Pharmacokinetics of enfuvirtide in pediatric human immunodeficiency virus 1-infected patients receiving combination therapy

BACKGROUND: Enfuvirtide is the first of a new class of antiretroviral agents, the fusion inhibitors. OBJECTIVES: The primary objective of this analysis was to evaluate the pharmacokinetics of 2.0 mg/kg enfuvirtide in human immunodeficiency virus 1 (HIV-1)-infected children and adolescents when administered in combination with at least 3 other antiretrovirals. METHODS: Twenty-five HIV-1-infected pediatric patients (5-16 years of age) enrolled in an ongoing phase I/II study were included in this analysis. Patients received enfuvirtide 2.0 mg/kg sc twice daily (bid) for at least 7 days. Blood samples were collected on day 7, and plasma concentrations of enfuvirtide and its metabolite were measured by a validated liquid chromatography-tandem mass spectrometry method. Pharmacokinetics measures [Cmax, tmax, Ctrough, and area under the concentration time curve time 0 to 12 hours (AUC12 hours)] were calculated from plasma concentration-time data by standard noncompartmental methods. RESULTS: There was no significant difference between children and adolescents for enfuvirtide Cmax (6.43 versus 5.88 microg/mL), Ctrough (2.87 versus 2.98 microg/mL) and AUC12 hours (56.1 versus 52.7 hours . microg/mL). Similarly no significant differences were found when the pharmacokinetic measures were compared based on sexual maturity stages. A post hoc regression analysis based on AUC12 hours showed that body weight-adjusted dosing of enfuvirtide provides drug exposure that is independent of age group, body weight and body surface area. CONCLUSIONS: Body weight-adjusted dosing of enfuvirtide, at a dose of 2.0 mg/kg sc bid, in HIV-1-infected pediatric patients at least 5 years of age, provides drug exposure comparable with that previously observed in HIV-1-infected adults after 90 mg sc bid dosing. Drug exposure in children and adolescents is independent of age group, body weight, body surface area and sexual maturity stage.     

Analysis of recurrences in 322 Tis, T1, or T2 glottic carcinomas treated by carbon dioxide laser

An endoscopic approach to early glottic carcinoma is considered a sound treatment for both previously untreated lesions and selected recurrent lesions. Between January 1988 and December 2000, we treated 322 patients by CO2 laser at a single institution; 37 had Tis, 191 T1a, 55 T1b, and 39 T2 lesions (mean follow-up, 77 months; range, 6 to 180 months). Kaplan-Meier curves showed a 5-year overall survival rate of 88%, a determinate survival rate of 99%, a disease-free survival rate of 81%, a rate of ultimate local control with laser alone of 91%, and a laryngeal preservation rate of 97%. Univariate and multivariate analysis showed that the only factor that statistically affected endoscopic control was lateral extension of the tumor with involvement of the bottom of the ventricle (hazard risk ratio, 4.0; 95% confidence interval, 1.71 to 9.35). The 58 recurrences were classified according to their location compared with the site of the primary tumor as follows: 14 in the same area (group A), 27 in adjacent subsites with superficial spreading or multifocal distribution (group B), and 17 in adjacent sites by submucosal diffusion to the visceral spaces, cartilaginous framework, or extralaryngeal tissues (group C). For each group, we analyzed the rate of patients who underwent salvage by endoscopic or open neck procedures and the rate of laryngeal preservation. Recurrences in groups A and B were endoscopically treated in 86% and 74% of cases, respectively. By contrast, in group C no patient was endoscopically cured, and there was a low laryngeal preservation rate (47%). The pathways of spread in recurrent carcinoma are therefore the single most important factor in predicting its endoscopic curability.     

Pimecrolimus for the treatment of vulvar lichen sclerosus: a report of 4 cases

BACKGROUND: Lichen sclerosus is a chronic cutaneous disorder with a predilection for the vulva. The etiology is unknown. Superpotent topical corticosteroids are the most effective treatment. Dermal atrophy, however, is a well-known complication associated with changes of lichen sclerosus superpotent topical corticosteroids. In addition, some women do not respond adequately to topical steroids. Therefore, a treatment regimen that does not rely on corticosteroids may be beneficial. As lichen sclerosus is a T-lymphocyte-mediated disorder, it has been suggested that a topical macrolide immunosuppressant, such as pimecrolimus, may be a safe and effective alternative treatment for lichen sclerosus. Since pimecrolimus does not affect collagen synthesis, it does not cause thinning of the dermis. CASES: Four patients with biopsy-proven lichen sclerosus were treated with 1% pimecrolimus cream twice daily. At the end of 3 months of treatment, 3 of the 4 patients reported complete resolution of their symptoms of vulvar itching and burning. Two patients had repeat vulvar biopsies at the end of treatment that showed reversal of the histologic changes of lichen sclerosus. CONCLUSION: In this small series, pimecrolimus appeared to be a safe and effective treatment of vulvar lichen sclerosus. A randomized, controlled trial comparing pimecrolimus and clobetasol propionate should be performed to determine which is the safer and more effective medication for the long-term treatment of lichen sclerosus.     

Effect of orlistat therapy on carbohydrate, lipid, vitamin and hormone plasma levels in obese subjects

Orlistat is an inhibitor of lipase which splits triglycerides into free fatty acides and glycerol. This drug, by inhibiting hydrolysis of triglycerides, is the cause of significant loss of fat in the faeces. 13 obese and 15 nonobese subjects were examined. Obese subjects received orlistat (Xenical, F. Hoffmann La Roche Ltd, Switzerland) 3 x 120 mg/d. Treatment with orlistat for 16 weeks was followed by a significant fall of BMI and MAP, insulinemia, insulin/glucose ratio, leptinemia, serum total cholesterol, triglycerides, HDL-cholesterol and 25-OH-D concentration respectively. Orlistat did not influence significantly serum LDL-cholesterol concentration but unexpectedly increased plasma levels of folic acid, vitamin B12 and NPY. CONCLUSIONS: (1) Monitoring of plasma 25-OH-D levels in obese patients on orlistat therapy seems to be mandatory. (2) In spite of significant changes (in opposite direction) in leptinemia and serum NPY level observed in obese subjects treated with orlistat, presence of a functional relationship between these hormones could not be confirmed.     

Coexistence of Addison-Biermer's anaemia with endocrine glands' dysfunctions

Addison-Biermer's anaemia is an autoimmune disease. It may coexist with other auto-aggressive diseases, precede them or join the other existing autoimmune diseases. It most often accompanies the Hashimoto disease but also may coexist polyglandular autoimmune syndrome (PGA). Three types of PGA are distinguished: PGA1--Blizzard's Syndrome, PGA2--Schmidt's Syndrome, and PGA3. The latter, unlike the remaining ones, is characterized by normal function of adrenal glands. Addison-Biermer's anaemia occurrence may be often difficult to diagnose as coexisting illnesses might ouflage its clinical symptoms. The aim of this paper was to analyse patients with different types of PGA with coexisting Addison-Biermer's anaemia. Group of 24 individuals was analysed: 2 women with PGA1, 10 patients with PGA2, 10 patients with PGA3. In 2 remaining ones PGA was not confirmed. Addison-Biermer's anaemia occurred in 7 patients (2 with PGA2 and 5 with PGA3 syndrome). Decreased concentration of vitamin B12 was diagnosed in 3 individuals among 24 examined patients (1 with type 3 and 2 with type 2), as well in 2 patients with unconfirmed PGA. Addison-Biermer's anaemia was not observed in patients with PGA1. We observed that megaloblastic anaemia occurred characteristic schedule depending on appearance of autoimmune diseases: in PGA2--many years after other immunopathies were found, in PGA3--as first auto-aggressive disease. Our analysis suggests the necessity of detailed check-ups on patients with Addison-Biermer's anaemia, as with time they may develop other diseases, especially hypothyroidism and/or PGA failure. On the contrary, in individuals with thyroid gland diseases and PGA syndromes further checkups should be megaloblastic anaemia-sensitive. In both cases it is important to consider substitutive treatment. The possibility of family coexisting both pernicious anaemia and autoimmune endocrinopathies needs diagnostics of members of the patient's family.     

Central nervous system disease in primary Sjogrens syndrome: the role of magnetic resonance imaging

OBJECTIVES: To examine the frequency of central nervous system (CNS) disease in primary Sjogrens syndrome (pSS) and indicate ways in which cerebral magnetic resonance imaging (MRI) may help determine the significance of CNS involvement. METHODS: The current review was based on a Medline (Pubmed) literature search through May 2003, focused on Sjogrens syndrome, other vasculitides, multiple sclerosis (MS), specific MRI techniques, and MRI findings with regard to the above-mentioned diseases. Additional literature was identified in the reference sections of articles listed in Medline. RESULTS: Severe CNS manifestations reminiscent of MS have been described in pSS patients. Moreover, the prevalence of nonfocal neuropsychological abnormalities has been found to be elevated in some pSS patient populations. MRI studies suggest discrete cerebral tissue damage even in neurologically asymptomatic patients. However, small white matter lesions are nonspecific and may be related to age or cerebrovascular risk factors such as hypertension. A large controlled study, complementing established T2-weighted MRI with fluid-attenuated inversion recovery (FLAIR) to achieve high sensitivity in lesion detection, could indicate the disease specificity of white matter lesions in pSS. Newer MR techniques, such as spectroscopy and magnetization transfer imaging, applied, for example, in MS and systemic lupus erythematosus (SLE) to evaluate CNS tissue injury, could help determine the extent and mechanisms of macroscopic and microscopic CNS lesions in pSS. CONCLUSIONS: Future controlled studies will be necessary to more precisely estimate the prevalence of CNS lesions in pSS, specifically of discrete white matter abnormalities. Newer MRI techniques have the potential to provide information on the severity and pathophysiological mechanisms of CNS tissue damage.     

A collaborative care approach to complex diabetic foot ulceration

This article highlights the complex issues that surround the management of diabetic foot ulceration. It describes how the disciplines of podiatry and tissue viability came together to care for a patient who required complex wound management. The importance of collaborative working is highlighted, which has been shown to reduce amputation rates by 50% (Edmonds, 2002). Through exploration of a case study, certain issues emerged--wound infection, wound management, psychosocial factors and teamworking--and these are discussed. The link between diabetic foot ulceration and amputation is explored and the argument put forward that amputation should have been the first choice for this patient bearing in mind that 30% of amputees lose their second leg within 5 years (Geary, 2002).     

Rehabilitation professionals' satisfaction with continuing education delivered at a distance using different technologies

This paper examines learner satisfaction with technologies used for distance delivery of continuing education across 10 Canadian sites: nine within the province of Alberta and one in Nunavut Territory. The technologies were satellite (or videotapes of) broadcasts, videoconferencing, and web-based technology. Learner satisfaction was evaluated using questionnaires. A survey on general issues related to continuing education was developed and mailed to random samples of health professionals and a convenience sample of stakeholders. The learners (n = 1,141) represented 20 types of health service providers who had attended at least one session delivered via satellite, videotape, or videoconferencing. Seven individuals completed the web-based course. Overall, the majority of participants were satisfied or very satisfied. In general, satellite delivery was received more favorably compared with videotapes of the same content. A total of 350 (33% response rate) health professionals and 37 (50% response rate) stakeholders returned the surveys. Nearly 50% of health professionals thought that clinical case presentations (rounds) were valuable to them, but over half of the stakeholders perceived that videotapes, rounds, and research seminars were valuable to health professionals. Ratings for the web-based course varied, indicating different learner characteristics. We conclude that it is possible to utilize multiple technologies to meet the continuing education needs of an interdisciplinary group of health service providers, but future research is needed to develop a framework for evaluating the usability of multiple existing and emerging technologies for distance education.