Exposure equivalence between IV (0.8 mg/kg) and oral (1 mg/kg) busulfan in adult patients.

OBJECTIVE: This study was conducted to retrospectively compare the area under the curve (AUC) and the total clearance of busulfan (Bu) following oral and intravenous (IV) administrations and to determine which intravenous dose generated equivalent exposure to that of the oral form that has been marketed for decades. METHODS: Patient pharmacokinetics were assessed at dose 9 during a conditioning regimen for stem-cell transplantation and included data from 277 patients for oral Bu (71 from fixed-dose studies and 206 from studies with dose adjustment allowed) and 120 patients for IV Bu (fixed dose). AUCs were compared between patients with fixed dose of oral Bu (n = 71, 1 mg/kg) and those of IV Bu (n = 120, 0.8 mg/kg). Total clearances were calculated for all 277 patients with oral Bu and compared to those with IV Bu, with the ratio of IV-to-oral clearance representing the absolute bioavailability of the oral form. RESULTS: Oral and IV populations differed on disease-type distribution but presented comparable demography parameters. IV Bu dosing was mostly based on the ideal body weight index while actual body weight or adjusted ideal body weight indexes were mostly used for oral. When normalised to comparable indexes, bioequivalent AUCs were achieved between oral and IV populations. Oral Bu bioavailability was about 80% when calculated from the ratio of IV-to-oral total clearances. CONCLUSION: This retrospective study carried out on a large set of data showed that similar plasma exposures were achieved with 1.0 mg/kg oral Bu or 0.8 mg/kg IV Bu.

Scintigraphic imaging of paediatric thyroid dysfunction.

Imaging of thyroid dysfunction is safe and clinically relevant in children. In congenital hypothyroidism (CH), thyroid imaging permits a precise characterization of the aetiology, which is important for genetic counselling and clinical management. CH may be due to thyroid dysgenesis (ectopia, hypoplasia and athyrosis) or occurs in eutopic glands. In the latter, hypothyroidism may be either transient, especially after iodine overload, or due to permanent autosomal recessive dyshormonogenesis. Thyroid scintigraphy (TS) with either 99mTcO4 or 123I will identify ectopic thyroid tissue, which is the commonest cause of CH. However, recent reports favour the use of 123I, which enhances the accuracy of the aetiological classification. In cases of eutopic thyroid, the measurement of 123I uptake before and after perchlorate administration evaluates the organification process. At all ages, colour Doppler ultrasound scanning (CDU) is helpful in assessing thyroid volume, in identifying nodules and in characterizing tissue vascularization. TS and CDU images of most paediatric thyroid dysfunctions are presented.

Clinical, sonographic and manometric characteristics and impact on quality of life of fecal incontinence in 92 men referred for endoanal ultrasonography.

UNLABELLED: Anal incontinence (AI) is a frequent symptom with considerable impact on quality of life. The aim of this study was to describe the clinical, sonographic and manometric characteristics of a male population with AI. MATERIALS AND METHODS: Endoanal ultrasonography (EAU) was performed in 92 men referred for exploration of AI. Anal incontinence severity was evaluated by the Jorge and Wexner score (JW). The gastrointestinal quality-of-life index (GIQLI) was determined in 57% of patients. Anorectal manometry was performed in 62.6% of patients. RESULTS: The average JW score was 11+/-1. Anal incontinence had considerable impact on quality of life: average GIQLI=81+/-4. Seventeen patients presented an anal sphincter defect on EAU, 16 of whom had a history of coloproctological surgery. Prior surgery was significantly more common among patients who had a defect on ultrasonography; manometry showed significantly lower resting anal pressure. CONCLUSION: Our study confirms the severity of AI in a male population and its impact on quality of life. It also highlights the high prevalence of anal sphincter defects in patients with a history of anal surgery.

Vinorelbine/docetaxel combination treatment of metastatic breast cancer: a phase I study.

PURPOSE: The aim of this study was to investigate the combination of vinorelbine (VRL) alternating intravenous (i.v.) and oral in combination with docetaxel (DCT) as first-line chemotherapy of patients with metastatic breast cancer. PATIENTS AND METHODS: Tested doses were 60 or 70 mg m(-2) given on day 1 for DCT, 20 to 25 mg m(-2) for i.v. VRL on day 1, 60 mg m(-2) on day 8 or day 15 for oral VRL. Day 1 was administered every 3 weeks. Three to six patients were treated per dose level. RESULTS: The median age of the 30 treated patients was 60 years. Four patients were non evaluable for the maximum tolerated dose (MTD) and were replaced. Reported dose-limiting toxicities were 11 omissions of oral VRL for neutropenia, two cases of febrile neutropenia and two grade 4 neutropenia >or=7 days. Dose levels using DCT doses >60 mg m(-2) and/or i.v. VRL doses >20 mg m(-2) met the criteria for MTD. Most frequent toxicities were febrile neutropenia in seven patients and neutropenic infection in four patients (one fatal). Therefore, the recommended schedule was established at i.v. VRL 20 mg m(-2) with DCT 60 mg m(-2) on day 1 and oral VRL 60 mg m(-2) given on day 15 every 3 weeks. At this recommended schedule, only one of six patients experienced febrile neutropenia. Among 22 patients evaluable for tumour response, 2 complete and 10 partial responses were reported. Pharmacokinetics of combined VRL and DCT demonstrated the absence of mutual interaction. CONCLUSIONS: This phase I study established the recommended doses and schedules of the combination alternating i.v. and oral VRL with DCT, this recommended regimen being further explored in a phase II study.

Intravenous busulfan in adults prior to haematopoietic stem cell transplantation: a population pharmacokinetic study.

An IV form of busulfan (IV Bu) has recently become available for high dose conditioning regimen before haematopoietic stem cell transplantation (HSCT). This IV form is expected to reduce the high pharmacokinetic variability exhibited with oral busulfan and as a result, to better target the plasma area under the curve (AUC). Pharmacokinetics (PK) of IV Bu was investigated on 127 adult patients (333 PK administrations) who received 0.8 mg.kg-1 of Bu as a 2-h infusion every 6 h over 4 days, followed by cyclophosphamide (60 mg.kg-1 day-1x2). A retrospective population PK analysis was carried out to search for important predictive factors of IV Bu PK and to develop a limited sampling strategy (LSS) through Bayesian methodology. The analysis was conducted using the Non Linear Mixed Effect methodology and included a validation process on an independent data set. Adjusted Ideal Body Weight (AIBW) and Body Surface Area (BSA) were the best covariates to explain the inter-patient variability. The final inter-patient variability (CV=16%) in IV Bu clearance (Cltot) was estimated close to the intra-patient variability (CV=13%). There was neither age-dependency nor gender effect. IV Bu Cltot was not affected by elevated hepatic enzymes or by co-administration of either fluconazole or acetaminophen, and was not altered in heavily pre-treated or pre-transplanted patients. Normalised Cltot based on either AIBW or BSA was comparable between normal and obese patients (BMI=18-26.9 kg.m-2, >26.9 kg.m-2, respectively) whereas significant differences existed when based on either actual (ABW) or ideal body weight (IBW). As a consequence, no dose adjustment is required in obese patients when using a AIBW- or BSA-based dose calculation. A fixed dose of 0.80 mg.kg-1 of AIBW or 29 mg.m-2 of BSA yielded an average AUC of 1,200 microM.min, with 80% of patients within the "therapeutic" AUC range of 900-1,500 microM.min. Alternatively, 0.80 mg.kg-1 based on either ABW or IBW for normal patients and on AIBW for obese patients would achieve the same performance. A limited sampling strategy based on a Bayesian methodology was developed and validated on an independent dataset: AUCs obtained from one to two samplings were demonstrated to be reliably estimated.

[Tissular and mechanical effects observed with an experimental femtosecond laser microkeratome for corneal refractive surgery]. / Effets tissulaires et mécaniques observés lors de l'expérimentation d'un microkératome laser femtoseconde pour la chirurgie réfractive cornéenne.

PURPOSE: Despite progress in mechanical microkeratomes used in refractive surgery, mechanical complications during cutting of the cornea still occur. Cutting by laser could reduce these complications and to date, the femtosecond laser is the only potential candidate for this purpose. Our study reports preliminary results with a femtosecond microkeratome for cutting porcine corneas ex vivo. METHODS: We first examined the fundamental principles of the interaction between the femtosecond laser and the corneal stroma, including the volume of tissue lesions, the laser breakdown threshold of the stroma and the laser ablation selectivity. We then analyzed the quality of cutting corneal flaps with the laser, focusing on collateral tissue effects and the roughness of the interfaces observed both histologically and with scanning electron microscopy. RESULTS: The photoablative and photodisruptive effects were very similar with the femtosecond laser. This characteristic is specific to ultrashort impulsion photodisruptor lasers and allows for a very precise surgical procedure. The laser-induced breakdown threshold of porcine corneal stroma was found to be 0.55 J/cm2. Collateral tissue lesions were on the submicrometer level. The roughness of the stromal bed was optimal for postage stamp cutting, providing very many contiguous points of impact which were as spherical as possible. CONCLUSION: Corneal photodisruption with a femtosecond laser is reproducible and extremely accurate. The optomechanical parameters involved with this technique require great technological skill and should be placed in experienced hands.

[Advantages and disadvantages of the femtosecond laser microkeratome]. / Avantages et inconvénients du microkératome laser femtoseconde.

Laser in situ keratomileusis (LASIK) complications are mainly attributable to imperfect cutting with the mechanical microkeratome. The femtosecond laser is an important challenger because it can provide extremely precise cutting beginning at any corneal point. We analyze the potential of this new tool from the results reported in the literature. The optomechanical control of the impact position provides freer and more effective intrastromal cutting than the blade. The best cutting matrix is obtained with the postage stamp method. If the plasma quality is not perfectly under control, side effects such as tissue streaks and secondary ultraviolet radiations can be observed. For LASIK surgery, femtolaser cutting can offer greater safety, reproducibility, predictability and flexibility. The risk of incomplete or irregular cutting and the free cap risk are reduced. Striae, epithelial defects and interface deposits should be minimized. A better flap congruence can limit the risk of secondary displacement and epithelial ingrowth. The results of making thinner flaps should be more predictable. Other than the high cost of the procedure, laser cutting has very few disadvantages. In 1999, Intralase Corporation introduced the first femtolaser microkeratome on the American market. Approximately 120,000 intra-LASIK procedures have been carried out with fewer cutting complications than with the mechanic blade.

Iodine-induced thyrotoxicosis in apparently normal thyroid glands.

Although iodine-induced thyrotoxicosis was reported to occur in patients with obvious underlying thyroid disorders, it is not known to occur in patients with apparently normal thyroid glands. From ten such cases evidence is presented that thyrotoxicosis: a) appeared during treatments by iodide or organic-iodine-containing drugs, in the absence of any past history of thyroid disorder; b) was accompanied by almost undetectable radioidine uptake which nevertheless could be activated by TSH; c) subsided spontaneously within a few weeks or months after stopping the high intake of iodine; d) and left, after a period of hypothyroidism, an apparently normal thyroid gland which had resumed normal size, function, uptake, and suppressibility.

Impact of the biochemical assay for serum creatinine measurement on the individual carboplatin dosing: a prospective study.

We previously developed a formula to estimate the individual carboplatin clearance (CL) based on serum creatinine (Scr) determined by an enzymatic assay using creatinine amidohydrolase. An analytical comparison had shown systematic differences between this method and the commonly used Jaffé method (with Jaffé Scr (in microM)=1.08 x enzymatic Scr+1.6, as regression equation). We performed a pharmacokinetic prospective clinical study using the Jaffé assay to evaluate the impact of the method used for Scr measurement on the prediction of the carboplatin CL. In forty patients, carboplatin dosing was performed according to the Chatelut formula where the serum creatinine level was corrected according to the above equation. The population pharmacokinetics of carboplatin were analysed using the NONMEM program to determine the individual carboplatin CL from a limited sampling strategy. Thanks to the correction of the Jaffé Scr, no significant difference was observed between the administered and the optimal dose. In contrast, if no correction of the Scr was done, the patients would have been significantly under-dosed. Moreover, a covariate analysis using NONMEM gave a very consistent result showing that Scr should be decreased by 11.6% when the Jaffé value is used within the Chatelut equation. This study confirmed that differences in the Scr assay has consequences with regard to carboplatin dosing. The correction we propose for Scr obtained by the Jaffé method may help to standardise clinical practice.

High expression of monoamine oxidases in human white adipose tissue: evidence for their involvement in noradrenaline clearance.

The clearance of plasma adrenaline and noradrenaline by human adipose tissue suggests the expression of the catecholamine-degrading enzyme monoamine oxidases and of catecholamine transport systems in adipocytes. In the present study, we identified and characterized the monoamine oxidases and an extraneuronal noradrenaline transporter expressed in human adipocytes. Enzyme assays using the monoamine oxidase A/B substrate [14C]tyramine showed that abdominal and mammary human adipocytes contain one of the highest monoamine oxidase activities in the body. Characterization of the enzyme isoforms by inhibition profiles of [14C]tyramine oxidation and Western and Northern blot analyses showed that mRNAs and proteins related to both monoamine oxidases A and B were expressed in adipocytes. Quantification of each enzyme isoform performed by enzyme assay and Western blot showed that monoamine oxidase A was predominant, representing 70-80% of the total enzyme activity. In uptake experiments, the monoamine oxidase substrate [3H]noradrenaline was transported into white adipocytes (Vmax 0.81+/-0.3 nmol/30 min/100 mg of lipid, Km 235+/-104 microM). The inhibition of [3H]noradrenaline uptake by specific inhibitors indicated that white human adipocytes contain an extraneuronal-type noradrenaline transporter. Competition studies of [14C]tyramine oxidation showed that noradrenaline is metabolized by monoamine oxidases in intact cells. In conclusion, the concomitant expression of monoamine oxidases and of a noradrenaline transporter in human white adipocytes supports the role of the adipose tissue in the clearance of peripheral catecholamines. These results suggest that adipocytes should be considered as a previously unknown potential target of drugs acting on monoamine oxidases and noradrenaline transporters.

I.V. busulfan in pediatrics: a novel dosing to improve safety/efficacy for hematopoietic progenitor cell transplantation recipients.

A retrospective population pharmacokinetic (PPK) analysis was performed in 24 pediatric patients (PEDS) (0.45-16.7 years old) receiving i.v. busulfan/cyclophosphamide (i.v. Bu/Cy 4) regimen prior to allogeneic hematopoietic stem cell transplantation. I.V. Bu doses were given as a 2-hour infusion every 6 h over 4 days. Initial dosing of i.v. Bu was 1 mg/kg for children < or =4 years old and 0.8 mg/kg for patients >4 years old. Bu plasma concentrations at doses 1, 9 and 13 were analyzed through a multivariate NONMEM analysis. A close log-linear relationship between body weight (BW) and i.v. Bu clearance was demonstrated with no further age-dependency or gender effect. The interpatient coefficient of variation (CV) in Bu clearance significantly decreased from 56% (covariate-free model) to 19% (BW covariate model) and reproducible i.v. Bu exposure between doses was illustrated (intraindividual CV=9%). Based on the PPK model, a novel Bu dosing regimen (ie: doses in mg/kg adjusted to discrete weight categories) for a better AUC targeting was developed by simulation on 1000 patients. Age-based dosing was demonstrated not to be clinically relevant with i.v. Bu. Use of the new BW-based dosing appears to be more appropriate for the PEDS.

Corneal myxoma associated with keratoconus and Down's syndrome.

PURPOSE: Primary myxoma of the cornea is extremely rare. Until now, only four primary corneal myxomas were reported in the literature, whereas secondary involvement of the cornea by conjunctival and limbal tumors is much more common. METHODS: We report an additional case in a 26-year-old woman with keratoconus and Down's syndrome. Excision of the corneal mass was performed by penetrating keratoplasty. Histochemical, immunohistochemistry, and ultrastructural studies were used to obtain a definitive diagnosis. RESULTS: The tumor exhibited the characteristic histologic features of myxoma. The tumor cells showed immunoreactivity for vimentin but not for S-100 protein, epithelial membrane antigen, CAM 5.2, HHF-35, or muscle-specific actin. Ultrastructural features were fibroblast-like or stellate cells with cytoplasm containing abundant, rough reticulum and dilated cisternae. No recurrence was observed 36 months after penetrating keratoplasty. CONCLUSION: This is only the fifth report of such an occurrence. Although the coexistence of myxoma in Down's syndrome with keratoconus is described here for the first time, the differential diagnosis of apparently evident acute hydrops on clinical inspection should not rule out the possibility of a corneal myxoma. Histologic analysis should therefore be performed.

Psammomatous melanotic schwannoma of a spinal nerve root. Relationship with the Carney complex.

A 36-year-old man had an oval, black, extradural tumor partly removed from the left C4 spinal root, with total removal 4 months later. In both specimens, most tumor cells were spindle-shaped. A few cells were large, epithelioid-like, with a prominent nucleolus. Mitoses were rarely seen. Many tumor cells contained coarse or fine granules of a brown pigment. Such cells were immunopositive for S-100 protein and HMB-45. Additionally, psammoma bodies were numerous in certain areas, indicating a diagnosis of psammomatous melanotic schwannoma (PMS). Periumbilical spotty pigmentation was found in the patient and in six of his siblings and their mother. The search for cardiac myxoma and endocrine overactivity was negative in the patient. Features of Carney's complex must be sought in a patient with PMS and in their primary relatives. So far, more than 150 patients and seven families with Carney's complex have been reported.

Pathologic correlations between ocular and cerebral lesions in 36 AIDS patients.

The eyes and brain have rarely been studied simultaneously in AIDS patients. We have examined both the eyes and brain of 36 patients autopsied these past 3 years. Ten cases had concomitant involvement of eyes and brain by the same pathology: cryptococcus neoformans in 1, aspergillus in another, cytomegalovirus (CMV) infection in 5, and B cell lymphomas in 2 (1 patient had the last 2 disorders associated). One patient presented pericapillary microhemorrhages in the retina of the left ocular globe as well as in the right occipital lobe. Six other patients had isolated CMV retinopathy and 4 others had B cell cerebral lymphomas. Eleven patients with foci of cerebral toxoplasmosis did not have visible cysts of toxoplasma gondii in their retina, in agreement with the other series devoted to the concomitant study of the eyes and brain in AIDS patients. On the other hand, their simultaneous involvement in an AIDS patient must first point to CMV infection.

Prevalence and pathogenicity of retroviruses in wildcats in France.

Feline leukaemia virus (FeLV) and feline immunodeficiency virus (FIV) are frequently encountered in domestic cats (Felis catus) and in wild felids, but only FeLV has been previously identified in wildcats (Fellis silvestris). Thirty-eight wildcats, either captured alive or found dead, were sampled in eastern and central France. Nine of them (23.7 per cent) carried the FeLV p27 antigen, and three (7.9 per cent) had antibodies to FIV. There was a significant relationship between two measures of body condition and FeLV status; the FeLV-positive cats being in poorer condition than the FeLV-negative cats. The results suggest that FeLV is common in wildcats and may increase mortality in this species. The FIV-positive results constitute the first indication of a FIV-related virus in wildcats.

Histologic findings in a series of 1,540 corneal allografts.

We present a series of 1,540 corneal allografts studied since 1982. Corneal edema was the major lesion in 439 corneal specimens (28.4%). Keratitis was the largest group with 378 cases (24.5%), including 134 cases of corneal scarring (8.7%). There were 113 cases of herpes simplex virus keratitis (7.3%), mostly of the disciform stromal type, and 60 cases of non herpetic interstitial keratitis (3.9%), 44 of superficial keratitis (2.8%) and 10 of ulcerative keratitis (0.6%). Among the 17 other cases (1.1%), there were 3 of fungal keratitis, 2 syphilitic keratitis and one case of acanthamoebic keratitis. The third group was formed by corneal dystrophies with 376 cases (24.4%). There were 192 keratoconus (12.5%), 121 Fuchs' dystrophies (7.9%), 28 calcific band keratopathies (1.8%), 18 had corneal dystrophies with amyloid deposits and 16 did not. There were 169 regrafts (11%) and 135 traumatic lesions (8,8%). Among the 43 miscellaneous cases (2,8%), there were 22 cases with previous refractive eye surgery, one corneal myxoma, 5 cases of dysplasia, 5 pterigia, 3 sclerocornea, one fish-eye disease, one floppy eyelid syndrome and 5 unclassifiable cases. The mechanisms of these lesions are mainly related to an autoimmune disease in most cases of herpes keratitis. Some rare forms of corneal dystrophies contain amyloid deposits produced by an abnormal kerato-epithelin. Cases of graft failure are not particulary frequent, due to the avascularity of the cornea and its particular immune status.

[Outcome of a corneal graft with antecedents of radial keratotomy]. / Devenir d'un greffon cornéen aux antécédents de kératotomie radiaire.

We performed a penetrating keratoplasty with a donor corneal graft who had been operated by radial keratotomy one year ago. The clinical and endothelial cell density follow-up was 18 months. The endothelial cell loss was comparable to that of a non-operated donor graft. No complications such as reopening or vascular invasion of the incisions occurred. The authors conclude that radial keratotomy is not a contraindication for transplantation and suggest the use of such grafts for eyes with bullous keratopathy with a poor functional prognosis.

[Bilateral corneal neovascularization and floppy eyelid syndrome. A case report]. / Néovascularisation cornéenne bilatérale et floppy eyelid syndrome. A propos d'un cas.

The conjunctival and corneal lesions usually observed in the floppy eyelid syndrome are benign and reversible as soon as the specific treatment of superior palpebral hyperlaxity is performed. A case of bilateral corneal vascularization, a rare but severe complication of floppy eyelid syndrome is reported. The floppy eyelid syndrome was identified late because keratoconjunctivitis was clinically predominant and palpebral tonicity was not initially considered. The treatment of palpebral hyperlaxity was the prerequisite for good results with keratoplasty.

[Quality of corneal incisions of ceramic and diamond blades. Comparison in optic microscopy]. / Qualité de coupe cornéenne des lames céramique et diamant. Comparaison en microscopie optique.

Six radial keratotomies were performed using a ceramic blade on corneas obtained from cadavers. These incisions were compared by light microscopy with 6 sections performed on the same corneas using a diamond blade. Microscopic examination showed no significant difference in the quality of the incision between the two blades studied.