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Norberto Perico

Publications and source records attributed to Norberto Perico.

At least 19 recordsLinked to original sources

Comparison of the Innofluor certican assay with HPLC-UV for the determination of everolimus concentrations in heart transplantation.

OBJECTIVES: Therapeutic monitoring of everolimus with chromatographic methods (HPLC) enabled effective immunosuppression while limiting the incidence of drug-related adverse events. A fluorescence polarization immunoassay (FPIA) has been recently developed for the assessment of everolimus levels. The present study was designed to evaluate FPIA performance and to compare it to HPLC. DESIGN AND METHODS: The performance of HPLC and FPIA was initially tested using drug-free whole blood spiked with different amount of everolimus concentrations and, subsequently, by analyzing 113 trough blood samples from heart transplant recipients chronically given everolimus as part of their immunosuppressive regimen. RESULTS: Inaccuracy and imprecision of both methods were below 15%. The correlation between everolimus concentrations and measured FPIA and HPLC was good, with a Pearson coefficient of 0.9118. The FPIA gave a mean overestimation of 24.3% as compared with HPLC. As additional analysis, cross-reactivity ranging from 85.4% to 138.0% was found with sirolimus, an immunosuppressant with a chemical structure close to everolimus. CONCLUSION: The FPIA demonstrated acceptable performance for therapeutic drug monitoring of everolimus, and is a viable alternative to HPLC-based methods.

Chromatography, High Pressure Liquid↗

Mycophenolic acid formulation affects cyclosporine pharmacokinetics in stable kidney transplant recipients.

A novel monitoring strategy based on the blood concentration at two hours post-dose (C2) has been recently proposed for the assessment of cyclosporine (CsA) absorption and daily exposure, and therapeutic windows for C2 levels have been identified. These guidelines have been derived from patients given mycophenolate mofetil (MMF) or azathioprine, and never tested in those treated with the enteric-coated formulation of mycophenolic acid (EC-MPS). The authors have compared full CsA pharmacokinetic evaluations in 12 kidney transplant recipients given EC-MPS with those from 20 patients on MMF at months 6, 12, 18 and 24 postsurgery. At month 6 postsurgery, patients on EC-MPS had a shift to the right in the CsA peak concentration as compared to that in patients given MMF, an effect associated with significant differences in CsA Tmax (1.9 +/- 0.3 h vs. 1.5 +/- 0.6 h, P < 0.05), C2 (988 +/- 259 vs. 720 +/- 214 ng/mL, P < 0.01), and C3 levels (539 +/- 119 vs. 435 +/- 119 ng/mL, P < 0.05). Interestingly, the authors found that the majority of patients on EC-MPS had CsA peaking at 2-h postdosing, whereas most of patients on MMF had CsA Cmax at 1 h. Similar results were observed also at months 12, 18, and 24 postsurgery. These findings indicate that the pharmacokinetics of CsA is significantly affected by the concomitant administration of different MPA formulations. This would imply the need of specific algorithms to adequately estimate CsA dose adjustment in patients given, in addition to CsA, EC-MPS or MMF.

Adult↗

Prevention programmes of progressive renal disease in developing nations.

Development of strategies for the early detection and prevention of non-communicable diseases, including kidney disease, is the only realistic strategy to avert an imminent global health and economic crisis and enhance equity in health care worldwide. In this article, we briefly examine the burden of non-communicable diseases, including diabetes, hypertension, cardiovascular disease and how chronic kidney disease (CKD) represents a key integrated element in the setting, even in developing countries. A possible explanation of the increasing number of people who have or are at risk to develop CKD in poor countries is also given. A survey of major screening and intervention programmes performed or ongoing globally is then presented, highlighting differences and hurdles of projects planned in developed or developing nations as well as in unprivileged communities in developed countries. Finally, some recommendations on future steps to implement prevention programmes in emerging worlds are provided.

Developing Countries↗

Cyclosporine formulation and Kaposi's sarcoma after renal transplantation.

BACKGROUND: Transplantation enhances the risk of malignancies, due to the chronic use of antirejection medication. In the case of Kaposi's sarcoma (KS) the permissive effect of immunosuppression has been extensively studied, and cyclosporine (CsA) appears to play a key role. Here we have compared the incidence of KS in transplant patients receiving Neoral or Sandimmune as a part of their immunosuppressive therapy. METHODS: In all, 668 kidney transplant recipient followed at our Nephrology Unit from 1970 to 2003 entered this retrospective analysis; 300 were on CsA Sandimmune-based and 308 on CsA Neoral-based therapy. The primary endpoint was the occurrence of KS. RESULTS: KS was diagnosed in 20 out of 608 patients given CsA with an incidence rate of 4.7 per 1000 patients per year. No episodes of KS was found in the preCsA era. Among patients on CsA, those treated with Neoral had fourfold higher incidence rate of KS than in the Sandimmune group (10.7 vs. 2.3 per 1000 patients per year). Kaplan-Meier analysis shows that patients on Neoral had lower cumulative KS-free probability than those on Sandimmune. Cox's analysis documented that Neoral was a positive predictor of KS development as compared to Sandimmune (hazard ratio: 2.237). Among patients on Neoral, those who developed KS had higher daily exposure to the drug assessed by pharmacokinetic studies. CONCLUSIONS: In recipients of kidney transplant CsA Neoral increases the risk of KS as compared to the Sandimmune formulation, possibly due to enhanced drug bioavailability and ultimately patients daily CsA exposure.

Chemistry, Pharmaceutical↗

Simultaneous determination of everolimus and cyclosporine concentrations by HPLC with ultraviolet detection.

In the clinical practice of organ transplantation everolimus (RAD) is used in combination with cyclosporine (CsA), the most common antirejection agent. Both drugs show a narrow therapeutic window, which requires strict monitoring of their blood concentration. Simple methods for simultaneous measurement of RAD and CsA concentration are needed. As we have recently developed an HPLC-UV assay for RAD determination, we decided to implement it to allow concomitant measurement of CsA. The within- and between-day coefficients of variation of the measurement were less than 12.1% for RAD and 9.8% for CsA. The within- and between-day inaccuracy of quality control samples were less than 9.7% for RAD and less than 4.9% for CsA. The method was found accurate and precise and useful for simultaneous therapeutic monitoring of the two drugs.

Calibration↗

High-performance liquid chromatography with ultraviolet detection for therapeutic drug monitoring of everolimus.

We developed and validated a high-performance liquid chromatography-ultraviolet (HPLC-UV) method for determining everolimus concentrations in human whole blood. Sample preparation involved a solid-phase extraction after protein precipitation. The separation of everolimus from internal standard (IS) and endogenous components was achieved using an isocratic elution on an octyl column. The method showed a linear relationship between peak height ratios and blood concentrations in the range of 1-200 ng/mL (r(2)=0.9997). The observed intra- and inter-day assay imprecision had a coefficient of variation (CV)=12.8%, and inaccuracy was 11.4%. The method was found to be precise, accurate, and sensible making it useful for routine therapeutic monitoring of everolimus.

Chromatography, High Pressure Liquid↗

Comparison of different cyclosporine immunoassays to monitor C0 and C2 blood levels from kidney transplant recipients: not simply overestimation.

BACKGROUND: Immunoassays used for the measurement of cyclosporine (CsA) usually show cross-reactivity for CsA metabolites, usually resulting in unacceptable bias. METHODS: To assess the performance of different immunoassays, CsA concentrations were analyzed in 132 samples using ACMIA, EMIT-VIVA, CEDIA-PLUS, and HPLC. Samples were collected from kidney transplant patients monitored with the traditional blood CsA trough level (C0, n=73) and the new sampling at 2-h post CsA dosing (C2, n=59). RESULTS: Overall, the correlations between HPLC and other methods were good (r values ranging from 0.85 to 0.97). The use of C2 concentrations to monitor CsA exposure were associated with an overall better performance of all the immunoassays as compared with C0 values. However, none of the immunoassays agreed with the guidelines proposed in the Lake Louis Consensus Conference. Of note, the CEDIA-PLUS was the only that provided a linear relationship with HPLC for both sampling times. A false positive case associated with ACMIA was also documented in blood samples from a patient withdrawn from CsA for 1 month. CONCLUSION: These data suggest that the performance of some of the most used immunoassays is not satisfactory, eventually leading to incorrect therapeutic decision guided by erroneous CsA monitoring.

Chromatography, High Pressure Liquid↗

Mechanisms of disease: Pre-eclampsia.

Pre-eclampsia, a syndrome of pregnant women, is one of the leading causes of maternal and fetal morbidity and mortality. Despite active research, the etiology of this disorder remains an enigma. Recent work has, however, provided promising explanations for the causation of the disorder and some of its phenotypes. Evidence indicates that the symptoms of hypertension and proteinuria, upon which the diagnosis of pre-eclampsia is based, have several underlying causes. Nevertheless, the treatment of pre-eclampsia has not changed significantly in over 50 years. This review describes the most recent insights into the pathophysiology of pre-eclampsia from both basic and clinical research, and attempts to provide a unifying hypothesis to reconcile the abnormalities at the feto-placental level and the clinical features of the maternal syndrome. The novel findings outlined in this review provide a rationale for potential future prophylactic and therapeutic interventions for pre-eclampsia.

Female↗

Generic cyclosporine formulations: more open questions than answers.

The introduction of cyclosporine (CsA) in clinical practice has significantly improved patient and allograft survival after organ transplantation. The new microemulsion CsA formulation, Neoral, has been associated with a more reproducible absorption and a better patient outcome as compared to the old formulation Sandimmune. Recently, several generic CsA formulations have been tested as bioequivalent to Neoral. Bioequivalence tests have been performed in selected groups of young, healthy male volunteers usually in single-dose studies, and then extended to completely different population, such as transplant recipients. However, growing body of evidence shows that CsA pharmacokinetics in healthy subjects is different from that of transplant patients, treated chronically with CsA. Therefore, converting patients from Neoral to the new generic formulations could be detrimental, exposing patients to increased risk of graft function deterioration and graft loss. Thus, more research and more accurate bioequivalence tests are required to address the unanswered problems dealing with the generic CsA formulations.

Cyclosporine↗

Strategies for national health care systems in emerging countries: the case of screening and prevention of renal disease progression in Bolivia.

There are close to 1 million people in the world who are alive simply because they have access to one form or another of renal replacement therapy (RRT). Ninety percent live in high-income countries. Little is known of prevalence and incidence of chronic kidney disease and of end-stage renal disease (ESRD) in middle-income and low-income countries, where the use of RRT is scarce or nonexistent. However, no intervention is undertaken, these people will experience progression to ESRD and death from uremia, because RRT is out of reach for them. These are the individuals for whom efforts should be focused to prevent or delay progression toward ESRD. In 1992, the Mario Negri Institute for Pharmacological Research in Bergamo, Italy, with the cooperation of the young doctors of the Ospedale Giovanni XXIII in La Paz (Bolivia), activated a specific project titled "El Proyecto de Enfermedades Renales en Bolivia" (The Project for Renal Diseases in Bolivia). The project sought to demonstrate that in emerging countries the best strategies against renal disease are prevention and early detection. After proper training of local personnel at the Clinical Research Center "Aldo e Cele Dacco" of the Mario Negri Institute in Bergamo, Italy, an educational campaign titled "First Clinical and Epidemiological Program of Renal Diseases"-under the auspices of the Renal Sister Center Program of the International Society of Nephrology-was conducted in 3 selected areas of Bolivia, including tropical, valley, and plains areas. The goal was to define the frequency of asymptomatic renal disease in these areas by screening a large population of patients at relatively low costs. The screening was formally performed at first-level health centers (Unidad de Salud). Participants were instructed to void a clean urine specimen, and a dipstick test was performed. Patients with positive urinalysis were enrolled in a follow-up program with subsequent laboratory and clinical checks. The study was conducted by 21 clinical centers. Apparently healthy patients (14,082) were enrolled over a period of 7 months. Urinary abnormalities were found on first screening in 4261 patients, but only 1019 patients (23.9%) were available for follow-up. At second urinalysis, 35% of patients had no abnormalities. In the remaining positive group of patients, further investigations disclosed the following abnormalities: urinary tract infection (48.4%), isolated hematuria (43.9%), chronic renal failure (1.6%), renal tuberculosis (1.6%), and other diagnoses 4.3% (kidney stones, 1.3%; diabetic nephropathy, 1%; polycystic kidney diseases, 1.9%). The experience gained from this initial screening program formed the basis for a second study aimed to prevent renal disease progression in a selected Bolivian population with high altitude polycythemia. In conclusion, our studies show that mass screening of the population for renal disease is feasible in developing countries and can provide useful information on frequency of renal diseases. Also, in patients with altitude polycythemia, long-term treatment with low doses of enalapril safely prevents increase in arterial blood pressure and progressively reduces hematocrit and proteinuria. Aside from its scientific value, this last study can be taken as an example of how, by rationalizing resources and investing in research programs, renal disease progression and cardiovascular risk may eventually improve, which ultimately should translate into less demand for dialysis, and thus provide alternatives to costly RRT. The transformation of the Bolivian pilot model into a systematic program applicable to most emerging countries may be seen as a task of national nephrology societies, along with methodologic and economic support of international bodies.

Bolivia↗

The future of renoprotection.

Chronic kidney diseases are emerging as a global threat to human health. Renal replacement therapy by dialysis or renal transplantation prolongs survival in patients with end-stage renal disease (ESRD) and, in most cases, provides a good quality of life. In all wealthy countries, new patients on dialysis outnumber those who die, and the group of patients on renal replacement therapy is growing. The provision of adequate treatment to all is absorbing a large proportion of the health care budget and is being looked at with concern by policymakers. Because rationing of dialysis or deciding that some patients cannot be treated is out of the question, clinicians should be looking for ways to prevent the need for dialysis in as many patients as possible. Simple and inexpensive treatments are plausible and possibly effective. There is robust experimental evidence that proteinuria is responsible for interstitial inflammation and subsequent fibrosis, which thereby contributes to progressive renal function loss. Clinical studies and clinicopathologic correlations in patients with progressive nephropathies indicate that observations in experimental models are relevant to understanding human disease. Researchers have identified an important correlation between urinary protein excretion and rate of glomerular filtration rate decline in patients with diabetic and nondiabetic chronic nephropathy. Renoprotection is a strategy that aims to interrupt or reverse this process. The current therapeutic approach for proteinuric chronic nephropathies is based on blockade of the renin-angiotensin system with angiotensin converting-enzyme inhibitors and/or angiotensin-receptor blockers that limit proteinuria, and reduce glomerular filtration rate decline and risk of ESRD more effectively than other antihypertensive treatments. Full remission of the disease, however, is seldom obtained, particularly when pharmacologic intervention is started late. For those who do not respond, treatment procedures to achieve remission and/or regression must include a multimodel strategy to implement renoprotection. The role of lifestyle changes, including smoking cessation, should not be overlooked. A more concerted, strategic, and multisectorial approach, underpinned by solid research evidence, is essential to help reverse the increasing incidence of these chronic diseases, not just for a few beneficiaries, but equitably and on a global scale.

Chronic Disease↗

Prevention of progression and remission/regression strategies for chronic renal diseases: can we do better now than five years ago?

The prevalence of chronic renal diseases is increasing worldwide. There is a great need to identify therapies that arrest disease progression to end-stage renal failure. Inhibition of renin-angiotensin system both by ACE inhibitors and angiotensin II receptor antagonists is probably the best therapeutic option available. Several large, multicenter studies have indeed shown a significant reduction in the risk of doubling baseline serum creatinine or progression toward end-stage renal failure in diabetic and nondiabetic patients with chronic nephropathies treated with ACE inhibitors or angiotensin II receptor antagonists. However, the number of patients that reach end-stage renal failure is still considerably high. Significant reduction of the incidence of end-stage renal disease is likely to be achieved in the next future for chronic nephropathies, provided that we can improve the degree of renoprotection. This goal may be attainable with a more complex strategy than with a single or dual pharmacologic intervention on the renin-angiotensin system. Strict control of blood pressure and protein excretion rate, lowering of blood lipids, tight glucose control for diabetics, and lifestyle changes form part of the future multimodal protocol for management of patients with chronic nephropathies.

Angiotensin Receptor Antagonists↗

The role of renin-angiotensin-aldosterone system in the progression of chronic kidney disease.

The renin-angiotensin-aldosterone system (RAAS) is a well known regulator of blood pressure (BP) and determinant of target-organ damage. It controls fluid and electrolyte balance through coordinated effects on the heart, blood vessels, and Kidneys. Angiotensin II (AII) is the main effector of the RAAS and exerts its vasoconstrictor effect predominantly on the postglomerular arterioles, thereby increasing the glomerular hydraulic pressure and the ultrafiltration of plasma proteins, effects that may contribute to the onset and progression of chronic renal damage. AII may also directly contribute to accelerate renal damage by sustaining cell growth, inflammation, and fibrosis. Interventions that inhibit the activity of the RAAS are renoprotective and may slow or even halt the progression of chronic nephropathies. ACE inhibitors and angiotensin II receptor antagonists can be used in combination to maximize RAAS inhibition and more effectively reduce proteinuria and GFR decline in diabetic and nondiabetic renal disease. Recent evidence suggests that add-on therapy with an aldosterone antagonist may further increase renoprotection, but may also enhance the risk hyperkalemia. Maximized RAAS inhibition, combined with intensified blood pressure control (and metabolic control in diabetics) and amelioration of dyslipidemia in a multimodal approach including lifestyle modifications (Remission Clinic), may achieve remission of proteinuria and renal function stabilization in a substantial proportion of patients with proteinuric renal disease. Ongoing studies will tell whether novel drugs inhibiting the RAAS, such as the renin inhibitors or the vasopeptidase inhibitors, may offer additional benefits to those who do not respond, or only partially respond, to this multimodal regimen.

Angiotensin II Type 1 Receptor Blockers↗