[Long-term treatment of Alzheimer's disease: followup of a cohort of 255 patients treated with lacrine for four years]. / Traitement de la maladie d'Alzheimer au long cours: à propos d'une cohorte de 255 patients traités quatre ans par tacrine.

We describe the follow-up of a cohort of 255 Alzheimer's disease (AD) patients (81 males, 174 females) treated by tacrine during 4 years. We performed the survey of hepatic, cholinergic and general tolérance. Drug efficacy was measured by MMS examination on weeks 0, 18, 30, 52, 104, 156 and 208. A total of 190 patients (74.5 percent) were dropped out of this study, 75 (29 percent) for adverse events. We found 85 hepatic (33 percent), 79 cholinergic (31 percent), 31 (12 percent) neuropsychiatric and 72 general (28 percent) side effects. In term of drug efficacy we observed a global decline of 2.5 MMS points during the first year and 2 MMS points between W52 and W156. Tacrine's symptomatic efficacy, defined as the number of patients improved or stabilized at W30, was present in 50 patients (46 percent) among the 109 patients reaching W30. The intensity of symptomatic efficacy was expressed by a 2.7 MMS points increase in 37 patients improved on W30. The long term effects of Tacrine, measured by the MMS score at one year, showed a positive impact as the MMS was 2.5 points above the expected score in non treated AD patients. This study raises the practical problem of optimal cholinesterase inhibitors use in AD and the theoretical question of long term action of cholinesterase inhibitors on cerebral lesions of AD.

Randomized, dose-escalation study of SD/01 compared with daily filgrastim in patients receiving chemotherapy.

PURPOSE: To explore the use of SD/01 (a polyethylene glycol-conjugated filgrastim shown in preclinical studies to have a prolonged half-life) in patients with chemotherapy-induced neutropenia. PATIENTS AND METHODS: Thirteen patients with non-small-cell lung cancer were randomized to receive daily filgrastim (5 microg/kg/d) or a single injection of SD/01 (30, 100, or 300 microg/kg) 2 weeks before chemotherapy and again 24 hours after administration of carboplatin and paclitaxel. Pharmacodynamic, pharmacokinetic, and safety analyses were performed. RESULTS: Peak serum concentrations of SD/01 and the duration of increased serum concentrations were dependent on the SD/01 dose. SD/01 concentrations remained increased longer in patients with chemotherapy-induced neutropenia. Prechemotherapy median absolute neutrophil counts (ANCs) in patients receiving SD/01 were increased in a dose-dependent fashion, with the duration of this effect also being dose dependent. After chemotherapy, median ANC nadirs were similar in the filgrastim cohort and the cohort receiving SD/01 30 microg/kg, with higher nadirs seen in the cohorts receiving SD/01 100 or 300 microg/kg. Dose-limiting toxicities were not noted. CD34(+) cells were mobilized in all cohorts. CONCLUSION: A single dose of SD/01 increases the serum concentration of SD/01 for several days in a dose-dependent fashion and is not associated with significant toxicity. The effects of SD/01 on ANC and CD34(+) cell mobilization are comparable or greater than those achieved with daily filgrastim. The self-regulation of this molecule provides a potential therapeutic advantage in a variety of clinical settings associated with neutropenia.

A new form of Filgrastim with sustained duration in vivo and enhanced ability to mobilize PBPC in both mice and humans.

Granulocyte colony-stimulating factor (G-CSF) has proven effective in the prophylaxis of chemotherapy-induced neutropenia and as a mobilizer of peripheral blood progenitor cells. The longevity of G-CSF action is limited by its removal from the body by two mechanisms. The first is thought to be mediated via receptors (receptor mediated clearance [RMC]) predominantly on neutrophils, the second process is likely the result of renal clearance. With the intention of developing a novel form of Filgrastim (r-met HuG-CSF) with a sustained duration of action in vivo, a new derivative named SD/01 has been made by association of Filgrastim with poly(ethylene glycol). The desired properties of this new agent would include a prolonged duration of action sufficient to cover a complete single course of chemotherapy. SD/01 is shown here to sustain significantly elevated neutrophil counts in hematopoietically normal mice for 5 days. In neutropenic mice effects were noted for at least 9 days, accompanying a significant reduction in the duration of chemotherapy induced neutropenia. Normal human volunteers showed higher than baseline ANC for around 9 to 10 days after a single injection of SD/01. Data from these normal volunteers also indicate that mobilization of CD34+ cells and progenitors may occur in a more timely manner and to around the same absolute numbers as with repeated daily injections of unmodified Filgrastim. These data indicate that SD/01 represents an efficacious novel form of Filgrastim with actions sustained for between one and two weeks from a single injection.

Studies on reactivation and transmission of pigeon herpes virus (PHV) for raising PHV-free pigeons (Columba livia dom.).

For raising pigeons free of herpes virus infection, 12 parental pigeons were monitored for shedding of pigeon herpes virus (PHV) during 18 weeks of reproduction. In most of the birds only a sporadic virus excretion, which was never associated with clinical signs could be observed. However, three out of seven squabs raised by their parents became infected during the first 3 weeks of life and all seven became PHV seropositive within 4 months. Therefore, we raised seven squabs hatched in an incubator by hand using heat-inactivated crop milk. By this method we were able to obtain pigeons free of PHV infection, i.e. no virus could be isolated during the first 5 weeks of life and they remained seronegative during an observation period of 8 months. These animals have been assigned to breed a live-stock of PHV -free pigeons, necessary for studies on the pathogenesis of PHV and other pathogens.