clinical stage, preoperative PSA, and biopsy Gleason score, a negative or positive erMRI for ECE or SVI stratified these patients into groups with a 78% versus 21% (P < .0001) 3-year rate of actuarial freedom from PSA failure. In this subgroup, the overall accuracy of the erMRI was 70% +/- 6% and 94% +/- 2% for ECE and SVI, respectively. The most significant predictor on multivariable analysis of PSM was the erMRI finding of ECE (P = .0001). CONCLUSION: This initial report suggests that a preoperative erMRI can identify clinically organ-confined prostate cancer patients at high risk for having ECE, SVI, and PSM that otherwise would be missed on the basis of the clinical stage, preoperative PSA, and biopsy Gleason score. Confirmatory studies are needed.
Adenocarcinoma↗
Strategy for repeat biopsy of patients with prostatic intraepithelial neoplasia detected by prostate needle biopsy.
PURPOSE: We evaluated the strategy for repeat biopsy of patients with prostatic intraepithelial neoplasia without concurrent carcinoma detected on prostate needle biopsy. MATERIALS AND METHODS: Of 1,275 consecutive patients undergoing prostate needle biopsy 61 were identified with prostatic intraepithelial neoplasia but without concurrent prostate carcinoma. Of the 61 patients 53 had undergone repeat biopsy. The medical records, transrectal ultrasound, and operative and pathological reports of these patients were reviewed. RESULTS: Repeat biopsy was done in 53 patients with prostatic intraepithelial neoplasia, yielding carcinoma in 15, prostatic intraepithelial neoplasia without carcinoma in 8 and benign tissue in 30. The yield of carcinoma from repeat biopsy of a prostatic intraepithelial neoplasia site was 8.3% (7 of 84 sites). A total of 18 sites of carcinoma was detected by repeat biopsy of a previous random biopsy site (8), a prostatic intraepithelial neoplasia site only (5), a transrectal ultrasound nodule (3), a palpable nodule and prostatic intraepithelial neoplasia site (1), and a transrectal ultrasound nodule and prostatic intraepithelial neoplasia site (1). Carcinoma was as frequently detected by repeat biopsy of a prostatic intraepithelial neoplasia site (6 patients) as by random repeat biopsy (6 patients). CONCLUSIONS: Repeat prostate needle biopsy of patients with prostatic intraepithelial neoplasia should include random repeat biopsy and repeat biopsy of transrectal ultrasound abnormalities as well as previous sites of prostatic intraepithelial neoplasia.
Adenocarcinoma↗
Identification of Epstein-Barr virus lytic activity in post-transplantation lymphoproliferative disease.
Post-transplantation lymphoproliferative disorder (PTLD) is a serious complication of organ transplantation. The majority of these lymphoid expansions are associated with latent Epstein-Barr virus (EBV) infection, but lytic activity may play an important role in initiating the disease process. Forty-eight specimens from 44 allograft recipients with EBV-associated PTLD were studied by immunohistochemical techniques for EBV lytic proteins, by use of monoclonal antibodies specific for the immediate early latent to lytic switch protein BZLF1 and two early antigens (diffuse and restricted). In addition, the specimens were studied by in situ hybridization for EBV DNA by use of an oligonucleotide probe for the EBV NotI tandem DNA repeats, whose expression seems confined to lytic infection. Thirty specimens were studied by in situ hybridization for immediate early (BZLF1) and late (gp350/220) lytic mRNA transcripts. Ninety-two percent of the specimens demonstrated at least one of the lytic EBV proteins. BZLF1 protein was seen in 81% of the specimens, whereas 54% and 52% of specimens expressed diffuse and restricted early antigens, respectively. Twenty-nine percent of specimens contained all three of the lytic proteins. The NotI tandem DNA probe produced staining in 88% of the specimens, whereas immediate early and late lytic transcripts were seen in 90% of the specimens. The amount of lytic activity did not significantly vary with PTLD histopathologic findings, but monomorphous proliferations localized to a single anatomic site showed a slightly lower reactivity with the antibodies and nucleic acid probes. Lytic activity was highest in patients with multisite disease, although this difference was not statistically significant. In conclusion, a significant proportion of patients with PTLD expressed lytic nucleic acids and proteins. Further work is necessary to analyze the role of lytic EBV infection in the initiation and maintenance of lymphoproliferative disorders in allograft recipients.
Adolescent↗
The measurement of complexity in surgical pathology.
The quantitation of effort both within and among surgical pathology laboratories is data which is being increasingly sought by physician managers, hospital administrators and managed care organizations. Simple measurement of case numbers fails to adequately represent the work of a laboratory. The complexity of the cases reviewed is likely to explain a significant portion of the variance in the time required to bring a case to final diagnosis. Measures which adequately reflect complexity in surgical pathology cases have not been developed. We have studied a variety of extractable report features and correlated these with the time required for case sign-out. Numbers of slides reviewed and total lines of factual data provided were strong correlates of the time required to complete case review, report construction and verification. Such data suggests that models can be constructed based on data that can be gleaned from case reports and records which will relate such data to actual work time.
Analysis of Variance↗
A recombinant vaccinia virus expressing human prostate-specific antigen (PSA): safety and immunogenicity in a non-human primate.
Prostate-specific antigen (PSA) is a serine protease secreted by prostatic epithelial cells and is widely used as a marker for prostate cancer. The tissue specificity of PSA makes it a potential target for active specific immunotherapy, especially in prostate cancer patients who have undergone prostatectomy and in whom the only PSA-expressing tissue in the body resides in metastatic deposits. We report here the cloning, construction and immunological consequences of immunization of rhesus monkeys with a recombinant vaccinia virus expressing human PSA (designated rV-PSA). The prostate gland of the rhesus is structurally and functionally similar to the human prostate. While rodent and other mammalian species do not share homology with human PSA, there is 94% homology between the amino acid sequences of rhesus and human PSA. Immunization of rhesus monkeys with wild-type vaccinia virus or rV-PSA elicited the usual low-grade constitutional symptoms of vaccinia virus infection. There was no evidence of any adverse effects in any immunized monkeys. A short-lived PSA-specific IgM antibody response was noted in all rV-PSA immunized monkeys regardless of dose level. All monkeys receiving the 10(8)pfu dose of rV-PSA demonstrated PSA-specific T-cell responses that were maintained up to 270 days. No differences in anti-PSA immune responses or toxicity were observed in animals that received prostatectomy prior to immunization. Our results thus demonstrate the safety and immunogenicity of rV-PSA in a non-human primate and have implications for potential specific immunotherapy protocols using PSA as a target.
Animals↗
Severe, irreversible renal failure after ifosfamide treatment. A clinicopathologic report of two patients.
BACKGROUND: Chronic renal failure has been described only rarely in patients treated with the alkylating agent ifosfamide, which is known to cause renal tubular dysfunction and acute renal failure, and the associated histopathologic features have not been well characterized. METHODS: This report describes the clinical course and renal histopathologic features in two patients in whom irreversible renal failure occurred requiring permanent dialysis after treatment with ifosfamide. RESULTS: Irreversible renal failure developed in a 60-year-old man with malignant fibrohistiocytoma, requiring chronic dialysis within several months after he received two cycles of ifosfamide in a cumulative dose of 28 g/m2. The second patient, a 53-year-old man with osteogenic sarcoma, received two cycles of ifosfamide with a cumulative dose of 26 g/m2, after initial therapy with cisplatin and doxorubicin. His renal function worsened over the next 11 months, at which time permanent dialysis was initiated. In neither patient were other causes of renal failure apparent. Renal biopsies in both patients showed diffuse tubular epithelial damage with degenerative and regenerative epithelial changes, diffuse interstitial fibrosis, and arterial and arteriolar sclerosis. CONCLUSIONS: Irreversible severe renal failure, which appears due to nephrotoxic damage of renal tubular epithelium and/or the renal microvasculature may develop after treatment with ifosfamide. Neither large cumulative doses of ifosfamide nor prior cisplatin treatment are necessary for this toxicity to occur. Because a rising serum creatinine may develop months after completion of treatment with ifosfamide, renal function should be monitored closely both during and after ifosfamide treatment.
Antineoplastic Agents, Alkylating↗
The impact of the inclusion of endorectal coil magnetic resonance imaging in a multivariate analysis to predict clinically unsuspected extraprostatic cancer.
BACKGROUND: The introduction of the endorectal coil magnetic resonance imaging (MRI) technique has improved the accuracy of preoperative staging for prostate cancer. This study quantifies the improvement in the ability to identify clinically unsuspected extraprostatic disease with the use of the endorectal coil MRI. METHODS: A retrospective review of the pathologic findings of 347 patients with prostate cancer treated with a radical retropubic prostatectomy was performed. The preoperative clinical indicators including prostate specific antigen (PSA), clinical stage, Gleason score, and endorectal coil MRI data were employed in a multivariate analysis to identify patients who were at high risk for seminal vesicle invasion (SVI) or extracapsular extension (ECE). The sensitivity, specificity, and positive and negative predictive values for predicting SVI and ECE were calculated using the significant clinical indicators found on the multivariate analysis. RESULTS: The clinical factors identified on multivariate analysis as significant predictors of SVI include the endorectal coil MRI data (P < 0.0001), PSA (P = 0.0096), and the Gleason score (P = 0.012). Endorectal coil MRI data (P < 0.0001), PSA (P = .0001), and Gleason score (P < .0001) were significant predictors of ECE. In the patient subgroup with PSA (> 10-20 ng/ml) and Gleason score of 5 to 7, the addition of the endorectal coil MRI data enabled an additional 71 and 27% of patients with SVI and ECE, respectively, to be correctly identified. These patients would have been missed based on the prediction obtained from the PSA and Gleason score alone. CONCLUSIONS: The use of the endorectal coil magnetic resonance imaging data, in addition to prostate specific antigen and Gleason score, provides a more accurate prediction of the pathologic outcome of seminal vesicle invasion and extracapsular extension than the PSA and Gleason score alone for the patient subgroup with a PSA of greater than 10 to 20 ng/ml and Gleason score of 5 to 7.
Adenocarcinoma↗
Migrating vascular smooth muscle cells polarize cell surface urokinase receptors after injury in vitro.
The localization of proteases to cell surfaces via receptors may facilitate cell migration, invasion, and matrix degradation. Since vascular smooth muscle cell (SMC) migration may be an important event in atherosclerosis and in intimal thickening after vascular injury, we studied the cell surface expression of a receptor for urokinase-type plasminogen activator (u-PAR) in cultured human vascular SMC. Using immunofluorescence microscopy, we demonstrated several staining patterns of SMC u-PAR: at the periphery of the cell membrane, at the leading edge, and at cell-cell contact sites. When migration experiments were performed using a wound assay, one-third of the SMC at the wound edge demonstrated polarization of cell surface u-PAR toward the leading edge of the cell membrane (32 +/- 2%, +/- SEM, n = 7). A similar pattern was seen with an antibody to caveolin, a transmembrane protein found in caveolae, but not with an antibody to 5'-nucleotidase, another cell surface glycophosphatidylinositol-anchored protein, which was homogeneously expressed on the cell surface. Low-density lipoprotein receptor-related protein, which mediates internalization of u-PAR bound ligands, was distributed in a diffuse punctate pattern, not polarized to the leading edge. Double immunofluorescent studies demonstrated codistribution of SMC u-PAR with vinculin and caveolin in migrating SMC at the leading edge in a wound assay. Polarization of cell surface u-PAR was not observed in either nonwounded or subconfluent cultures, despite random migratory behavior. These studies suggest that in response to wounding, human vascular SMC polarize and concentrate cell surface u-PAR to their leading edge, perhaps facilitating directional migration.
5'-Nucleotidase↗
Acute cardiotoxicity of the Anti-HIV dideoxynucleoside, F-ddA, in the rat.
2'-beta-Fluoro-2',3'-dideoxyadenosine (F-ddA), an acid-stable, purine dideoxynucleoside with in vitro anti-HIV activity, has been selected by the NCI as a clinical trial candidate. A recent report that high, single doses of F-ddA produce cardiotoxicity in rats prompted the present investigation whose objective was to quantitate this effect and establish a relationship between this toxicity and F-ddA plasma concentrations. Microscopic examination of cardiac tissues for degenerative lesions established the effects of F-ddA and ddA on three iv schedules [daily x 1(2.5-250 mg/kg); daily x 5(125, 250 mg/kg), and BID x 1 (250 mg/kg)] as well as one oral schedule [BID x 1 (500 mg/kg) using 8- to 12-week old female Sprague-Dawley rats. For both F-ddA and ddA, the group mean severity of the cardiac lesions was dose-dependent and proportional to the measured plasma concentrations of the undeaminated parent drugs. F-ddI and ddI, were essentially nontoxic in this study (iv, 250 mg/kg, daily x 1 and daily x 5), since plasma concentrations exceeding 2 mM produced only minimal cardiac lesions. The cardiomyopathy of F-ddA was minimal to mild for all iv doses except 250 mg/kg (daily x 1) and usually was greater than that of ddA at any given dose. This is a consequence of the fact that F-ddA is deaminated 20 times more slowly than ddA, resulting in higher plasma concentrations of F-ddA relative to ddA at any given time for any given dose. Neither F-ddA nor ddA was more cardiotoxic on a repeated iv schedule (daily x 5) than when administered only once, suggesting that rat cardiotoxicity is related Cmax rather than total exposure. In this most sensitive species, the formation of cardiac lesions above the background level is associated with i.v. F-ddA administration when the F-ddA plasma concentration approaches 300 microM, 30-50 times the anticipated therapeutic level in humans.
Administration, Oral↗