ABSTRACT
The purpose of this study was to assess the association of GI events with HRQoL and treatment satisfaction. The effect of baseline GI events persisted through 1 year of follow-up, as indicated by lower EQ-5D, OPAQ-SV, and treatment satisfaction scores among patients with vs without baseline GI events. The presence of GI events is an independent predictor of decreased HRQoL and treatment satisfaction in patients being treated for osteoporosis. INTRODUCTION: The goal of this study was to assess the association of gastrointestinal (GI) events with health-related quality of life (HRQoL) and treatment satisfaction in patients being treated for osteoporosis. METHODS: MUSIC OS was a multinational, prospective, observational study examining the impact of GI events on osteoporosis management in postmenopausal women. In this analysis, HRQoL and treatment satisfaction were assessed at baseline, 6, and 12 months and compared between patients with and without GI events. Covariate-adjusted scores were calculated using multivariate least-squares regression analysis, and differences between the mean scores of patients with and without baseline and post-baseline GI events were determined. RESULTS: Among the 2959 patients in the analysis, unadjusted scores at each time point were lower (i.e., worse) for patients with GI events than patients without GI events. In adjusted analyses, the effect of baseline GI events persisted through 1 year of follow-up, as indicated by lower EQ-5D and OPAQ-SV scores at 12 months among patients with vs without baseline GI events (-0.04 for the EQ-5D utility score, -5.07 for the EQ-5D visual analog scale, -3.35 for OPAQ physical function, -4.60 for OPAQ emotional status, and -8.50 for OPAQ back pain; P ≤ 0.001 for all values). Decrements in month 12 treatment satisfaction scores were -6.46 for patients with baseline GI events and -7.88 for patients with post-baseline GI events. CONCLUSIONS: The presence of GI events is an independent predictor of decreased HRQoL and treatment satisfaction in patients being treated for osteoporosis.
Subject(s)
Bone Density Conservation Agents/adverse effects , Gastrointestinal Diseases/chemically induced , Osteoporosis, Postmenopausal/drug therapy , Patient Satisfaction/statistics & numerical data , Quality of Life , Aged , Bone Density Conservation Agents/therapeutic use , Canada/epidemiology , Drug Utilization/statistics & numerical data , Europe/epidemiology , Female , Follow-Up Studies , Gastrointestinal Diseases/epidemiology , Gastrointestinal Diseases/psychology , Humans , Middle Aged , Osteoporosis, Postmenopausal/epidemiology , Osteoporosis, Postmenopausal/psychology , Prospective Studies , PsychometricsABSTRACT
The Human Proteome Project (HPP) is designed to generate a comprehensive map of the protein-based molecular architecture of the human body, to provide a resource to help elucidate biological and molecular function, and to advance diagnosis and treatment of diseases. Within this framework, the chromosome-based HPP (C-HPP) has allocated responsibility for mapping individual chromosomes by country or region, while the biology/disease HPP (B/D-HPP) coordinates these teams in cross-functional disease-based groups. Chromosome 6 (Ch6) provides an excellent model for integration of these two tasks. This metacentric chromosome has a complement of 1002-1034 genes that code for known, novel or putative proteins. Ch6 is functionally associated with more than 120 major human diseases, many with high population prevalence, devastating clinical impact and profound societal consequences. The unique combination of genomic, proteomic, metabolomic, phenomic and health services data being drawn together within the Ch6 program has enormous potential to advance personalized medicine by promoting robust biomarkers, subunit vaccines and new drug targets. The strong liaison between the clinical and laboratory teams, and the structured framework for technology transfer and health policy decisions within Canada will increase the speed and efficacy of this transition, and the value of this translational research. BIOLOGICAL SIGNIFICANCE: Canada has been selected to play a leading role in the international Human Proteome Project, the global counterpart of the Human Genome Project designed to understand the structure and function of the human proteome in health and disease. Canada will lead an international team focusing on chromosome 6, which is functionally associated with more than 120 major human diseases, including immune and inflammatory disorders affecting the brain, skeletal system, heart and blood vessels, lungs, kidney, liver, gastrointestinal tract and endocrine system. Many of these chronic and persistent diseases have a high population prevalence, devastating clinical impact and profound societal consequences. As a result, they impose a multi-billion dollar economic burden on Canada and on all advanced societies through direct costs of patient care, the loss of health and productivity, and extensive caregiver burden. There is no definitive treatment at the present time for any of these disorders. The manuscript outlines the research which will involve a systematic assessment of all chromosome 6 genes, development of a knowledge base, and development of assays and reagents for all chromosome 6 proteins. We feel that the informatic infrastructure and MRM assays developed will place the chromosome 6 consortium in an excellent position to be a leading player in this major international research initiative. This article is part of a Special Issue: Can Proteomics Fill the Gap Between Genomics and Phenotypes?
Subject(s)
Genetic Diseases, Inborn/genetics , Human Genome Project/organization & administration , Canada , Chromosomes, Human, Pair 6 , Chronic Disease , Genetic Diseases, Inborn/diagnosis , Genomics , HLA Antigens/genetics , HLA-DQ beta-Chains/genetics , HLA-DQ beta-Chains/metabolism , Humans , Ligands , Major Histocompatibility Complex/genetics , Membrane Proteins/genetics , Proteome/metabolism , Transcription Factors/geneticsABSTRACT
Cytomegalovirus (CMV) infection imposes a significant economic burden on susceptible patients after renal transplantation. Our study was conducted to determine the prediction, probability, consequences, and treatment costs of CMV infection under Canadian consensus guidelines in 270 sequential transplant patients. Transplant patients from donors positive (D(+)) for CMV into recipients negative (R(-)) for CMV received antiviral prophylaxis for 14 weeks and all but donor negative (D(-))/R(-) patients were monitored weekly for the CMVpp65 marker expression. Marker-positive patients and patients with CMV infection or disease received antiviral treatment. Within the first 6 months, 27% of the 270 patients tested had incidences of asymptomatic CMV infection, while 9% had CMV syndrome or disease. Only 1% of patients had infection after 6 months. The CMVpp65 marker levels were significantly greater in patients with syndrome or disease; but post-test probabilities and predictive value of the marker assay were low. Mean direct costs for care were $2256 and ranged from $927 for D(-)/R(-) patients to $7069 in the D(+)/R(-) patients. Extension of antiviral prophylaxis to D(+) or D(+)/R(+) patients significantly increased the estimated mean costs for an absolute reduction to 4% in CMV syndrome or disease. Our studies show that current guidelines for treatment enable effective control of CMV infection; however, alternative strategies have different economic impact.
Subject(s)
Antiviral Agents/therapeutic use , Cytomegalovirus Infections/prevention & control , Cytomegalovirus , Kidney Diseases/prevention & control , Kidney Diseases/virology , Kidney Transplantation/adverse effects , Practice Guidelines as Topic , Adult , Antiviral Agents/administration & dosage , Antiviral Agents/economics , Canada , Cohort Studies , Cost-Benefit Analysis , Cytomegalovirus Infections/drug therapy , Cytomegalovirus Infections/economics , Dose-Response Relationship, Drug , Drug Administration Schedule , Female , Ganciclovir/administration & dosage , Ganciclovir/analogs & derivatives , Ganciclovir/economics , Ganciclovir/therapeutic use , Humans , Kaplan-Meier Estimate , Kidney/metabolism , Kidney Diseases/drug therapy , Male , Middle Aged , Phosphoproteins/metabolism , Prospective Studies , Valganciclovir , Viral Matrix Proteins/metabolismABSTRACT
This prospective, blinded observational study was conducted to measure the predictive value the of flow cytometric crossmatch for biopsy-proven acute rejection, graft loss, or death following kidney transplantation. Patients were selected for renal transplantation on the basis of a conventional antihuman globulin cytotoxic T-cell crossmatch. Flow crossmatch was performed simultaneously, but the results were not disclosed to the transplant team. A total of 257 kidney transplant recipients were enrolled in the study; 78 patients experienced biopsy-proven rejection in the first post-transplant year, and 41 patients lost their graft or died during the period of follow-up (mean: 2046 days). Kaplan-Meier estimates of rejection, graft loss, or patient death did not differ between subjects with a positive or negative flow crossmatch. Cox analyses showed no influence of the flow crossmatch on the risk of biopsy-proven acute rejection (P = 0.987). The sensitivity and specificity of the flow crossmatch for prediction of biopsy-proven rejection were 0.128 and 0.883, and the positive and negative post-test probabilities were 0.323 and 0.301, respectively. The magnitude of the channel shift did not influence the multivariate Cox regression model. The area under the receiver operating characteristic curve of the flow crossmatch was 0.483 (P = 0.71) and 0.572 (P = 0.38), respectively for the living and cadaver transplant recipients, indicating no discriminative value in this study population. Flow crossmatch appears to have no significant incremental value in predicting biopsy-proven acute rejection, graft loss, or death following kidney transplantation in patients who have a negative antihuman globulin cytotoxic T-cell crossmatch against their donor.
Subject(s)
Antibodies, Anti-Idiotypic/immunology , Flow Cytometry , Histocompatibility Testing , Kidney Transplantation/immunology , T-Lymphocytes/immunology , Adolescent , Adult , Antibodies, Anti-Idiotypic/analysis , Biomarkers , Cadaver , Graft Rejection/immunology , Graft Rejection/pathology , Humans , Kidney Transplantation/pathology , Living Donors , Middle Aged , Multivariate Analysis , Predictive Value of Tests , Prospective Studies , Single-Blind Method , T-Lymphocytes/pathologyABSTRACT
UNLABELLED: Monitoring of cyclosporine (microemulsion CsA) at 2 hours post-dose (C2), a measure of absorption and exposure, appears superior to trough (C0) monitoring for prediction of rejection risk. The purpose of this study was to determine whether C2 was cost-effective compared to C0 in Argentina. METHODS: A predictive decision model was adapted to Argentina to predict costs associated with C0 and C2 measurements in the first year after transplantation. Patients were treated with microemulsion CsA, steroids and azathioprine or MMF. Parameter estimates for the C0 strategy were based on event rates observed in published clinical trials. The model was adapted to Argentinean health system through local protocols and expert opinions; costs were valued in Argentinean pesos and converted to US dollars (1 USD = 2.85 ARS). RESULTS: Incidence of acute rejection was predicted to be 25.0% at 1-year among patients monitored by C0 and 18.0% by C2. Graft survival was predicted to be 1.4% lower in the C0 group. No important differences were identified in co-morbidity, C0 and C2 monitoring costs, and in ambulatory-based adverse events between C0 and C2 cohorts. The model predicted an average cost per patient of $16,269 for C0 and $16,343 for C2 testing (year 1). Sensitivity analyses indicated that the average daily dose of microemulsion CsA was the most important parameter leading to the incremental cost per patient. CONCLUSIONS: C2 is expected to provide a potentially important reduction in the risk of acute rejection without increasing the estimated cost of care in the first year post-transplant.
Subject(s)
Cyclosporine/blood , Graft Rejection/prevention & control , Kidney Transplantation/immunology , Acute Disease , Argentina , Azathioprine/therapeutic use , Costs and Cost Analysis , Cyclosporine/economics , Cyclosporine/pharmacokinetics , Cyclosporine/therapeutic use , Decision Support Techniques , Drug Therapy, Combination , Emulsions , Graft Survival/drug effects , Graft Survival/immunology , Humans , Immunosuppressive Agents/blood , Immunosuppressive Agents/economics , Immunosuppressive Agents/pharmacokinetics , Immunosuppressive Agents/therapeutic use , Mycophenolic Acid/analogs & derivatives , Mycophenolic Acid/therapeutic use , Time FactorsABSTRACT
BACKGROUND: Basiliximab is a chimeric monoclonal directed against the alpha-chain of the interleukin-2 receptor. International studies have shown that it is highly effective in preventing acute rejection in patients receiving Neoral, and causes no measurable incremental toxicity, but its economic value remains unknown. METHODS: This study employed an economic model to examine the potential economic benefit of basiliximab. Parameter estimates were derived from a randomized, prospective, double-blind study conducted in 21 renal transplant centers in seven countries in which 380 adult primary allograft recipients were randomized within center to receive basiliximab (20 mg i.v.) on days 0 and 4 or placebo in addition to dual immunosuppression with Neoral and steroids. Key clinical events included primary hospitalization, immunosuppressive drug use, patient and graft survival, graft rejection, treatment of rejection, dialysis, and repeat hospitalization. Health resources were valued via a comprehensive electronic cost dictionary, based upon a detailed economic evaluation of renal transplantation in Canada. Medication costs were calculated from hospital pharmacy acquisition costs; basiliximab was assessed a zero cost. RESULTS: The average estimated cost per patient for the first year after transplant was $55,393 (Canadian dollars) for placebo and $50,839 for basiliximab, rising to $141,690 and $130,592, respectively, after 5 years. A principal component of the cost in both groups was accrued during the initial transplant hospitalization ($14,663 for standard therapy and $14,099 for basiliximab). An additional $15,852 and $14,130 was attributable to continued care, graft loss, and dialysis in the two groups, whereas follow-up hospitalization consumed an additional $15,538 for placebo and $13,916 for basiliximab. The mean incremental cost of dialysis was $5,397 for placebo compared with $3,821 for basiliximab, whereas incremental costs of graft loss were $2,548 compared with $2,295 in the two treatment groups. The principal costs associated with repeat admission to the transplant ward and the general ward were marginally higher for placebo ($7,395 vs. $6,300 and $5,986 vs. $4,625). Treatment of acute rejection and maintenance immunosuppressive drug use were associated with only limited savings as a result of basiliximab (savings <$200 each). Sensitivity analysis indicated that the most influential parameters affecting the savings as a result of using basiliximab were a reduction in the duration of initial and repeat hospitalization followed by the reduced risks of acute rejection and graft loss. CONCLUSIONS: Before accounting for the cost of the therapy itself, basiliximab produces an estimated economic saving of $4,554 during the first year after transplant, of which $3,344 is attributable to the reduced costs of graft dysfunction, including graft loss and dialysis ($1,722) and follow-up hospitalizations ($1,622). When marketed, basiliximab is expected to cost approximately $3,000 per course (two doses of 20 mg), resulting in a net first-year saving of $1,554. Under these circumstances, basiliximab can be considered a dominant therapy in renal transplantation.
Subject(s)
Antibodies, Monoclonal/economics , Antibodies, Monoclonal/therapeutic use , Drug Costs , Immunosuppressive Agents/economics , Immunosuppressive Agents/therapeutic use , Kidney Transplantation , Recombinant Fusion Proteins , Azathioprine/therapeutic use , Basiliximab , Cost Control , Cyclosporine/therapeutic use , Double-Blind Method , Drug Therapy, Combination , Female , Humans , Male , Middle Aged , Prednisone/therapeutic use , Prospective StudiesABSTRACT
Cyclosporin A (CsA) absorption is highly variable in BMT patients. Neoral, a new microemulsion formulation of CsA, permits increased absorption with less variable pharmacokinetic parameters in non-BMT patients. We evaluated the pharmacokinetics of CsA after BMT in patients received microemulsion CsA. Two oral doses of 3mg/kg were given 48 h apart between 14 and 28 days after allogeneic BMT in 20 adults, and one dose in seven children, while subjects were receiving a continuous i.v. infusion of CsA. Whole blood samples were taken throughout the dosing interval to calculate the incremental CsA exposure using maximum concentration (Cmax), time to Cmax (tmax), concentration at 12 h after the dose (C12), the area under the concentration-time curve (AUC), and to establish inter- and intra-patient pharmacokinetic variability. Drug exposure was substantially lower in children than adults, with an AUC of 861+/-805 vs 2629+/-1487 micromg x h/l (P = 0.001), respectively, and absorption was delayed and diminished in both groups by comparison with solid organ recipients. Intra-patient variability in adults for AUC was high at 0.59+/-0.34, while inter-patient variability, measured as the coefficient of variation (c.v.), was 0.55 for the first and 0.54 for the second dose. In adults, gastrointestinal (GI) inflammation due to either mucositis or GVHD resulted in a higher AUC of 3077+/-1551 microg x h/l compared to 1795+/-973 microg x h/l (P = 0.02), and a similar trend was observed in children. AUC seemed little affected by the CsA formulation (liquid or capsule), or co-administration with liquids or food. Trough (12 h) CsA levels correlated poorly with incremental AUC. Sparse sample modeling of the AUC using two-point predictors taken at 2.5 and 5 h after dosing accurately approximated AUC in adults (r2 = 0.94), while 1.5 and 5 h was superior in children (r2 = 0.98). These data suggest that 12 h postdose trough measurements of CsA may not be the most appropriate way to evaluate CsA blood concentrations in order to establish therapeutic efficacy in BMT patients. Based on this study, the dose of microemulsion CsA should be adjusted based on recipient age, and the presence of GI inflammation secondary to mucositis or GVHD. These data would suggest that sparse sampling at time points earlier than the trough more accurately reflects the AUC and may correlate more closely with therapeutic efficacy early post-BMT.
Subject(s)
Aging/physiology , Bone Marrow Transplantation , Cyclosporine/administration & dosage , Cyclosporine/pharmacokinetics , Gastroenteritis/physiopathology , Administration, Oral , Adolescent , Adult , Area Under Curve , Bone Marrow Transplantation/methods , Child , Child, Preschool , Cohort Studies , Cyclosporine/blood , Drug Compounding , Emulsions , Humans , Immunosuppressive Agents/administration & dosage , Immunosuppressive Agents/blood , Immunosuppressive Agents/pharmacokinetics , Infant , Infusions, Intravenous , Middle Aged , Time FactorsABSTRACT
BACKGROUND: Rheumatoid arthritis ranges from a mild, non-deforming arthropathy with little long-term disability to severe, incapacitating, deforming arthritis which may be refractory to conventional disease-modifying agents. Epidemiological studies show an important genetic influence in rheumatoid arthritis, and MHC region genes and cytokine genes within and outside this region have been considered as candidates. We did a case-control study to test whether polymorphisms in the interferon-gamma gene are associated with severity of rheumatoid arthritis. METHODS: Interferon gamma dinucleotide repeat polymorphisms were examined with quantitative genescan technology, and HLA-DR alleles were identified by PCR and restriction-fragment-length polymorphism analysis. We studied 60 patients with severe rheumatoid arthritis, 39 with mild disease, and 65 normal controls. FINDINGS: Susceptibility to, and severity of, rheumatoid arthritis were related to a microsatellite polymorphism within the first intron of the interferon-gamma gene. A 126 bp allele was seen in 44 (73%) of 60 patients with severe rheumatoid arthritis, compared with eight (21%) of 39 with mild disease (odds ratio 10.66 [95% CI 4.1-24.9]), and with eight (12%) of 65 normal controls (19.59 [7.7-49.9]). Conversely, a 122 bp allele at the same locus was found in four (7%) patients with severe disease compared with 25 (64%) of those with mild disease (0.04 [0.01-0.1]) and with 52 (80%) of controls (0.018 [0.005-0.06]). INTERPRETATION: This association may be valuable for understanding the mechanism of disease progression, for predicting the course of the disease, and for guiding therapy.
Subject(s)
Arthritis, Rheumatoid/genetics , Dinucleotide Repeats/genetics , Interferon-gamma/genetics , Adult , Aged , Alleles , Arthritis, Rheumatoid/blood , Arthritis, Rheumatoid/classification , Case-Control Studies , Female , Genetic Predisposition to Disease , Humans , Male , Middle Aged , Polymerase Chain Reaction , Polymorphism, Genetic , Polymorphism, Restriction Fragment Length , Severity of Illness IndexABSTRACT
Post-transplant lymphoproliferative disorder (PTLD) is a known complication of both solid organ transplantation and allogeneic bone marrow transplantation (BMT) but is rarely seen following autologous BMT. We report the case of a 45 year-old female who developed Burkitt's lymphoma eight years after a renal allograft. This PTLD was found to have lambda light chain restriction, contained del(8)(q24) and add(14)(q32), and was negative for EBV on immunohistochemical and DNA-based PCR analyses. Immunoglobulin heavy chain (IgH) PCR studies revealed a prominent clonal rearrangement. She responded to intravenous cyclophosphamide and proceeded to high-dose chemoradiotherapy and mafosfamide-purged autologous BMT. Thirty-nine days post-BMT she presented with cough and fever and developed hepatic dysfunction; abnormal lymphoplasmacytoid cells were noted in the peripheral blood. Investigations revealed kappa light chain restriction, an oligoclonal IgH rearrangement, a normal karyotype and PCR studies for EBV were positive, consistent with a clinically and biologically distinct PTLD. She initially improved following discontinuation of immunosuppression, but then deteriorated abruptly and died 58 days post-BMT. It is likely that the two separate episodes of PTLD in this patient, one of which was atypical, arose as a result of both the chronic use of cyclosporine and the impairment of cell-mediated immunity associated with autologous BMT. The sequence of events in this patient should contribute to a better understanding of late-onset, EBV-negative PTLD.
Subject(s)
Bone Marrow Transplantation/adverse effects , Burkitt Lymphoma/surgery , Epstein-Barr Virus Infections/complications , Epstein-Barr Virus Infections/etiology , Lymphoproliferative Disorders/virology , Female , Humans , Immunosuppressive Agents/administration & dosage , Immunosuppressive Agents/adverse effects , Kidney Transplantation/adverse effects , Lymphoproliferative Disorders/drug therapy , Lymphoproliferative Disorders/etiology , Middle Aged , Neoplasms, Second Primary/etiology , Neoplasms, Second Primary/virology , Transplantation, Autologous , Transplantation, Homologous/adverse effectsABSTRACT
Occupational asthma caused by western red cedar is a common problem in sawmill industries. The objective of this study was to examine a possible association of human leukocyte antigen (HLA) class II genetic markers with susceptibility or resistance to western red cedar induced asthma. The distribution of DRB1 and DQB1 HLA class II alleles and DRB1-DQB1 haplotypes was studied in 56 Caucasian patients with proven red cedar asthma and 63 healthy Caucasian control subjects exposed to red cedar dust. DRB1 and DQB1 high resolution typing was performed by the polymerase chain reaction-based method. Patients with red cedar asthma had a higher frequency of HLA DQB1*0603 and DQB1*0302 alleles compared to a group of healthy exposed control subjects and a reduced frequency of DQB1*0501 allele. The frequency of the DRB1*0401-DQB1* 0302 haplotype was increased and the DRB1*0101-DQB1*0501 haplotype was reduced. These findings suggest that genetic factors such as human leukocyte antigen class II antigens may be associated with susceptibility or resistance to development of red cedar asthma.
Subject(s)
Alleles , Asthma/genetics , HLA-DQ Antigens/genetics , HLA-DR Antigens/genetics , Occupational Diseases/genetics , Wood , Adult , DNA/analysis , Disease Susceptibility , HLA-DQ beta-Chains , HLA-DRB1 Chains , HumansABSTRACT
Our previous study suggested that inflammatory mediators released due to IRI lead to host's immune response by upregulating MHC II in the host's peripheral T lymphocytes. This study hypothesized the role of platelet-activating factor (PAF) in the mechanism of induced MHC II upregulation due to IRI on peripheral T lymphocytes. The objectives of this study were to investigate the role of PAF in the induction of host immune reactivity and the protective effect of PAF-antagonist TCV-309 in combination with prostaglandin E1 (PGE1) against the host's immune response caused by IRI. Thirty female domestic swine were divided into three groups. Group A (6 donors, 6 recipients) had no pharmacological intervention. Group B (6 donors, 6 recipients) was the experimental group treated with TCV-309 + PGE1. Group C underwent sham operation. The ex vivo preservation time for groups A and B was 4 hr at 4 degrees C. To detect the changes in MHC II expression on T cells due to IRI, blood samples were collected before reperfusion (baseline level), 1, 2, and 3 days post-reperfusion. Two-colour flow cytometry analysis (FACS) was used to study MHC II-DR-beta expression in peripheral T lymphocytes. Swine anti-MHC II and anti-CD3 antibodies were used for this purpose. The FACS analyses demonstrated that in group A, there was a significant increase (p < 0.05) in MHC II intensity on peripheral T lymphocytes on day 2 post-reperfusion. By the third day post-reperfusion, MHC intensity had a tendency to decrease but did not reached the baseline level. In group B and C, however, there was no significant change in the level of MHC II in T lymphocytes at any of the post-reperfusion times. In group A, the number of CD3+MHC+ T lymphocytes significantly decreased (p < 0.05) by one day post-reperfusion and remained at this level until the third day post-reperfusion. In groups B and C, no significant change in the number of CD3+MHC+ T cells was observed. The results of this study suggested that the release of inflammatory mediators (e.g. PAF) due to IRI played a role in the mechanism of IRI-induced host's immune response. The results also suggested that the combination of TCV-309 + PGE1 could reduce this immune response.
Subject(s)
Inflammation Mediators/physiology , Reperfusion Injury/immunology , Tetrahydroisoquinolines , Alprostadil/administration & dosage , Animals , Female , Histocompatibility Antigens Class II/biosynthesis , Infusions, Intravenous , Isoquinolines/pharmacology , Isoquinolines/therapeutic use , Platelet Activating Factor/physiology , Pyridinium Compounds/pharmacology , Pyridinium Compounds/therapeutic use , Regression Analysis , Reperfusion Injury/metabolism , Swine , T-Lymphocyte Subsets/drug effects , T-Lymphocyte Subsets/metabolism , Up-Regulation/immunologyABSTRACT
Discovery of novel biological and pharmaceutical agents directed against discrete molecular targets in the lympnocyte activation sequence has enabled the effective control of graft rejection by the use of combinatorial immunosuppressive therapy. Chimeric and humanized monoclonal antibodies against T-cell receptor CD3 complex chains or the IL-2 receptor block T-cell function without inducing activation, and do not cause the cytokine release syndrome of first generation products. Biological blockade of co-stimulatory molecules including CD40L and CD28 produces immunological allograft unresponsiveness in primates, though this effect is not yet proven in humans. Heterogeneity in clinical response to pharmaceutical agents is often explained by pharmacokinetic factors of absorption, metabolism and elimination. The use of microemulsion technology has increased the absorption and efficacy of cyclosporine in all organ transplants, so that there is little difference in efficacy between this agent and tacrolimus. Mycophenolate mofetil is not maximally effective alone, but significantly reduces the relative risk of acute rejection in combination with an immunophilin binding agent. It is also effective when introduced at the time of rejection. Whether it can replace other agents for maintenance immunosuppression is now under investigation. Sirolimus, the latest pharmaceutical agent to complete phase III trials, acts to inhibit IL-2 driven lymphocyte proliferation and reduces the risk of acute rejection to below 20%. Multiple pharmacokinetic interactions occur within and between these agents, so that pharmacokinetic monitoring is increasingly important. At present there are few tools to detect pharmacodynamic interactions, although reporter gene constructs and intracellular cytokine labeling offer exciting possibilities for biological monitoring. Despite these advances, none of these interventions confers demonstrable long-term benefit in graft survival or function. Acute rejection can not therefore be assumed to be a simple surrogate for chronic injury, and research must be re-focused to determine the relevant targets for long-term immunosuppression.
Subject(s)
Immunosuppression Therapy , Immunosuppressive Agents , Adjuvants, Immunologic , CD28 Antigens/immunology , CD40 Ligand , Humans , Membrane Glycoproteins/immunology , Receptors, Antigen, T-Cell/immunology , T-Lymphocytes/immunologySubject(s)
Bone Marrow Transplantation/immunology , Cyclosporine/pharmacokinetics , Cyclosporine/therapeutic use , Immunosuppressive Agents/pharmacokinetics , Immunosuppressive Agents/therapeutic use , Administration, Oral , Adolescent , Adult , Age Factors , Bone Marrow Transplantation/physiology , Child , Child, Preschool , Cyclosporine/administration & dosage , Cyclosporine/blood , Graft vs Host Disease/prevention & control , Humans , Immunosuppressive Agents/administration & dosage , Immunosuppressive Agents/blood , Infant , Infusions, Intravenous , Intestinal Absorption , Metabolic Clearance Rate , Middle Aged , Reproducibility of Results , Time FactorsSubject(s)
Cyclosporine/therapeutic use , Graft Rejection/prevention & control , Immunosuppressive Agents/therapeutic use , Kidney Transplantation/immunology , Administration, Oral , Cyclosporine/administration & dosage , Cyclosporine/blood , Drug Therapy, Combination , Emulsions , Graft Rejection/epidemiology , Humans , Immunosuppression Therapy/methods , Immunosuppressive Agents/administration & dosage , Immunosuppressive Agents/blood , Risk Factors , Tacrolimus/therapeutic useABSTRACT
The recent introduction of a cyclosporine microemulsion demonstrating less pharmacokinetic variability than the conventional formulation offers the potential for accurately and precisely predicting area under the curve (AUC) with a limited-sampling monitoring strategy. This was studied based on the pharmacokinetic profiles from 55 stable patients with renal transplants who were observed on two occasions at steady state on both formulations. Multiple linear regression analyses were performed on a training dataset from 27 patients, in which combinations of cyclosporine concentrations drawn from 0 to 4 hours postdose were regressed against the full AUC over the dosing interval. Predictor regression equations used concentration combinations ranging from one-point (concentrations at 0, 1, 2, 3, or 4 hours) through five-points (all five concentrations 0 to 4 hours). The predictive performance of these equations was then assessed in the training group with data from a subsequent profiling occasion and in the remaining 28 patients who constituted an independent test group. Prediction bias (mean prediction error) and prediction precision (absolute prediction error) were quantified and compared between formulations. Correlations between predicted and actual AUC were consistently stronger for the microemulsion, suggesting the possibility of more accurate and precise predictions of exposure than from the conventional formulation. For both formulations, the one-point predictors rendered the lowest prediction precision, and predictive performance improved considerably when multiple-point predictors were used. Significantly higher precision and lower variability were observed with the microemulsion for most predictors in the both training and test groups. For the microemulsion, two-point (C0 + C1 or C0 + C2) and three-point (C0 + C1 + C2) predictors yielded relatively unbiased and precise exposure predictions, inasmuch as mean absolute prediction error was less than 10% and 5%, respectively. Hence, a two- or three-point method may provide a clinically important improvement over the use of trough levels in monitoring cyclosporine therapy in patients with renal transplants.
Subject(s)
Cyclosporine/pharmacokinetics , Drug Monitoring/methods , Drug Monitoring/statistics & numerical data , Immunosuppressive Agents/pharmacokinetics , Kidney Transplantation , Area Under Curve , Cyclosporine/administration & dosage , Cyclosporine/blood , Drug Administration Schedule , Drug Compounding , Female , Humans , Immunosuppressive Agents/administration & dosage , Immunosuppressive Agents/blood , Linear Models , Male , Predictive Value of Tests , Sensitivity and SpecificityABSTRACT
OBJECTIVES: This study was designed to examine the relationship between ex vivo preservation time of the transplanted lung and the extent of injury and to relate this to the severity of rejection with and without allogenicity. METHODS: Single lung transplantation was performed on two groups of domestic swine. Group A (n = 7) and group B (n = 6) had ex vivo preservation times of 4 and 15 hours, respectively, at 4 degrees C hypothermia. Group C (n = 6) underwent 2 hours of warm ischemia via dissection and isolation of the left lung with ligation of its bronchial artery and crossclamping of the left pulmonary artery, vein, and bronchus without explantation. Assessment measures included lung function, antioxidant enzyme activities in the plasma and lung tissue, levels of inflammatory mediators in the recipient plasma, and quantification of major histocompatibility complex II HLA-DR-beta on host peripheral lymphocytes. RESULTS: All groups demonstrated increases in interleukin-10, lung weight, and HLA-DR-1beta expression and decreases in lung-tissue antioxidant enzyme activities, gas exchange, and lung compliance. There was a strong positive correlation between ex vivo preservation time and the expression of HLA-DR-beta and a negative correlation between ischemic time and lung-tissue superoxide dismutase. CONCLUSIONS: These results suggest that the intensity of the host immunogenic response is related to the severity of ischemia-reperfusion injury and is independent of tissue incompatibility and/or the type of ischemic insult. We conclude that the extension of ex vivo preservation time may predispose the transplanted lung to more severe rejection.
Subject(s)
HLA-DR Antigens/metabolism , Lung Transplantation , Reperfusion Injury/metabolism , T-Lymphocytes/metabolism , Animals , CD3 Complex/metabolism , Follow-Up Studies , Graft Rejection/immunology , Graft Rejection/metabolism , Graft Rejection/pathology , Immunocompromised Host , Immunohistochemistry , Interleukin-10/metabolism , Lymphocyte Activation/immunology , Organ Preservation , Reperfusion Injury/immunology , Reperfusion Injury/pathology , Respiratory Function Tests , Superoxide Dismutase/metabolism , Swine , T-Lymphocytes/pathology , Up-RegulationABSTRACT
BACKGROUND: Bacterial infection is a common complication during the first few months after renal transplantation. Ciprofloxacin, a fluoroquinolone broad-spectrum antibiotic, is used frequently in treating infections in the early posttransplant period. Evidence from in vitro studies has suggested that ciprofloxacin can antagonize the cyclosporine (CsA)-dependent inhibition of interleukin-2 production. Such an effect in renal transplant patients could antagonize the immunosuppressive activity of CsA and lead to rejection of the graft. METHODS: To investigate the possibility of a pharmacodynamic interaction between ciprofloxacin and CsA, we conducted a case-control study in 42 patients who had received a kidney transplant and who were prescribed ciprofloxacin in the first 1-6 months after transplantation and in their matched controls (two per case) who did not receive ciprofloxacin during the study period. RESULTS: There was a twofold greater incidence (P=0.008) of ciprofloxacin use at 1-3 months (65%) than was observed at 4-7 months (35%) after transplantation. The proportion of cases experiencing at least one episode of biopsy-proven rejection 1-3 months posttransplant (45%) was significantly greater (P=0.004) than that of controls (19%). Furthermore, there was a marked increase (P<0.001) in the incidence of rejection temporally associated with ciprofloxacin use among cases (29%) compared with that experienced by the controls (2%). CONCLUSIONS: The possibility that ciprofloxacin increases rejection rates in renal transplant patients may be of clinical importance and therefore warrants further investigation.
Subject(s)
Anti-Infective Agents/therapeutic use , Ciprofloxacin/therapeutic use , Cyclosporine/antagonists & inhibitors , Cyclosporine/therapeutic use , Graft Rejection/epidemiology , Immunosuppressive Agents/therapeutic use , Kidney Transplantation/immunology , Biopsy , Case-Control Studies , Chi-Square Distribution , Cyclosporine/blood , Drug Interactions , Female , Graft Rejection/immunology , Graft Rejection/pathology , Humans , Immunosuppressive Agents/antagonists & inhibitors , Immunosuppressive Agents/blood , Kidney Transplantation/pathology , Male , Middle Aged , Reoperation , Retrospective StudiesABSTRACT
A critique of the current bioequivalence regulations is presented with reference to critical dose drugs. Using the development of a new cyclosporine formulation as an example, the deficiencies in current bioequivalence testing guidelines are examined and discussed. Based on the experience gained with cyclosporine, recommendations are made on how therapeutic equivalence, rather than just bioequivalence, should be established.