Optimizing maintenance therapy in responders to abrocitinib induction: A post hoc analysis of JADE REGIMEN.

BACKGROUND: Treatment optimization may require dosing flexibility. The Phase 3 JADE REGIMEN trial (NCT03627767) evaluated maintenance of abrocitinib 200 mg-induced response in patients with moderate-to-severe atopic dermatitis (AD) randomly assigned to subsequent maintenance with continuous-dose abrocitinib (200 mg), reduced-dose abrocitinib (100 mg) or placebo. Maintenance with continuous-dose abrocitinib was associated with a stronger prevention of disease flares, but also with a higher occurrence of adverse events, compared with the reduced dose. OBJECTIVE: This post hoc analysis of JADE REGIMEN aimed to identify predictors of not flaring during the maintenance period and to generate tools that can be used to assess probability of not flaring. METHODS: Data were analysed from patients who responded to abrocitinib 200 mg induction therapy (12 weeks) and were randomly assigned to receive abrocitinib (200 mg or 100 mg) or placebo in the 40-week maintenance period. Demographic and baseline disease characteristics and level of response to induction were evaluated for association with not flaring using logistic regression. Parameters with a significant (p < 0.15) interaction with the treatment arm were fitted into a multivariable regression model, which was used to assess probability of not flaring. RESULTS: Lower percentage body surface area affected at baseline (p = 0.09), absence of prior exposure to systemic agents (p = 0.02) and greater percentage change in EASI from baseline to randomization (p < 0.001) were identified as predictors of not flaring with abrocitinib. In both abrocitinib arms, percentage change in EASI from baseline to end of induction (Week 12) was the major contributor to the probability of not flaring in the maintenance period. CONCLUSIONS: Maintenance of response using reduced-dose abrocitinib 100 mg may be feasible for patients with lower baseline disease severity and strong response to abrocitinib 200 mg induction treatment.

Evolution of appraisal tool usage preferences in PROSPERO records: a study of non-Cochrane systematic reviews.

OBJECTIVES: This research-on-research substudy uses a data-driven approach to investigate the range of appraisal tools in non-Cochrane systematic reviews and meta-analyses registered in the International Prospective Register of Systematic Reviews (PROSPERO). STUDY DESIGN AND SETTING: A comprehensive web scraping of all completed non-Cochrane registrations in PROSPERO from February 2011 to December 2017 was performed. The focus was classifying the appraisal tools based on study type, assessment aspects, and research topics. RESULTS: After analyzing 17,708 complete records, we found a predominant use of methodological quality assessment tools compared to those for reporting quality or risk of bias (RoB). This indicates a greater emphasis on methodological rigor in the studied protocols. Various tools for assessing methodological quality were observed, reflecting the complexity of such evaluations. Instruments designed for evaluating methodological or reporting quality were mainly intended for non-randomized clinical trials or observational studies, unlike RoB tools more commonly used in randomized clinical trials. No distinct trends in tool usage were observed in specific research conditions or domains, suggesting that tool choice is influenced more by study design than research topic. CONCLUSION: This study provides insights into the preferential use of various assessment tools in conducting non-Cochrane systematic reviews, as evidenced in PROSPERO records. The findings reveal various methodological assessment tools, underscoring their versatility across different study designs and research areas.

Short-term efficacy and safety of new biological agents targeting the interleukin-23-T helper 17 pathway for moderate-to-severe plaque psoriasis: a systematic review and network meta-analysis.

A new generation of biologics targeting the interleukin-23-T helper 17 pathway has been developed. This study aimed to assess the short-term effectiveness and safety of these new agents using a network meta-analysis. Twenty-seven randomized clinical trials (10 629 patients) were identified by a comprehensive systematic literature review (PROSPERO 2015: CRD42015025472). Quality of evidence was assessed following Cochrane-compliant rules and the Grading of Recommendations, Assessment, Development and Evaluations approach. Efficacy and safety outcomes at weeks 10-16 were compared using a random-effects network meta-analysis within a frequentist framework to estimate pooled odds ratios (ORs) of direct and indirect comparisons among the therapeutic options. There were six direct drug-to-drug comparisons in the network, with a high degree of consistency between the direct and indirect evidence. From the available evidence, infliximab 5 mg kg-1 every 8 weeks [OR 118·89, 95% confidence interval (CI) 60·91-232·04] and secukinumab 300 mg every 4 weeks (OR 87·07, 95% CI 55·01-137·82) are shown to be among the most effective short-term treatments, but are ranked as the biologics most likely to produce any adverse event or an infectious adverse event, respectively. Ustekinumab 90 mg every 12 weeks, the third most efficacious treatment (OR 73·67, 95% CI 46·97-115·56), was the only agent that did not show increased risk of adverse events compared with placebo. Treatment recommendations should also consider long-term outcomes and costs.

Systematic reviews and meta-analyses on psoriasis: role of funding sources, conflict of interest and bibliometric indices as predictors of methodological quality.

BACKGROUND: The quality of systematic reviews and meta-analyses on psoriasis, a chronic inflammatory skin disease that severely impairs quality of life and is associated with high costs, remains unknown. OBJECTIVES: To assess the methodological quality of systematic reviews published on psoriasis. METHODS: After a comprehensive search in MEDLINE, Embase and the Cochrane Database (PROSPERO: CDR42016041611), the quality of studies was assessed by two raters using the Assessment of Multiple Systematic Reviews (AMSTAR) tool. Article metadata and journal-related bibliometric indices were also obtained. Systematic reviews were classified as low (0-4), moderate (5-8) or high (9-11) quality. A prediction model for methodological quality was fitted using principal component and multivariate ordinal logistic regression analyses. RESULTS: We classified 220 studies as high (17·2%), moderate (55·0%) or low (27·8%) quality. Lower compliance rates were found for AMSTAR question (Q)5 (list of studies provided, 11·4%), Q10 (publication bias assessed, 27·7%), Q4 (status of publication included, 39·5%) and Q1 (a priori design provided, 40·9%). Factors such as meta-analysis inclusion [odds ratio (OR) 6·22; 95% confidence interval (CI) 2·78-14·86], funding by academic institutions (OR 2·90, 95% CI 1·11-7·89), Article Influence score (OR 2·14, 95% CI 1·05-6·67), 5-year impact factor (OR 1·34, 95% CI 1·02-1·40) and article page count (OR 1·08, 95% CI 1·02-1·15) significantly predicted higher quality. A high number of authors with a conflict of interest (OR 0·90, 95% CI 0·82-0·99) was significantly associated with lower quality. CONCLUSIONS: The methodological quality of systematic reviews published about psoriasis remains suboptimal. The type of funding sources and author conflicts may compromise study quality, increasing the risk of bias.

Facial Angiofibroma Severity Index (FASI): reliability assessment of a new tool developed to measure severity and responsiveness to therapy in tuberous sclerosis-associated facial angiofibroma.

BACKGROUND: Tuberous sclerosis complex (TSC) is an autosomal dominant neurocutaneous disorder characterized by the development of multisystem hamartomatous tumours. Topical sirolimus has recently been suggested as a potential treatment for TSC-associated facial angiofibroma (FA). AIM: To validate a reproducible scale created for the assessment of clinical severity and treatment response in these patients. METHODS: We developed a new tool, the Facial Angiofibroma Severity Index (FASI) to evaluate the grade of erythema and the size and extent of FAs. In total, 30 different photographs of patients with TSC were shown to 56 dermatologists at each evaluation. Three evaluations using the same photographs but in a different random order were performed 1 week apart. Test and retest reliability and interobserver reproducibility were determined. RESULTS: There was good agreement between the investigators. Inter-rater reliability showed strong correlations (> 0.98; range 0.97-0.99) with inter-rater correlation coefficients (ICCs) for the FASI. The global estimated kappa coefficient for the degree of intra-rater agreement (test-retest) was 0.94 (range 0.91-0.97). CONCLUSIONS: The FASI is a valid and reliable tool for measuring the clinical severity of TSC-associated FAs, which can be applied in clinical practice to evaluate the response to treatment in these patients.

[Facing fever in the pediatric patient: Checklist as a tool for parents]. / Checklist como herramienta para los padres ante la fiebre en el paciente pediátrico.

INTRODUCTION: In Western Europe, 20%-40% of children with fever request health care. Most of them present trivial viral infections, however, it is essential in pediatrics to distinguish patients who present a severe infection. This process begins with the recognition of the seriousness and the subsequent search for medical attention by the parents. METHODOLOGY: Analytical and cross-sectional observational study. One hundred patients were selected in two health centers. Sociodemographic data were collected, together with the responses to a checklist containing the signs and symptoms to request health care in case of fever. Subsequently, the checklist was filled out by the pediatrician. RESULTS: The mean age of the patients was 5.41 years. 50% consulted in the first 48h of fever evolution. In 42%, the response to all the items on the checklist was exactly the same between the companion and the pediatrician. There were no significant differences according to variables: first episode of fever (P=.262), age of the patient (P=.859), having a sibling (P=.880), family relationship of the companion (P=.648) or educational level of the companion (P=.828). CONCLUSIONS: Medical consultations for fever in pediatrics are carried out very early. A high percentage do not present alarm signs when they consult. There is a need to expand training on the alarm signs of fever in all parents, regardless of the number of children, age or educational level. The checklist as a tool for home assessment of fever has received high marks for its usefulness.

Differences between objective efficacy and perceived efficacy in patients with palmar hyperhidrosis treated with either botulinum toxin or endoscopic thoracic sympathectomy.

BACKGROUND: Moderate to severe palmar hyperhidrosis can disturb people's work and social and emotional lives. Botulinum toxin and sympathectomy are currently considered the most effective treatment options but few studies have analysed the concordance between efficacy and patient satisfaction in comparisons of these two types of treatments. OBJECTIVE: To assess the relation between efficacy and the satisfaction of patients with palmar hyperhidrosis treated with either botulinum toxin or endoscopic thoracic sympathectomy. MATERIAL AND METHODS: This retrospective, observational study included all patients treated with either botulinum toxin or endoscopic thoracic sympathectomy in a single reference hospital in 2005-2010. Information was obtained from computerized medical records and a telephone survey about patients' educational and socio-economic level, awareness of treatment options, pre- and post-treatment severity of palmar hyperhidrosis, satisfaction and associated side effects. Predictors of efficacy and patient satisfaction with each treatment were analysed with ordinal and multinomial logistic regression models. RESULTS: Patients who underwent sympathectomy had more severe palmar hyperhidrosis but efficacy and patient satisfaction were greater compared with patients given botulinum toxin. The severity of the compensatory palmar hyperhidrosis was predictive of less satisfaction after sympathectomy. In the group treated with botulinum toxin, low socio-economic status, lack of information about treatment options, fewer sessions and a shorter anhidrotic effect were associated with less satisfaction. CONCLUSION: In studies of expectations regarding the outcome of palmar hyperhidrosis treatment, doctors should consider the factors that determine patient satisfaction in relation to the treatment options.

Characterization of nephropathogenic infectious bronchitis virus DMV/1639/11 recovered from Delmarva broiler chickens in 2011.

A limited outbreak of nephropathogenic infectious bronchitis (NIB) occurred in three Delmarva (DMV) commercial broiler chicken flocks in 2011. Isolates of NIB virus (NIBV)--DMV/1639/11, DMV/3432/11, and DMV/3902/11--were characterized by sequence analysis of the N-terminal subunit (S1) of the spike (S) gene. Findings indicated that the isolates were identical to each other and to PA/9579A/10, a 2010 isolate from poultry in Pennsylvania. The 2010 and 2011 isolates appear to have originated from a 1997-2000 NIB outbreak in Pennsylvania. DMV/1639/11 and PA/9579A/10 were determined to be nephropathogenic in susceptible chickens, yielding virus reisolations from kidney and inducing characteristic interstitial nephritis microscopic lesions. In a controlled laboratory study, 40% of chickens vaccinated with a combination live vaccine containing infectious bronchitis virus (IBV) strains Massachusetts (Mass) + Connecticut (Conn) were positive on virus isolation attempts after challenge with DMV/1639/11, compared with only 13% of Mass + Arkansas (Ark) vaccinates. Both combination vaccines gave partial protection against the development of DMV/1639/11-induced renal lesions. Although numerically fewer chickens vaccinated with Mass + Conn had interstitial nephritis compared with those vaccinated with Mass + Ark, neither vaccine combination offered greater protection (P < 0.05) than observed in unvaccinated chickens challenged with DMV/1639/11. Mass + Ark vaccinations, applied under commercial conditions in the hatchery (spray) and on-farm (spray), did not protect the trachea or kidney from DMV/1639/11 challenge. Serologic testing of broiler flocks found < 3% (2 of 69) tested to possess specific antibodies to DMV/1639/11, indicating the virus had not become established in the region.

Sustained clinical effectiveness and favorable safety profile of topical sirolimus for tuberous sclerosis - associated facial angiofibroma.

BACKGROUND: Tuberous sclerosis complex (TSC) is an autosomal dominant neurocutaneous disorder characterized by the development of multisystem hamartomatous tumours. Facial angiofibroma appears in up to 80% of patients and has a considerable psychological impact. Various invasive procedures have been used, although they show limited effectiveness and potential adverse effects. OBJECTIVES: To evaluate the sustained clinical benefits and safety profile of topical sirolimus applied to treat facial angiofibromas. METHODS: This study was a non-blinded, uncontrolled case-series comprising 10 patients with TSC-associated facial angiofibroma that was treated with 0.4% sirolimus ointment 3 times a week for 9 months. Patients were clinically evaluated at baseline and at 6, 12, 24 and 36 weeks. Plasma levels of sirolimus were determined. RESULTS: A sustained improvement was observed in erythema and in the size and extension of the lesions as early as the first weeks of treatment. Sirolimus plasma levels remained below detection limits (0.3 ng/mL) in all cases. The formula was well-tolerated with no local or systemic adverse effects. CONCLUSIONS: Topical sirolimus seems to be an effective and safe medical alternative to surgery or laser-based treatments in patients with TSC-associated facial angiofibromas.

Characterization of infectious bursal disease viruses isolated in 2007 from Delmarva commercial broiler chickens.

A study was performed in 2007 to isolate and characterize infectious bursal disease viruses (IBDVs) in commercial broilers grown in the Delmarva (DMV) Peninsula region of the United States. Bursae of Fabricius were collected weekly from 1 to 4 wk of age from broilers on 10 farms with a history of poor performance. Microscopic pathology was used to determine the infectious bursal disease (IBD) status of the broilers. Bursae from 1- and 2-wk-old broilers did not show IBD microscopic lesions. Moreover, broilers on 1 of the 10 farms were IBD lesion free at 3 and 4 wk of age. However, 3 of 9 and 9 of 9 farms yielded broilers with IBD-affected bursae from 3- and 4-wk-old commercial broilers, respectively. Ten IBDV isolates were recovered from 3 of 3 lesion-positive bursal pools at 3 wk of age and 7 of 9 lesion-positive bursal pools at 4 wk of age. Analysis of the viral protein (VP) 2 genes identified all isolates as serotype 1 Delaware (Del) variant viruses. Five field isolates, each representing different molecular clades of the Delaware variant viruses, were selected for further study. Experimental infection of specific-pathogen-free white leghorn chickens with isolates DMV/4813/07, DMV/4947/07, DMV/4955/07, DMV/5038/07, and DMV/5041/07 produced gross and microscopic pathology of the bursa consistent with Delaware variant infection. Monoclonal antibody testing showed DMV/4813/07, DMV/4947/07, DMV/ 4955/07, and DMV/5041/07 to be similar to previous recognized variant viruses. However, DMV/5038/07 was found to be unreactive with the monoclonal antibodies that typically recognize reference strains STC, Del E, GLS, RS593, and AL2. In a challenge of immunity study, 10-day-old progeny from breeders immunized with a commercially available inactivated IBDV vaccine containing the Del E and classic strains were protected to a lesser degree against isolate DMV/5038/07 compared to Del E challenge based on microscopic lesion scores (P < 0.01) of the bursa. This result suggests the virus is antigenically different from the Del E strain contained in the vaccine. Collectively, the monoclonal antibody and progeny challenge of immunity findings suggest DMV/5038/07 is antigenically different from the Del E strain contained in the vaccine.

Olive oil and health: summary of the II international conference on olive oil and health consensus report, Jaén and Córdoba (Spain) 2008.

Olive oil (OO) is the most representative food of the traditional Mediterranean Diet (MedDiet). Increasing evidence suggests that monounsaturated fatty acids (MUFA) as a nutrient, OO as a food, and the MedDiet as a food pattern are associated with a decreased risk of cardiovascular disease, obesity, metabolic syndrome, type 2 diabetes and hypertension. A MedDiet rich in OO and OO per se has been shown to improve cardiovascular risk factors, such as lipid profiles, blood pressure, postprandial hyperlipidemia, endothelial dysfunction, oxidative stress, and antithrombotic profiles. Some of these beneficial effects can be attributed to the OO minor components. Therefore, the definition of the MedDiet should include OO. Phenolic compounds in OO have shown antioxidant and anti-inflammatory properties, prevent lipoperoxidation, induce favorable changes of lipid profile, improve endothelial function, and disclose antithrombotic properties. Observational studies from Mediterranean cohorts have suggested that dietary MUFA may be protective against age-related cognitive decline and Alzheimer's disease. Recent studies consistently support the concept that the OO-rich MedDiet is compatible with healthier aging and increased longevity. In countries where the population adheres to the MedDiet, such as Spain, Greece and Italy, and OO is the principal source of fat, rates of cancer incidence are lower than in northern European countries. Experimental and human cellular studies have provided new evidence on the potential protective effect of OO on cancer. Furthermore, results of case-control and cohort studies suggest that MUFA intake including OO is associated with a reduction in cancer risk (mainly breast, colorectal and prostate cancers).

Anaesthetic management of a paediatric patient with congenital fibre type disproportion myopathy. / Tratamiento anestésico en una paciente pediátrica con miopatía congénita por desproporción del tipo de fibras.

Congenital fibre type disproportion (CFTD) is a rare type of myopathy that is characterised by muscle weakness and hypotonia during childhood. Clinical features include motor delay, feeding difficulties, limb weakness, joint contractures, and scoliosis. A report is presented of the anaesthetic management of a 3-year-old girl with CFTD myopathy associated with a mutation of the TPM3 gene, scheduled for adenotonsillectomy because of obstructive sleep apnoea hypopnoea syndrome (OSAHS). The main concerns were the possible susceptibility to malignant hyperthermia, the risk of anaesthesia-induced rhabdomyolysis, a greater sensitivity to non-depolarising muscle relaxants, and the presence of OSAHS. Total intravenous anaesthesia with propofol and the use of rocuronium/sugammadex appear to be safe options. Given the high risk of respiratory compromise and other complications, patients should be closely monitored in the post-operative period.

Descriptive study of ultrasound images of the upper airway obtained after insertion of laryngeal mask. / Imágenes ultrasonográficas de vía aérea superior tras la inserción de mascarilla laríngea: estudio descriptivo y utilidad clínica.

OBJECTIVE: To evaluate clinical usefulness of ultrasound images of the upper airway in order to check correct laryngeal mask placement. MATERIAL AND METHODS: A prospective observational study was conducted on patients scheduled for abdominal surgery under general anaesthesia, in whom the patency of the upper airway was ensured using an Ambu®AuraGainTM laryngeal mask. An ultrasound scan was performed of the upper-airway in the cranio-caudal direction and with longitudinal scans in the anterior midline and parasagittal axis, in three moments: before, after inserting and after removing the mask. All recorded images were evaluated in a second time by a radiologist-expert in upper airway ultrasound. Subsequently, the ultrasound data were related to the clinical difficulty of the insertion and presence of air leaks. RESULTS: Data was collected from 30 patients (20 females and 10 males) being operated on for abdominal hysterectomy (15), eventroplasty (6), uterine myomectomy (3), and umbilical (4) and inguinal herniorrhaphy (2). The blind insertion of the masks did not present difficulties in 24 (80%) patients. Air leakage was detected in 8 (26.7%) patients, which was moderate in 7 cases and severe in one of them. The ultrasound findings confirmed good mask placement in 22 (73.3%) patients. Anatomical airway changes after laryngeal mask extraction were only observed in 3 (12%) patients, all of them minor. There was a statistically significant association (P<.05) between difficulty in inserting the device and the level of air leakage. CONCLUSIONS: Upper airway ultrasound is a useful diagnostic method to evaluate laryngeal mask placement. Laryngeal oedema was not observed after removal of the device.

Relationships between abstract features and methodological quality explained variations of social media activity derived from systematic reviews about psoriasis interventions.

OBJECTIVES: The aim of this study was to describe the relationship among abstract structure, readability, and completeness, and how these features may influence social media activity and bibliometric results, considering systematic reviews (SRs) about interventions in psoriasis classified by methodological quality. STUDY DESIGN AND SETTING: Systematic literature searches about psoriasis interventions were undertaken on relevant databases. For each review, methodological quality was evaluated using the assessing the methodological quality of systematic reviews tool. Abstract extension, structure, readability, and quality and completeness of reporting were analyzed. Social media activity, which consider Twitter and Facebook mention counts, as well as Mendeley readers and Google scholar citations were obtained for each article. Analyses were conducted to describe any potential influence of abstract characteristics on review's social media diffusion. RESULTS: We classified 139 intervention SRs as displaying high/moderate/low methodological quality. We observed that abstract readability of SRs has been maintained high for last 20 years, although there are some differences based on their methodological quality. Free format abstracts were most sensitive to the increase of text readability as compared with more structured abstracts (Introduction, Methods, Results, and Discussion or eight headings), yielding opposite effects on their quality and completeness depending on the methodological quality: a worsening in low quality reviews and an improvement in those of high quality. Both readability indices and preferred reporting items of systematic reviews and meta-analyses for Abstract total scores showed an inverse relationship with social media activity and bibliometric results in high methodological quality reviews but not in those of lower quality. CONCLUSION: Our results suggest that increasing abstract readability must be specially considered when writing free format summaries of high-quality reviews because this fact correlates with an improvement of their completeness and quality, and this may help to achieve broader social media visibility and article usage.

Treatment of chronic he1patitis C genotype 1 with peginterferon-alpha2a (40 kDa) plus ribavirin under routine clinical practice in Spain: early prediction of sustained virological response rate.

BACKGROUND: Sustained virological response rates of up to 52% have been obtained with peginterferon alpha2a (40 kDa) plus ribavirin in patients suffering from chronic hepatitis C genotype 1 in randomized-controlled trials. AIM: To assess early virological response and its clinical utility in predicting an sustained virological response in patients suffering from chronic hepatitis C genotype 1 in routine clinical practice in Spain. METHODS: Treatment-naïve patients received pegylated interferon alpha2a (40 kDa) 180 microg/week plus ribavirin 1000/1200 mg/day for 48 weeks, and were followed for a further 24 weeks. Overall, 475 patients received at least one dose of medication and were included in the efficacy population. RESULTS: The overall sustained virological response rate was 48%. Of those with week 12 virological data, 83% had an early virological response. The negative predictive value of an early virological response was 93%. CONCLUSION: If sustained virological response is the goal, a treatment-decision based on a 12-week evaluation during routine clinical practice is feasible.

[Angioma-like liver lesions in patients with chronic liver disease]. / Lesiones hepáticas sugestivas de angioma en pacientes con hepatopatía crónica.

OBJECTIVE: The aim of this study was to evaluate in our healthcare area the clinical, ultrasonographic, and evolutionary features of patients with chronic liver disease and angioma-like liver lesions on ultrasonography. MATERIALS AND METHODS: We conducted a retrospective study amongst patients seen at the Ultrasonography Unit, Gastroenterology Department between January 2000 and June 2004. Included in the study were patients that presented with clinical and/or laboratory complaints consistent with chronic liver disease of any etiology, and those in which abdominal ultrasounds revealed the existence of at least one angioma-like liver lesion. All relevant epidemiological, clinical, ultrasonographic, and evolutionary data were carefully collected and recorded. RESULTS: In the course of our study, 58 patients were diagnosed with chronic liver disease and angioma-like liver lesions, of which 13 showed clinical, laboratory, ultrasonographic, and/or histological signs of liver cirrhosis. In 50% of patients these lesions were less than 10 mm in diameter, and in most cases were located in the right hepatic lobe. During an average follow-up period of 35 months (6-168 months) we verified that, in two patients, these lesions, initially interpreted as angiomas were in fact malignancies (one hepatocellular carcinoma and one metastatic adenocarcinoma of the gallbladder). In both cases, the patients were cirrhotic. Thus, our study revealed that 15% of lesions found in cirrhotic patients initially interpreted as angiomas were actually malignant. CONCLUSIONS: Our study revealed that, in patients with chronic liver disease, particularly in cirrhotic patients, a considerable percentage of ultrasonographic lesions originally interpreted as angiomas are in fact malignant tumors.

Sirolimus as an alternative to anticalcineurin therapy in heart transplantation: experience of a single center.

We report a series of 26 heart transplant recipients with renal impairment in which sirolimus was used as the basic immunosuppresive drug (without associated calcineurin inhibitors) to avoid further nephrotoxicity. Sirolimus (trough levels 10 to 12 ng/mL, average daily dose 3 mg) was used in two settings: de novo in 7 patients with significant preexistent renal impairment and as a chronic conversion in 19 stable patients with established renal failure (creatinine level >2 mg/dL). In all de novo patients (n = 7), the renal function significantly improved. Creatinine fell from 2.95 +/- 0.9 mg/dL to 1.41 +/- 0.4 mg/dL at follow-up (P = .0017). One patient died suddenly of a massive pulmonary embolism. Only one patient experienced histologic but reversible rejection. In one patient, anemia and diarrhea prompted sirolimus withdrawal. Five patients had infectious episodes: three bacterial pneumonias, one mediastinitis, and two CMV infections. In the chronic conversion group (n = 19), the improvement was mostly limited to patients with moderate renal failure (creatinine < or =2.5 mg/dL) in which creatinine fell from 2.24 +/- 0.2 to 1.9 +/- 0.27 mg/dL, P = .009). When basal creatinine was over 2.5 mg/dL, only one third of the patients improved after conversion. Two patients died: terminal renal failure and cerebrovascular accident. There were no clinical episodes of rejection. Secondary effects prompted the discontinuation of sirolimus in five patients: two definite and one possible interstitial pneumonitis and two cases of anemia). The symptoms resolved after sirolimus withdrawal. Six patients had infection: four pneumonias, one sepsis, and one cutaneous abscess. Sirolimus is an interesting alternative to calcineurin inhibitors in selected patients with renal impairment. It prevents renal failure in de novo recipients at high risk of catastrophic renal damage and ameliorates renal dysfunction in chronic patients with moderate renal dysfunction. Given the high incidence of secondary effects, the adequate dosage and the secondary effects profile needs further study.

Analysis of two cycloplatinated compounds derived from N-(4-methoxyphenyl)-alpha-benzoylbenzylidenamine. Comparison of the activity of these compounds with other isostructural cyclopalladated compounds.

In the present paper we report the synthesis, structural characterization, biochemical properties, and antiproliferative activity of two organo-cis-platinum cyclometalated compounds of formula [M(4-OMeC6H4N=C(COC6H5)C6H4)X]2, where M = Pt and X=Cl (4) or OAc (5). The IR and 1H and 13C NMR data of the chloro-bridged compound 4 showed that it has a planar structure. As indicated by IR and 1H and 13C NMR, the acetate-bridged compound 5 has an open-book shape structure. This structure was further confirmed by X-ray diffraction. The comparison of the biochemical properties and antiproliferative activity of these compounds relative to the isostructural palladium compounds [Pd(4-OMeC6H4N=C(COC6H5)C6H4)X]2 [X = AcO (1) and (2) or Cl (3)] indicated that the activity of compounds 4 and 5 is higher than that of the corresponding isostructural compounds 3 and 1-2, respectively, since their ID50 are 2-9-fold lower. It seems that there are not differences in the antiproliferative activity of all these compounds against leukemia HL-60 cells or mammary cancer MDA-MB 468 cells. Compounds 4 and 5 modify also the DNA structure of the oc and ccc forms of plasmid DNA. The acetate-bridged compound 5 showed the highest antiproliferative activity which is even higher than that of cis-DPP. Our data indicate that the Pt(II) compounds are more active than those having Pd(II) as the metal center.