A meta-analysis of the efficacy and safety of unboosted atazanavir compared with ritonavir-boosted protease inhibitor maintenance therapy in HIV-infected adults with established virological suppression after induction.

OBJECTIVES: Treatment simplification involving induction with a ritonavir (RTV)-boosted protease inhibitor (PI) replaced by a nonboosted PI (i.e. atazanavir) has been shown to be a viable option for long-term antiretroviral therapy. To evaluate the clinical evidence for this approach, we conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) evaluating efficacy and safety in patients with established virological suppression. METHODS: Several databases were searched without limits on time or language. Searches of conferences were also conducted. RCTs were included if they compared a PI/RTV regimen to unboosted atazanavir, after induction with PI/RTV. The meta-analysis was conducted using a random effects model for the proportion achieving virological suppression (i.e. HIV RNA < 50 and <400 HIV-1 RNA copies/mL), CD4 cell counts, lipid levels and liver function tests. Dichotomous outcomes were reported as risk ratios (RRs) and continuous outcomes as mean differences (MDs). RESULTS: Five studies (n = 1249) met the inclusion criteria. The meta-analysis demonstrated no statistically significant difference in efficacy (i.e. HIV RNA < 50 copies/mL) between PI/RTV and unboosted atazanavir [RR = 1.04; 95% confidence interval (CI) 0.99 to 1.10], with no heterogeneity. Findings were similar in a subanalysis of studies where atazanavir/RTV was the only PI/RTV used during induction. Additional efficacy results support these findings. A significant reduction in total cholesterol (P < 0.00001), triglycerides (P = 0.0002), low-density lipoprotein (LDL) cholesterol (P = 0.009) and hyperbilirubinaemia (P = 0.02) was observed with unboosted atazanavir vs. PI/RTV. CONCLUSIONS: The meta-analysis demonstrated that switching patients with virological suppression from an RTV-boosted PI to unboosted atazanavir leads to improvements in safety (i.e. blood parameter abnormalities) without sacrificing virological efficacy.

Interactions between protease inhibitors and acid-reducing agents: a systematic review.

OBJECTIVE: The purpose of this article is to provide a systematic review of the available pharmacokinetic and clinical data on drug interactions between protease inhibitors (PIs) and acid-reducing agents, and their clinical relevance. METHODS: A literature search was performed using Medline and EMBASE, abstracts of the previous 2 years of major conferences were searched and the drug information service of the manufacturer of every currently available PI was contacted. All data were summarized, and verified by at least two authors. RESULTS: A total of 1231 references were identified, 22 of which were studies of pharmacokinetic interactions between PIs and acid-suppressive agents and a further 12 of which provided pharmacokinetic and/or clinical data. CONCLUSIONS: Many pharmacokinetic studies show a lack of a drug interaction between at least one acid-reducing agent and most PIs. Little clinical information is available, except on interactions between atazanavir and acid-reducing agents. This is probably a consequence of the complexity of the interaction.

Absence of circadian variation in the pharmacokinetics of lopinavir/ritonavir given as a once daily dosing regimen in HIV-1-infected patients.

AIMS: To compare the pharmacokinetics of lopinavir/ritonavir (LPV/r) 800/200 mg administered once daily in the morning compared with the evening. METHODS: This was a randomized, two-way, cross-over study in HIV+ subjects. In each subject the pharmacokinetics of each drug were characterized after 2 weeks of LPV/r 800/200 mg administered once daily at 08.00 h and 19.00 h. On study days, LPV/r was taken with a standardized meal (800 kCal, 25% from fat) after fasting for at least 5 h. LPV/r concentrations were measured by LC-MS/MS, and the data were analyzed by noncompartmental pharmacokinetic analysis. RESULTS: Fourteen subjects completed the study (all men, mean age/weight 44 year/81 kg). The median (interquartile range) LPV AUC(0,24 h), maximum plasma concentration (C(max)) and concentration at the end of the dosing interval (C(24 h)) after am and pm dosing was, respectively, 143 (116-214) mg l(-1) h, 12.8 (10.3-17.2) mg l(-1), 1.34 (0.58-3.25) mg l(-1), and 171 (120-232) mg l(-1) h, 12.9 (8.22-16.3) mg l(-1), 1.15 (0.59-1.98) mg l(-1). The geometric mean ratio (GMR, am : pm) and 95% CI of the LPV AUC(0,24 h), C(max), and C(24 h) was 0.91 (0.79, 1.06), 1.11 (0.94, 1.32), and 1.19 (0.72, 1.96), respectively. The median ritonavir C(max) after am and pm dosing was 1.05 and 0.90 mg l(-1), respectively. The GMR (95% CI) of the RTV AUC(0,24 h), C(max), and C(24 h) was 0.93 (0.80, 1.08), 1.27 (1.00, 1.63), and 1.04 (0.68, 1.60), respectively. Administration of LPV/r in a once-daily regimen was generally well tolerated. CONCLUSIONS: No differences were observed in the pharmacokinetics of LPV/r after am or pm dosing with food, which suggests that this once daily combination, can be taken in the morning or evening. Such flexibility in dosing may improve adherence.

High efficiency transient transfection of genes in human umbilical vein endothelial cells by electroporation.

Endothelial cells derived from the human umbilical vein (HUVEC) are used to study the mechanisms involved in EC response to various stimuli as well as to investigate the basis of pathological conditions of the vascular system such as altered endothelium permeability, tumor-induced angiogenesis, atherosclerosis and leukocyte extravasation in chronic inflammatory responses. However, investigations of gene involvement related to these conditions have progressed slowly because of the difficulty of transfecting HUVEC with high efficiency. Whereas several technical approaches have been described, they usually result in low levels of transfected cells or they require several steps or sophisticated instrumentation. We describe here a straightforward protocol of transfection of freshly isolated HUVEC that is based on the simple technique of electroporation. Efficiencies of gene transfection greater than 40% were routinely obtained by using a combination of optimized conditions of HUVEC isolation, composition of the electroporation medium and homogeneity of the plasmids. The protocol has been applied to the functional transient transfection of functional genes in HUVEC as illustrated in the case of the cDNA encoding GFP, protein kinase C (alpha and epsilon isotypes) and beta-galactosidase.

Chronic PMA treatment of Jurkat T lymphocytes results in decreased protein tyrosine phosphorylation and inhibition of CD3- but not Ti-dependent antibody-triggered Ca2+ signaling.

We have treated Jurkat T lymphocytes with a concentration (160 nM) of phorbol myristyl acetate (PMA) that down-regulates conventional and novel protein kinase C (PKC) isozymes and we have investigated the effects on Ca2+ signaling and protein tyrosine phosphorylation using mAb (C305) directed against the beta-subunit of the Ti heterodimer or the epsilon/delta-component of the CD3 complex (mAb Leu 4 or OKT 3). The levels of expression of PKC alpha, betaI, betaII, and delta were reduced by 90% or more in PMA-treated cells, whereas the expression of PKCtheta decreased by approximately 30%. In contrast, the chronic treatment with PMA increased the expression of PKCepsilon and PKCzeta. There was a lack of Ca2+ response and myo-inositol trisphosphate (IP3) production in PMA-treated cells when they were exposed to mAb Leu 4 but the cells responded to mAb C305. The treatment with PMA did not affect the surface expression of Ti or CD3. The overall levels of tyrosine-phosphorylated proteins were markedly reduced in PMA-treated cells. We investigated whether these observations were related to defects in signal transduction related to protein tyrosine kinase (PTK) of the src and syk families. The electrophoretic mobilities of p59(fyn) or ZAP-70 were not changed in PMA-treated cells but p56(Ick) migrated as a large band of M(r) 60-62 kDa. The decreased mobility of p56(Ick) was related to a state of hyperphosphorylation. The activity of modified p56(Ick) was not up-regulated in activated Jurkat cells. Our data suggest that clonotypic Ti can trigger Ca2+ mobilization independently of conventional PKC isoforms. Our observations further suggest that conventional PKC isoforms are involved early in the cascade of events associated with Jurkat T lymphocyte activation.

[Transformation techniques for the fibula of the mandible]. / Technique de transformation du péroné en mandibule.

Free flaps from the fibula to rebuild the mandible have allowed for improved results in the reconstruction of this bone. We propose a new and more precise technique to further enhance the functional and esthetic reconstructive result. We base the planning for the free flap on specific measurements obtained on the cephalometric analysis. Preoperative angular determinations allow for more precise fibula osteotomies prior to transection of the donor vessels.

[Multiple free transplants in microsurgery for cervicofacial reconstruction]. / Les transplants libres multiples en microchirurgie pour la reconstruction cervico-faciale.

Microsurgical techniques open the way for much creativity and originality for cervicofacial reconstruction and tumoral repair. Between 1976 and 1994, we performed 481 free transplants for cervico-facial reconstruction. A recently developed strategy has been the use of multiple free transplants, either simultaneously or successively. Between 1990 and 1994, we operated and reconstructed 9 patients using multiple free cervico-cephalic transplants after multitissular and agressive exeresis for tumoral or traumatic lesions. In 3 cases, the transplants were made simultaneously and in the 6 others successively. Three patients received 3 free transplants and 6 patients had 2. In 8 cases, each of the transplants was micro-anastomosed on different vessels. In one case, the two transplants were anastomosed in series, the most distal portion being connected to the most proximal portion (in comparison with the cervical vessels). One death occurred at 6 weeks due to infectious complications. The final result for the 8 other patients was good both morphologically and functionally. Indications for multiple free transplants include: complex tissue loss, multiple and massive tissue loss of the cervicocephalic region. This situation occurs particularly in case of voluminous tumours invading several structures, in multiple tumours and in firearm wounds. These series of patients allowed a definition of recommended techniques in case of difficulties in these very elaborate surgical procedures and confirmed that if the strategy is correctly planned, it is possible to greatly improve the quality of survival in these patients in terms of aesthetics, morphology and function.

[Free myocutaneous flap of the latissimus dorsi in cervicofacial surgery]. / Le transplant libre myocutané de grand dorsal en chirurgie cervicofaciale.

Free myocutaneous latissimus dorsi transplants are exceptionally used in cervicofacial surgery. The authors have performed an anatomical study of 23 non-embalmed subjects, using injections of neoprene latex and barium sulfate into the axillary artery and dye injections. Dissections, arteriographs and corrosion show that the lower scapular pedicle is constant, with an average length of 9.5 cm and a caliber that is sufficient for vasuclar microsurgery. Eight patients with large T4 cervicocephalic neoplasms were operated, including two with tongue tumors, one with a tumor of the oropharynx, two oromandibular lesions, two lesions of the maxillary sinus and a neuroblastoma involving the middle level of the facial structures. A free myocutaneous latissimus dorsi transplant was used. The transplant was revascularised by neck vessels using microsurgical techniques. Complete success was obtained in all eight patients. Good functional, cosmetic and morphological results were obtained as a rule. In cervicofacial surgery, the authors have thus chosen and used a free myocutaneous latissimus dorsi transplant in three topographic indications: for the oropharynx, to fill large cavities, especially the maxillary sinus, and to fill the middle level of the facial structures and of the base of the skull.

Enniatins fromFusarium avenaceum isolated from balsam fir foliage and their toxicity to spruce budworm larvae,Choristoneura fumiferana (Clem.) (Lepidoptera: Tortricidae).

Material extracted from hyphae ofFusarium avenaceum, isolated from foliage of balsam fir,Abies balsamea, was toxic to spruce budworm larvae when incorporated into insect diet. The major insecticidal component of the toxic fraction was identified by chemical and spectroscopic methods as enniatin complex, rich in enniatin A/A1. Possible ecological implications of these observations are considered.

Synthesis of pungenin, a foliar constituent of some spruce species, and investigation of its efficacy as a feeding deterrent for spruce budworm [Choristoneura fumiferana (Clem.)].

Pungenin was synthesized from 3,4-dihydroxyacetophenone by a short sequence involving manipulation of protecting groups on the 3 and 4 hydroxyl functions. Bioassays indicated that the glucoside is a modest feeding deterrent for sixth-instar spruce budworm larvae, but it does not appear to retard the development of small larvae or lead to increased mortality.

[Homografts of irradiated costal cartilage]. / Les homogreffes de cartilage costal irradié.

Preserved irradiated homologous rib cartilage is not frequently used in spite of many publications confirming its value. To draw attention of Canadian otolaryngologists, a review of 62 cases with at least two years follow-up is presented confirming the absence of resorption or immunology response. Furthermore preserved irradiated rib cartilage has been used as replacement for bone grafts in a series presented with illustrations of the stable results obtained. The change of behavior of homologous cartilage in human introduced by gamma irradiation would need to be investigated.

[Homografts of irradiated costal cartilage]. / Les homogreffes de cartilage costal irradié.

Preserved irradiated homologous rib cartilage are not frequently used in spite of many publications confirming its value. A review of 62 cases with at least two years follow-up is presented confirming the absence of resorbtion or immunology response. Further more preserved irradiated rib cartilage has been used as replacement for bone grafts in a serie presented with illustrations of the stable results obtained. The change of behavior of homologous cartilage in human introduced by gamma irradiation would need to be investigated.

[Bone grafting in facial malformations]. / Greffe osseuse dans les malformations de la face

The possibilities of bone graft to the face are multiple. After reviewing the anatomy and physiology of bone grafting, the authors present different types of cases illustrating some of these possibilities. Each case of malformation of the face presents problems in which bone grafting is often an elegant solution with or without osteotomies. After describing the principles and techniques used in these cases, the authors comment upon 26 personal cases using mostly the intraoral approach for laying bone around the face. Three out of 26 have developed postoperative infections but only one case has needed removal of part of the bone grafts. Their youngest patient was 12 years old.

[Malignant bilateral external otitis in a 10-year-old girl]. / Otite exterune maligne bilatérale chez une fillette de 10 ans

Malignant external otitis in which the prognosis is very severe has been recently described, as related to diabetes in old age. We present a case with malignant external otitis which occurred in a 10 year old girl, with a very peculiar development. Indeed, the external otitis which appeared at first on the left side was accompanied on this side by a facial paralysis, and six months later in the right, a malignant external otitis was also found without facial palsy. Furthermore, this young girl has been affected by an insipid diabetes, for which no hypophysial or renal pathology has been found. After reviewing the literature on that subject, the authors discuss the clinical aspect of that case and its treatment.