Liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) methods for the therapeutic drug monitoring of cytotoxic anticancer drugs: An update.

In the era of precision medicine, there is increasing evidence that conventional cytotoxic agents may be suitable candidates for therapeutic drug monitoring (TDM)- guided drug dosage adjustments and patient's tailored personalization of non-selective chemotherapies. To that end, many liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) assays have been developed for the quantification of conventional cytotoxic anticancer chemotherapies, that have been comprehensively and critically reviewed. The use of stable isotopically labelled internal standards (IS) of cytotoxic drugs was strikingly uncommon, accounting for only 48 % of the methods found, although their use could possible to suitably circumvent patients' samples matrix effects variability. Furthermore, this approach would increase the reliability of cytotoxic drug quantification in highly multi-mediated cancer patients with complex fluctuating pathophysiological and clinical conditions. LC-MS/MS assays can accommodate multiplexed analyses of cytotoxic drugs with optimal selectivity and specificity as well as short analytical times and, when using stable-isotopically labelled IS for quantification, provide concentrations measurements with a high degree of certainty. However, there are still organisational, pharmacological, and medical constraints to tackle before TDM of cytotoxic drugs can be more largely adopted in the clinics for contributing to our ever-lasting quest to improve cancer treatment outcomes.

Improving safety of preparation and administration of medicines and enteral nutrition in a neonatal care unit: Global risk analysis.

OBJECTIVE: To date, few adapted pharmaceutical forms are available for infants leading to multiple steps of preparation and medicines dilution before administration. The main purpose of this study was to assess the risks on the steps of preparation and administration of medicines in a neonatal care unit and to propose corrective actions to ensure the medicines safety. METHODS: A global risk analysis was performed, conducted by a multidisciplinary working group of 9 experts, that is 9 meetings. RESULTS: We identified 57 scenarios: 59,6% of scenarios had an initial criticality C1, 31,6% C2 and 8,8% C3. The most risky phases were phases of needs identification including the step of doses calculation and phases of preparation. The strategic management together with the human factor were the most risky dangers. Nineteen corrective actions were proposed. After implementing those actions, 82,5% of scenarios had residual criticality C1, 17,5% C2 and no scenario had residual criticality C3. Follow-up actions have been implemented to control the residual risk as in service training. CONCLUSION: Neonatal unit care is a risky service and should be a priority in the risk management policy. This analysis joins the quality policy implemented in the hospital and similar risk analysis is on process.

[Aldosterone receptor antagonists]. / Les antagonistes du récepteur minératocorticoïde.

Mineralocorticoid signaling pathway plays a pivotal role in cardiovascular physiopathology. Evidences from clinical and experimental studies have linked mineralocorticoid hormones with cardiovascular morbiditiy and mortality. Thus, antagonist of the mineralocorticoid receptor (AMR) has reappeared. In addition, a novel mineralocorticoid receptor antagonist has been developped, named eplerenone, which lack the side effect of former ARMs as gynecomastia. Based on two studies named RALES et EPHESUS, guidelines of the european and american societies of cardiology recommend the use of ARMs as a treatment for cardiac failure NYHA III and IV, and post-infarct cardiac failure (ejection fraction < 40%).

Percutaneous closure of atrial septal defect type ostium secundum using the new Intrasept occluder: initial experience.

We report the first experience obtained with the new Intrasept device. We attempted to treat 35 patients with a mean age of 43 +/- 21 years. The mean size of the defect was 17/15 mm. It was successfully closed in 31 patients. In the remaining four the device could not be stabilized because of excessive defect size. A small residual shunt was present immediately following implantation in three patients. No complications occurred during the procedure and at 6 months, 31 patients had an uneventful outcome. Only one patient had a small residual shunt. No thrombus, embolization, or device fracture was documented during a mean follow-up of 17 +/- 11 months. Percutaneous closure of ASD ostium secundum is feasible with the Intrasept device with a high success rate and very good medium-term outcome. Our initial experience and results were excellent with small to medium size defects, however, large defects (>20 mm) remain challenging.

[Surgical options for terminal heart failure]. / Options chirurgicates pour l'insuffisance cardiaque terminale.

Terminal heart failure can be the cause or the result of major dysfunctions of the organisms. Although, the outcome of the natural history is the same in both situations, it is of prime importance to differentiate the two, as only heart failure as the primary cause allows for successful mechanical circulatory support as bridge to transplantation or towards recovery. Various objective parameters allow for the establishment of the diagnosis of terminal heart failure despite optimal medical treatment. A cardiac index <2.0 l/min, and a mixed venous oxygen saturation <60%, in combination with progressive renal failure, should trigger a diagnostic work-up in order to identify cardiac defects that can be corrected or to list the patient for transplantation with/without mechanical circulatory support.

Treatment of cytomegalovirus infection or disease in solid organ transplant recipients with valganciclovir.

Valganciclovir (VGC) has proved efficacious and safe for the prophylaxis against cytomegalovirus (CMV) in high-risk transplant recipients and for the treatment of CMV retinitis in AIDS patients. We used VGC for the treatment of CMV infection (viremia without symptoms) or disease (CMV syndrome or tissue-invasive disease) in kidney, heart, and lung transplant recipients. Fourteen transplant recipients were treated: five for asymptomatic CMV infection and nine for CMV disease. VGC was administered in doses adjusted to renal function for 4 to 12 weeks (induction and maintenance therapy). Clinically, all nine patients with CMV disease responded to treatment. Microbiologically, treatment with VGC turned blood culture negative for CMV within 2 weeks in all patients and was associated with a > or =2 log decrease in blood CMV DNA within 3 weeks in 8 of 8 tested patients. With a follow-up of 6 months (n = 12 patients), asymptomatic recurrent CMV viremia was noted in five cases, and CMV syndrome noted in one case (all cases in the first 2 months after the end of treatment). VGC was clinically well tolerated in all patients; however, laboratory abnormalities occurred in three cases (mild increase in transaminases, thrombocytopenia, and pancytopenia). This preliminary experience strongly suggests that therapy with VGC is effective against CMV in organ transplant recipients; however, the exact duration of therapy remains to be determined: a longer course may be necessary to prevent early recurrence.

[Percutaneous closure of patent foramen ovale: preliminary experience with the PFO Star]. / Fermeture percutanée de foramen ovale perméable: expérience préliminaire avec le PFO Star.

This article reports the experience of percutaneous closure of patent foramen ovale with the PFO Star device. Between January 2000 and December 2002, 44 consecutive patients with a mean age of 53 years were included in this registry. The implantation of the prosthesis was successful in 43 patients (98%): in 1 patient the atrial septum could not be crossed at operation. An early complication was observed in 3 patients (7%): one had transient amnesia and two patients had temporary ST elevation in the inferior ECG leads. Four patients (7%) had late complications: there was one case of spontaneously regressive atrial fibrillation, two recurrences of stroke (one in the patient without an implanted prosthesis and the other in a patient in whom the patent foramen ovale had been closed). Finally, one patient developed a fistula between the aorta and right atrium which occluded spontaneously when the anticoagulants were stopped. Complete closure of the patent foramen ovale was confirmed at 1 year in 92% of patients. The authors conclude that this preliminary experience shows that closure of patent foramen ovale with this device is effective and safe.

[The heart transplant in Lausanne from 1987 to 2003]. / La greffe cardiaque à Lausanne de 1987 à 2003.

Since the availability of ciclosporine, the survival after heart transplantation has dramatically improved. We present our results since the beginning of our experience in 1987. We treated in the Lausanne University hospital, 150 patients for end-stage cardiac disease. Hundred and fifty-two transplantations were performed. The survival rate is comparable to the literature with 81% at one year, 70% at five year and 63 at ten year included the hospital mortality. We review the incidence of complications during the follow-up and report the modification in the management of these patients especially concerning the immunosuppression.

Intravenous pamidronate as treatment for osteoporosis after heart transplantation: a prospective study.

Fractures due to osteoporosis are one of the major complications after heart transplantation, occurring mostly during the first 6 months after the graft, with an incidence ranging from 18% to 50% for vertebral fractures. Bone mineral density (BMD) decreases dramatically following the graft, at trabecular sites as well as cortical sites. This is explained by the relatively high doses of glucocorticoids used during the months following the graft, and by a long-term increase of bone turnover which is probably due to cyclosporine. There is some evidence for a beneficial effect on BMD of antiresorptive treatments after heart transplantation. The aim of this study was to assess prospectively the effect on BMD of a 3-year treatment of quarterly infusions of 60 mg of pamidronate, combined with 1 g calcium and 1000 U vitamin D per day, in osteoporotic heart transplant recipients, and that of a treatment with calcium and vitamin D in heart transplant recipients with no osteoporosis. BMD of the lumbar spine and the femoral neck was measured by dual-energy X-ray absorptiometry in all patients every 6 months for 2 years and after 3 years. Seventeen patients, (1 woman, 16 men) aged 46+/-4 years (mean +/- SEM) received only calcium and vitamin D. A significant decrease in BMD was observed after 6 months following the graft, at the lumbar spine (- 6.6%) as well as at the femoral neck (-7.8%). After 2 years, BMD tended to recover at the lumbar spine, whereas the loss persisted after 3 years at the femoral neck. Eleven patients (1 woman and 10 men) aged 46+/-4 years (mean +/- SEM) started treatment with pamidronate on average 6 months after the graft, because they had osteoporosis of the lumbar spine and/or femoral neck (BMD T-score below -2.5 SD). Over the whole treatment period, a continuous increase in BMD at the lumbar spine was noticed, reaching 18.3% after 3 years (14.3% compared with the BMD at the time of the graft). BMD at the femoral neck was lowered in the first year by -3.4%, but recovered totally after 3 years of treatment. In conclusion, a 3-year study of treatment with pamidronate given every 3 months to patients with existing osteoporosis led to a significant increase in lumbar spine BMD and prevented loss at the femoral neck. However, since some of these patients were treated up to 14 months after the transplant, they may already have passed through the phase of most rapid bone loss. In patients who were not osteoporotic at baseline, treatment with calcium and vitamin D alone was not able to prevent the rapid bone loss that occurs immediately after transplantation.

Preemptive treatment approach to cytomegalovirus (CMV) infection in solid organ transplant patients: relationship between compliance with the guidelines and prevention of CMV morbidity.

Cytomegalovirus (CMV) remains a major cause of morbidity in solid organ transplant patients. In order to reduce CMV morbidity, we designed a program of routine virological monitoring that included throat and urine CMV shell vial culture, along with peripheral blood leukocyte (PBL) shell vial quantitative culture for 12 weeks post-transplantation, as well as 8 weeks after treatment for acute rejection. The program also included preemptive ganciclovir treatment for those patients with the highest risk of developing CMV disease, i.e., with either high-level viremia (>10 infectious units [IU]/106 PBL) or low-level viremia (<10 IU/106 PBL) and either D+/R- CMV serostatus or treatment for graft rejection. During 1995-96, 90 solid organ transplant recipients (39 kidneys, 28 livers, and 23 hearts) were followed up. A total of 60 CMV infection episodes occurred in 45 patients. Seventeen episodes were symptomatic. Of 26 episodes managed according to the program, only 4 presented with CMV disease and none died. No patient treated preemptively for asymptomatic infection developed disease. In contrast, among 21 episodes managed in non-compliance with the program (i.e., the monitoring was not performed or preemptive treatment was not initiated despite a high risk of developing CMV disease), 12 episodes turned into symptomatic infection (P=0.0048 compared to patients treated preemptively), and 2 deaths possibly related to CMV were recorded. This difference could not be explained by an increased proportion of D+/R- patients or an increased incidence of rejection among patients with episodes treated in non-compliance with the program. Our data identify compliance with guidelines as an important factor in effectively reducing CMV morbidity through preemptive treatment, and suggest that the complexity of the preemptive approach may represent an important obstacle to the successful prevention of CMV morbidity by this approach in the regular healthcare setting.

Extramediastinal surgical problems in heart transplant recipients.

BACKGROUND: As heart transplantation has gained wide acceptance, a growing number of recipients are at risk of experiencing extramediastinal surgical problems. STUDY DESIGN: We retrospectively reviewed our experience in the diagnosis and management of surgical problems occurring in 94 consecutive patients having heart transplantation. During the period of the study, we progressively adopted a policy of low-level immunosuppression, aiming toward monotherapy with cyclosporine. RESULTS: Seventy-four extramediastinal surgical problems developed in 44 of 94 patients (47%). The type of problems were gastrointestinal in 17 of 74 (23%), vascular in 13 of 74 (17.5%), urogenital in 8 of 74 (11%), and neurologic in 4 of 74 (5.5%). There were also 9 of 74 cases of trauma (12%), 9 of 74 skin tumors (12%), and 14 of 74 miscellaneous diseases (19%). Sixty-two surgical diseases occurring in 40 patients required 75 surgical interventions, 11 of them (15%) on an emergency basis. Operations were performed for 12 of 74 neoplasms (16%) and 12 of 74 infectious or potentially infectious diseases (16%). Surgical diseases occurred most commonly within the first 6 months after transplantation (20 of 74; 27%). Complications occurred in 8 of 75 surgical interventions (9%). A high proportion of surgical disease was potentially related to immunosuppressive therapy (37 of 74; 50%) or to transplantation itself (7 of 74; 9%). CONCLUSIONS: Extramediastinal diseases after heart transplantation involve most surgical specialties. Most of them are potentially linked with either the immunosuppressive therapy or the transplantation procedure, supporting our low-level immunosuppression policy. Expectant management is not justified in this population, who withstands operations well both early and late after transplantation.

Gastrointestinal disease following heart transplantation.

With advances in heart transplantation, a growing number of recipients are at risk of developing gastrointestinal disease. We reviewed our experience with gastrointestinal disease in 92 patients undergoing 93 heart transplants. All had follow-up, with the median time 4.8 years (range 0.5-9.6 years). During the period of the study we progressively adopted a policy of low immunosuppression aiming toward monotherapy with cyclosporine. Nineteen patients (20.6%) developed 28 diseases related to the gastrointestinal tract. Thirteen patients required 18 surgical interventions, five as emergencies: closure of a duodenal ulcer, five cholecystectomies (one with biliary tract drainage), a sigmoid resection for a diverticulitis with a colovesical fistula, a colostomy followed by a colostomy takedown for an iatrogenic colon perforation, appendectomy, two anorectal procedures, and six abdominal wall herniorrhaphies. At the onset of gastrointestinal disease, 8 patients were on standard triple-drug immunosuppression, all of them within 6 months of transplantation; 13 were on double-drug immunosuppression; and 7 were on cyclosporine alone. All the patients with perforations/fistulas were on steroids. Among the 11 infectious or potentially infectious diseases, 10 were on triple- or double-drug immunosuppression. One death, a patient who was on triple-drug immunosuppression, had a postmortem diagnosis of necrotic and hemorrhagic pancreatitis. Except for an incisional hernia following a laparoscopic cholecystectomy, there was no morbidity and, importantly, no septic complications. We concluded that a low immunosuppression policy is likely to be responsible for the low morbidity and mortality of posttransplant gastrointestinal disease, with a lower incidence of viscous perforation/fistula and infectious gastrointestinal disease.

Renal function one year after switching from Sandimmun to Neoral.

BACKGROUND: The replacement of Sandimmun by Neoral in 1995 was thought to cause subsequent renal function deterioration due to the better bioavailability of the new drug. We prospectively analyzed the effect of a dose-to-dose drug replacement on renal function over 12 months. METHODS AND RESULTS: The renal function of 47 consecutive heart transplanted patients was prospectively evaluated before (T0), at 1 (T1), 3 (T3), and 12 (T12) months after drug replacement. Mean serum creatinine was not significantly different at T0 and T12 (142 +/- 55 and 154 +/- 60 micromol/L, p = 0.1). We were able to reduce cyclosporine total and weight-indexed doses by, respectively, 11% and 14% between T0 and T12 (274 +/- 86 to 244 +/- 72 mg/d, p = 0.0003; and 3.7 +/- 1.4 to 3.2 +/- 1.2 mg/kg/d, respectively, p = 0.0005). CONCLUSIONS: This study demonstrates that the dose-to-dose replacement of Sandimmun by Neoral is feasible, with no direct influence on renal function over a 1-yr follow-up.

Incidence and prognostic value of electrocardiographic abnormalities after heart transplantation.

BACKGROUND: The improvement of surgical techniques and the use of immunosuppressive drugs within the past 15 years has made heart transplantation an increasingly performed procedure and an accepted treatment for end-stage cardiac failure. HYPOTHESIS: The aim of this study was to describe the changes of the 12-lead electrocardiogram (ECG) after heart transplantation and to determine their prognostic value on complications such as rejection or graft coronary artery disease during follow-up. METHODS: The ECGs of 62 consecutive patients were analyzed for 5 years at follow-up periods of 1, 2, 3, 6 months and yearly after transplantation. RESULTS: The most prevalent abnormality was the presence of complete or incomplete right bundle-branch block (RBBB). New RBBB appeared in 69% (43/62) of the patients, mainly during the first month (21/43). There was no left bundle-branch block. We detected nine episodes of supraventricular arrhythmias: one atrial fibrillation, six atrial flutter, one junctional tachycardia, one orthodromic tachycardia on a Wolff-Parkinson-White syndrome; all appearing during the first 3 months. Three of the six episodes of atrial flutter occurred during an episode of acute rejection. There was no relation between RBBB and the gender and age of recipients and donors, nor with the graft ischemic time and the pretransplantation hemodynamic values. Right bundle-branch block was not associated with acute rejection nor with graft coronary artery disease. CONCLUSION: The ECG abnormalities after heart transplantation have no predictive value on the long-term evolution. Right bundle-branch block is very frequent and is not associated with adverse prognosis.

Uricosuric effect of the angiotensin II receptor antagonist losartan in heart transplant recipients.

BACKGROUND: The angiotensin II receptor antagonist losartan is an effective antihypertensive agent with unique uricosuric properties. This study evaluates the uricosuric effects of losartan in 10 hypertensive heart transplant patients with hyperuricemia. METHODS: The patients were randomized to receive losartan 50 mg once daily and enalapril 20 mg once daily for 4 weeks according to a double-blind crossover design. Office blood pressure, plasma uric acid levels, and urinary uric acid excretion were monitored throughout the study. RESULTS: Plasma uric acid levels decreased significantly after 4 weeks of treatment with losartan (P<0.05) but not with enalapril. On day 1 and after 1 month of treatment, a significant increase in uric acid excretion was observed only with losartan. Significant decreases in office systolic and diastolic blood pressures were obtained with enalapril but not with losartan. CONCLUSIONS: Losartan effectively lowers plasma uric acid levels in hyperuricemic heart transplant patients.

Impairment of the myocardial vasomotor response to cold pressor stress in collateral dependent myocardium.

OBJECTIVE: To study the vasomotor response (cold pressor/basal flow) in myocardium perfused entirely by collaterals, using the reflex sympathetic stimulation of cold pressor stress. DESIGN: Regional myocardial blood flow was measured in collateral dependent and in remote myocardium using positron emission tomography with 15O water at basal and at cold pressor stress. Regional ischaemia was measured with 18F-fluorodeoxyglucose (FDG). PATIENTS: Nine patients (mean (SD) age 53 (6) years) with an occluded coronary artery supplied entirely by collaterals from other angiographically normal arteries. RESULTS: In remote myocardium, basal and cold pressor flow were 0.99 (0.26) and 1.46 (0.60) ml/min/g (P < 0.05), respectively, a myocardial vasomotor response of 1.46 (0.45). In collateral dependent myocardium, basal and cold pressor flow were 0.91 (0.20) and 0.87 (0.35) ml/min/g, respectively (the latter value, P < 0.05 v remote region), a myocardial vasomotor response of 0.97 (0.43) (P < 0.05 v remote region). The myocardial vascular resistance (mean arterial pressure/flow) during cold pressor was higher in the collateral dependent than in remote myocardium, at 147.0 (61.1) and 85.6 (32.3) mm Hg.min.g/ml (P < 0.05), respectively, but with no relative increase in FDG uptake. CONCLUSIONS: In contrast to the decrease in myocardial resistance in remote myocardium with cold pressor, an increase was observed in collateral dependent myocardium suggesting a vasoconstrictor response in resistive vessels, without demonstrable myocardial ischaemia.

[Follow-up after heart transplantation]. / Suivi du patient après transplantation cardiaque.

The prognosis of patients with end-stage cardiac disease has dramatically changed with transplantation. The incidence of complications remains relatively high and needs a very careful follow-up to have good long term results.