Biomedical subjects
Publications and source records attributed to Julio Pascual.
Headache, and migraine in particular, is the main neurological reason for consultation. We present the case of a 48-year-old woman who experienced a transformation of her episodic migraine attacks into daily headache episodes due to the ingestion of biscuits containing wheat as their main ingredient. This experience emphasises that a good clinical interview remains the most important point in the diagnosis and management of headache.
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BACKGROUND: Cyclosporin A (CsA) concentration monitoring with 2 h post-dosing levels (C2) correlates with the incidence of rejection and graft outcome in de novo renal transplant patients. The advantages of this policy beyond the first 12 months remain a matter of debate. The purpose of the present work was to evaluate the C2 target ranges on CsA monitoring after the first year in stable kidney transplant patients. METHODS: We studied 142 patients, 94 on CsA-steroids and 48 on triple therapy (CsA-azathioprin-steroids), transplanted for 104+/-42 months and with a serum creatinine of 1.53+/-0.52 mg/dl. C2 and C0 measurements were performed at baseline and at least twice more during the year of follow-up. RESULTS: The mean annual C2 blood levels in double therapy patients showed C2 in 23 (24.5%) of <600 ng/ml; in 53 (56.4%) of between 600 and 850 ng/ml; and in 18 patients (19.1%) of >850 ng/ml. In the triple therapy group, C2 in 12 (25%) was <500 ng/ml, in 24 (50%) between 500 and 700 ng/ml and in 12 patients (25%) >700 ng/ml. In both groups, higher C2 levels were associated with a better absorption of the drug measured by the ratio C2/C0 and C2/dose. There were no differences in incidence of infections, need for hospitalization and the presence of hypertension, hyperuricaemia, hypercholesterolaemia or diabetes between patients with low and high C2 blood levels. However, serum creatinine was higher in triple therapy patients with lower C0 levels (P = 0.004). In 135 patients (90 on double and 45 on triple therapy), renal function remained stable during follow-up and 120 of them (89%) had C2 values under the recommended ranges. CONCLUSIONS: C2 monitoring in maintenance patients enabled us to identify overexposure to CsA. Target levels of C2 should be adjusted according to the immunosuppressive regime. C2 levels between 600 and 800 ng/ml in double therapy patients and between 500 and 700 ng/ml in triple therapy patients are sufficient to give an adequate immunosuppression. The superiority of C2 with respect to C0 levels could not be demonstrated.
Primary cough headache is defined as head pain brought on by coughing or other Valsalva maneuvers, but not by prolonged physical exercise, in the absence of any intracranial disorder. Primary cough headache is considered to be a rare condition, accounting for 0.4% of all headaches consulting our Neurology Department. Its pathophysiology remains a mystery. Primary cough headache is a sudden-onset headache that usually lasts from 1 second to 30 minutes, tends to be bilateral and posterior, does not begin earlier than the fifth decade of life, is more frequent in men, is not accompanied by other neurologic manifestations, and responds to indomethacin. These clinical characteristics allow its differential diagnosis from other entities, even though a craniocervical magnetic resonance imaging study is mandatory to rule out posterior fossa lesions, especially Chiari type-I malformation.
BACKGROUND: More than half of patients with migraine suffer moderate to severe functional disability during migraine attacks. OBJECTIVE: To compare effects on functional disability at 2 hours after treating a migraine with rizatriptan 10-mg wafer versus usual nontriptan therapy for triptan-naïve patients with migraine. DESIGN: Open-label, prospective, two-attack study conducted at 111 neurology clinics. METHODS: Adult patients with migraine treated two migraine attacks, the first with their usual nontriptan therapy (nonsteroidal anti-inflammatory drugs, 57%; analgesics, 27%; or ergot derivatives, 16%) and the second with rizatriptan 10-mg wafer. Patients recorded pain intensity and functional disability at the start, and functional disability at 2 hours, as well as the time of return to normal function. RESULTS: A total of 1353 patients, 76% of them female, completed the study and were considered evaluable. During first and second migraine attacks, 55% and 63% of patients, respectively, reported severe disability or requiring bed rest. At 2 hours after treatment, the likelihood of experiencing any disability was more than five times greater after usual nontriptan therapy than after rizatriptan (odds ratio, 5.68; 95% confidence interval (CI), 4.66 to 6.94; P < .001). Rizatriptan was twice as likely to return patients to normal function than usual nontriptan therapy after adjusting for confounding factors (adjusted hazard ratio, 2.08; 95% CI, 1.92 to 2.25; P < .001). Assessed over all time points up to 6 hours, the speed of return to normal function was 52% faster after rizatriptan therapy (P < .001). Significantly more patients preferred rizatriptan than usual nontriptan therapy (78.8% vs. 21.2%; P < .001). The most common reasons cited for preference for rizatriptan were faster relief of headache pain and faster return to normal function. CONCLUSIONS: Patients in this study were more likely to experience a return to normal function at 2 hours after receiving rizatriptan than after their usual nontriptan therapy for migraine. The results of this study, using patient-oriented, clinically relevant endpoints such as functional disability and preference, will help to guide practitioners in making recommendations for acute migraine treatment.
BACKGROUND: It has been suggested that triptans achieving higher central nervous system (CNS) levels should have an advantage in efficacy, if central actions are important. Objective.-Our aim was to correlate the efficacy and tolerability results of triptans with their lipophilicity. METHODS: Data for response and pain free at 2 hours, recurrence, adverse events (AE), CNS AE, and chest symptoms taken from Ferrari et al's meta-analysis publications for the recommended doses of oral triptans were correlated with their lipophilicity coefficients (logD(pH)7.4 = -2.1 almotriptan < -1.5 sumatriptan < -1.0 zolmitriptan < -0.7 rizatriptan < -0.2 naratriptan < 0.5 eletriptan). RESULTS: We found no significant correlation between lipophilicity coefficients and any of the analyzed parameters. There was, however, some correlation between lipophilicity and CNS AE (P = .09, r = 0.74) and, to a lesser degree, with a reduction in recurrence rate (r = -0.36). The r values for response and pain free with placebo correction ranged from 0.04 to 0.34, suggesting almost no correlation between lipophilicity and efficacy variables. CONCLUSIONS: According to this analysis, a higher lipophilicity does not seem crucial to improve triptan efficacy. This physico-chemical property, however, correlates with higher CNS AE and, possibly, lower recurrence rates.
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Modern immunosuppressive regimens reduce the acute rejection rate by combining a cornerstone immunosuppressant like tacrolimus or cyclosporine with adjunctive agents like corticosteroids, mycophenolate mofetil (MMF) or azathioprine, often associated with untoward side effects. A 6-month randomized study was conducted in 47 European centers. Triple therapy with tacrolimus (trough levels 5-15 ng/mL), corticosteroids (dosage 10 mg/day) and MMF (1 g/day) was administered for 3 months. From day 92, patients either continued with triple therapy (control, n = 277), or stopped steroids (n = 279), or stopped MMF (n = 277). Surrogate markers for long-term benefits were changes in lipid profiles and occurrence of hematological, gastrointestinal and infectious complications. The 6-month acute rejection incidence (biopsy-proven) was similar in all groups (17.0% vs. 15.1% vs. 14.8%, p = 0.744), although the incidence after month 3 was higher in the steroid stop group than in the two other groups. Mean reductions in total cholesterol (18.9 mg/dL [0.49 mmol/L]) and LDL-cholesterol (8.1 mg/dL [0.21 mmol/L]) between months 4 and 6 were greater in the steroid stop group (p < 0.001). Leukopenia (p = 0.0082), serious CMV infection (p = 0.024), anemia (p = NS) and diarrhea (p = NS) were less frequent in the MMF stop group. In a study population of immunologically low-risk patients' withdrawal of corticosteroids or MMF from a tacrolimus-based therapy at 3 months was feasible. A longer follow-up will be needed to confirm the expected advantages for the long-term outcome and to assess the long-term safety of this minimization of immunosuppressive therapy.
BACKGROUND: Two previous meta-analyses of randomized, controlled trials of steroid withdrawal after renal transplantation have shown significant increases in acute rejection (both analyses) and graft failure rates (the last analysis). A new examination of this topic including only randomized, controlled trials based on currently used, new, potent therapy with calcineurin inhibitors and mycophenolate mofetil (MMF), avoiding early trials with azathioprine, is justified. METHODS: Steroid withdrawal in patients on triple therapy including a calcineurin inhibitor and MMF was assessed through meta-analysis of randomized, controlled trials in which intention-to-treat rates of acute rejection and renal allograft failure were established after steroid withdrawal or continuation. RESULTS: Six trials were included, four in patients receiving cyclosporine and two in patients receiving tacrolimus. The risk ratio (RR) for acute rejection was 2.28 (95% confidence interval [CI], 1.65-3.16; P < 0.00001) and the pooled risk difference (RD) was 0.08 (95% CI, 0.05-0.11; P < 0.001), indicating that the proportion of patients with acute rejection after prednisone withdrawal was significantly higher compared with controls. The RR for graft failure was 0.73 (95% CI, 0.42-1.28; P = 0.27) and the RD was -0.01 (95% CI, -0.03-0.01; P = 0.28), indicating that the proportion of patients with graft failure after withdrawal was not significantly different from that observed in controls. Total cholesterol was significantly lower after steroid withdrawal (weighted mean difference, -0.53 microM (95% CI, -0.70 to -0.36; P < 0.0001). CONCLUSIONS: Renal allograft recipients on triple therapy with a calcineurin inhibitor, MMF, and steroids are at low but significant risk of acute rejection after steroid withdrawal but do not suffer an increased risk of early graft failure. It is necessary to extend controlled follow-up to confirm graft function stabilization.
Our aim is to review the utility of the different imaging techniques in the field of renal transplantation (RT). A total of 500 potential RT recipients have been evaluated and were included in the waiting list. From 1978 to 2003, a total of 900 RT recipients were clinically followed-up and different imaging techniques assessed. The main indications for the different techniques were: (1) MR angiography to establish the vascular anatomy of the living donor with 95% accuracy for the detection of multiple renal vessels. (2) Abdominal ultrasound of the donor in order to detect lithiasis, incidental renal tumors or anatomic anomalies. (3) Vascular evaluation of the recipients was essential considering the aging character of this population. X-ray film of the abdomen was a routine technique. Doppler ultrasound (DOP-US) of the iliac vessels and an angiographic study (DSA, CT, MR) of the iliac and splenic arteries were indicated only in selected cases. (4) DOP-US was useful in the diagnosis of graft dysfunction after RT. It allowed the exclusion of thrombosis and urinary obstruction, and was useful to distinguish between acute tubular necrosis, cyclosporine nephrotoxicity and acute rejection (AR). (5) Finally, ultrasound was used as a percutaneous approach to pyelocaliceal systems of grafts affected by ureteral stenosis or fistula and for draining fluid collections after RT (lymphocele, abscess, hematoma or urinoma).
We describe an exceptional spinocerebellar ataxia type 2 (SCA2) phenotype combining cerebellar ataxia, levodopa-responsive parkinsonism, and motor neuron symptoms. We conclude that motor neuron symptoms and signs may be a striking manifestation in SCA2, masking pre-existing cerebellar and extrapyramidal semeiology.
We describe the clinical and electrophysiological features of an elderly woman presenting with persistent clonic twitching of the abdominal muscles that were considered to represent a rare manifestation of epilepsia partialis continua due to a metastatic cortical lesion.
One of the leading causes of late graft loss is chronic allograft nephropathy, characterized in part by deteriorating renal function. Registry data have demonstrated that renal function within the first year post-transplant is an important predictor of long-term transplant outcome, with serum creatinine concentrations < or =1.5 mg/dl at 6 or 12 months being associated with the highest rate of 5 year graft survival. These findings are supported by a retrospective, pooled analysis of two multicentre trials in the USA, as well as by our own data showing that serum creatinine concentrations may be predictive of long-term survival as early as 1 month post-transplant. Analysis of 216 renal transplantations carried out at our centre (1996-2000) using immunosuppressive therapy based on tacrolimus, corticosteroids and azathioprine (n = 51) or mycophenolate mofetil (MMF; n = 70) vs ciclosporin microemulsion, azathioprine and corticosteroids (n = 95) showed that the best 3 year graft survival was achieved with tacrolimus/MMF therapy. While serum creatinine concentrations at this time point were similar for the tacrolimus and ciclosporin treatment groups (1.69 and 1.65 mg/dl, respectively), the proportion of patients with functioning grafts was significantly higher in the tacrolimus group (84 vs 67%, P = 0.007). Similar findings of improved renal function or graft outcomes with tacrolimus- vs ciclosporin-based therapy have been reported in other single-centre and multicentre trials and a USRDS registry survey. Accumulating data suggest that renal function compares well between tacrolimus-based and calcineurin inhibitor (CNI)-sparing regimens. Consequently, the vast majority of renal transplant recipients maintain good long-term renal function with tacrolimus cornerstone immunosuppression without adopting CNI minimization or withdrawal strategies.
Prospective therapeutic drug monitoring of everolimus was performed in a 1-year multicenter trial in 237 de novo kidney transplant patients. Trough blood levels, rejection episodes, and safety parameters were evaluated to define an appropriate therapeutic concentration range for everolimus in this setting. Patients were randomized to everolimus starting doses of 0.75 mg bid (n = 112) or 1.5 mg bid (n = 125). Doses were then individualized based on everolimus trough blood levels (C0) in an attempt to maintain troughs > or = 3 ng/mL; no upper limit was specified. The regimen also contained corticosteroids and cyclosporine with an early dose reduction in months 2-3 posttransplant based on concentrations 2 hours postdose (C2). Cyclosporine C0 levels were also collected. Prospective therapeutic drug monitoring of everolimus C0 in patients starting at 0.75 mg bid led to dose adjustments in 52% of patients to an average long-term dose of 0.93 +/- 0.36 mg bid. This gave median (10th to 90th percentile) C0 levels of 5.3 (3.4-7.9) ng/mL. In patients starting at 1.5 mg bid, 55% had dose adjustments leading to an average long-term dose of 1.24 +/- 0.35 mg bid. This yielded C0 levels of 7.2 (4.4-11.6) ng/mL. Cyclosporine dosing began on average at 274 +/- 78 mg bid, was down-titrated in months 2-3 from 181 +/- 80 mg to 81 +/- 33 mg bid, and stabilized at 70 +/- 26 mg bid thereafter. This yielded median C2 levels of 1165 ng/mL in month 1, a down-titration with levels of 853 and 630 ng/mL in months 2 and 3, and a posttitration level of 472 ng/mL. The corresponding median cyclosporine C0 was 242 ng/mL initially and 70 ng/mL in the posttitration phase. In patients starting at 0.75 mg bid everolimus and an early down-titration of cyclosporine, everolimus C0 between 3 and 8 ng/mL was an effective and safe concentration range. Concentrations up to 12 ng/mL were tolerated over the first year posttransplant. This trial demonstrated that therapeutic monitoring of everolimus can be prospectively performed for dose individualization. Maintaining everolimus troughs in the range 3 to 8 ng/mL in the first posttransplant year with reduced-exposure cyclosporine is associated with good efficacy and safety profiles.
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A 14-year-old adolescent was seen with an 8-month history of almost daily incapacitating headaches due to idiopathic intracranial hypertension in Behçet syndrome. All his clinical signs and symptoms, including headache, resolved 2 to 4 weeks after topiramate was initiated. An effect on carbonic anhydrase isoenzymes II and IV, reducing cerebrospinal fluid production, could potentially explain the beneficial effect of topiramate in intracranial hypertension. Further studies are necessary, however, to confirm the significance of topiramate in this indication.
Two prospective, randomized studies evaluated everolimus 1.5 vs. 3 mg/day with steroids and low-exposure cyclosporine (CsA) (C2 monitoring) in de novo renal transplant patients. Everolimus dosing was adjusted to maintain a minimum trough level of 3 ng/mL. Study 1 (A2306; n=237) had no induction therapy; in Study 2 (A2307; n=256) basiliximab was administered (Days 0 and 4). The primary endpoint was renal function at 6 months. CsA C2 target levels, initially 1200 ng/mL in Study 1 and 600 ng/mL in Study 2, were tapered over time post-transplant. Median creatinine levels in Study 1 were 133 and 132 micromol/L at 6 months in the 1.5 and 3 mg/day groups, respectively, and 130 micromol/L in both groups in Study 2. Biopsy-proven acute rejection (BPAR) occurred in 25.0% and 15.2% of patients in the 1.5 and 3 mg/day groups in Study 1, and 13.7% and 15.1% in Study 2. Incidence of BPAR was significantly higher in patients with an everolimus trough <3 ng/mL. There were no significant between-group differences in the composite endpoint of BPAR, graft loss or death, nor any significant between-group differences in adverse events in either study. Concentration-controlled everolimus with low-exposure CsA provided effective protection against rejection with good renal function.
Rizatriptan is a second-generation triptan marketed as 5 and 10 mg tablets and rapidly disintegrating wafer formulations. In > 5000 acute migraine patients enrolled in short-term trials and almost 1800 patients in long-term, open-label trials treating approximately 47000 attacks, rizatriptan was effective and well-tolerated. Controlled head-to-head data and a meta-analysis of 53 randomised, placebo-controlled trials of oral triptans in > 24000 patients have shown that rizatriptan 10 mg offers efficacy advantages over oral sumatriptan 50 and 100 mg and other oral triptans, both in terms of speed of onset of action and consistency. These advantages may reflect its improved pharmacological profile over sumatriptan in terms of higher oral bioavailability and a shorter time to maximum concentration. The wafer formulation offers the convenience of being administered without water. As a result of its superior efficacy profile and generally good tolerability, rizatriptan can be considered as a first-line treatment for acute migraine.