RESUMO
BACKGROUND: Alzheimer's disease (AD) prevention trials require a large outreach and screening funnel to identify cognitively unimpaired adults who meet the study's inclusion criteria, such as certain clinical or demographic criteria, genetic risk factors, and/or biomarker evidence of the disease. OBJECTIVES: Describe tactics and strategies to identify and enroll cognitively unimpaired adults with one (heterozygotes [HT]) or two (homozygotes [HM]) copies of the APOE ε4 allele, a genetic risk factor for dementia due to AD, into the Alzheimer's Prevention Initiative (API) Generation Program, the largest and only prevention trials for late onset AD using this enrichment technique. DESIGN AND SETTING: The Generation Program was comprised of two global, randomized, double-blind, placebo-controlled, parallel group adaptive design with variable treatment duration clinical trials. Generation Study 1 randomized participants into one of two cohorts: Cohort 1 which evaluated CAD106 vs. placebo or Cohort 2 which evaluated umibecestat vs placebo. Generation Study 2 randomized participants into two doses of umibecestat vs. placebo. The Generation Program was terminated early in 2019, while enrollment was still occurring. PARTICIPANTS: Both Generation Study 1 and Generation Study 2 enrolled cognitively unimpaired APOE ε4 HMs aged 60-75; Generation Study 2 also enrolled APOE ε4 HTs ages 60-75 with elevated brain amyloid. METHODS AND MEASUREMENTS: Describe results of the centralized and localized outreach, recruitment, screening strategies and tactics as well as characteristics of sites successful at enrolling genetically eligible participants, with a particular focus on APOE ε4 HMs given the 2-3% prevalence of this genotype. RESULTS: At the time the trial program was terminated, 35,333 individuals had consented to the optional prescreening ICF1a/ICFA and provided a sample of DNA for APOE genotyping, 1,138 APOE ε4 HMs consented to screening for Generation Study 1 (ICF1b), and 1,626 APOE ε4 carriers were randomized into either Generation Study 1 or Generation Study 2. Genetic testing registries, partnerships with genetic testing/counseling companies, and the optional prescreening ICF1a/ICFA were the most successful strategies for identifying genetically eligible participants for screening. CONCLUSIONS: It is feasible to recruit, screen and randomize cognitively unimpaired APOE ε4 carriers, particularly APOE ε4 HMs for a global AD prevention trial. The Generation Program was on track to complete enrollment by end of 2019. Factors that were key to this success included: working with sites to develop customizable outreach, recruitment, and screening programs specific to their site needs, providing forums for sites to exchange best practices, and developing partnerships between the sponsor team and trial sites.
Assuntos
Doença de Alzheimer , Adulto , Humanos , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/genética , Doença de Alzheimer/prevenção & controle , Heterozigoto , Apolipoproteína E4/genética , Distribuição Aleatória , GenótipoRESUMO
Interleukin 2 (IL-2) mediates the regression of metastatic cancer but clinical use has been limited due to associated toxicities. Tumor necrosis factor (TNF) is an important mediator of IL-2 toxicity and may have a limited role in IL-2 antitumor efficacy. Because pentoxifylline (PTXF) inhibits TNF production, we hypothesized that PTXF would ameliorate IL-2 toxicity without compromising antitumor efficacy. Four groups of female C57BL/6 mice with pulmonary metastases from a 3-methylcholanthrene-induced fibrosarcoma (MCA-105) and four groups of nontumored mice were treated every 6 h for 4 d by intraperitoneal injections of either IL-2 alone, IL-2 and PTXF, PTXF alone, or equal volumes of saline. Upon completion of therapy, we found that PTXF suppressed many of the IL-2-induced effects including TNF production, lymphocytic infiltration of multiple organs, multiple organ edema, hepatic dysfunction, leukopenia, and thrombocytopenia. Tumor response was determined 21 d after cessation of therapy by quantitating the number and surface area of pulmonary metastases. PTXF preserved antitumor efficacy while reducing the morbidity and mortality caused by IL-2 treatment. These data strongly support the use of PTXF in extending the therapeutic index of IL-2 in the treatment of cancer.
Assuntos
Interleucina-2/antagonistas & inibidores , Pentoxifilina/farmacologia , Animais , Antineoplásicos , Interleucina-2/toxicidade , Camundongos , Camundongos Endogâmicos C57BL , Sarcoma Experimental/tratamento farmacológico , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Thromboxane and prostacyclin levels in serum were measured following photodynamic therapy (PDT) to assess the role of these vasoactive agents on vascular damage and tumor destruction. Sprague Dawley rats were given injections i.v. of Photofrin II doses ranging from 0 to 25 mg/kg. Twenty-four h later, the right hindlimbs of animals bearing chondrosarcoma tumor or controls were exposed to 0-135 J/cm2 630 nm light. Serum concentrations of thromboxane and prostacyclin were determined by radioimmunoassay. A dose-response relationship was established between the amount of photosensitizer administered and the light dose delivered with the release of thromboxane immediately following PDT. Treatment of tumor induced higher levels of thromboxane than did the treatment of tumor-free tissue, suggesting that tumor is more sensitive to PDT-induced damage. The porphyrin and light doses found to induce the release of thromboxane into serum were the same as those required to evoke vascular stasis and tumor destruction. Prostacyclin release was not altered by PDT. The administration of indomethacin (10 mg/kg, i.p.) 3 h before light treatment was found to suppress the intravascular release of thromboxane at the highest porphyrin and light doses studied. Indomethacin treatment also inhibited PDT-induced vascular stasis and tumor destruction, suggesting that the release of thromboxane is linked to these events. Since prostacyclin levels in serum were unchanged following PDT treatment of tumor and controls, thromboxane release appears to be a specific response to PDT and may mediate the vascular stasis observed following PDT.
Assuntos
Epoprostenol/metabolismo , Neoplasias Experimentais/tratamento farmacológico , Fotoquimioterapia , Tromboxanos/metabolismo , Animais , Plaquetas/efeitos dos fármacos , Éter de Diematoporfirina , Relação Dose-Resposta a Droga , Endotélio/efeitos dos fármacos , Feminino , Hematoporfirinas/farmacologia , Indometacina/farmacologia , Neoplasias Experimentais/metabolismo , Ratos , Ratos EndogâmicosRESUMO
STUDY OBJECTIVE: To compare the absolute bioavailability of phenytoin (PHT) sodium solution and PHT acid suspension in healthy volunteers receiving continuously infused enteral feedings. DESIGN: Randomized, open-label, single-dose, three-period crossover study. SETTING: University clinical research center. SUBJECTS: Ten healthy volunteers age 23-43 years. INTERVENTIONS: The three phases of the study were separated by at least 7 days. During phase A, subjects received PHT sodium 435 mg intravenously over 30 minutes. During phases B and C, subjects had a nasogastric feeding tube placed through which PHT acid suspension 400 mg and PHT sodium solution 435 mg were administered, respectively. For phases B and C, continuous enteral feedings were given by feeding tube for 14 hours before and after the PHT dose. Blood samples were collected over 72 hours after each PHT dose, and the serum was analyzed for PHT. MEASUREMENTS AND MAIN RESULTS: The rate and extent of PHT absorption and PHT pharmacokinetics were determined using an empirical quadratic function of time method. Bioavailability, rate of absorption, maximum concentration (Cmax), and time to maximum concentration (Tmax) were compared for the two enteral doses by paired Student's t test. There were no significant differences in bioavailability for PHT acid suspension and PHT sodium solution (0.88 +/- 0.15 vs 0.91 +/- 0.7, p=0.57, 90% CI -0.14-0.071). The Cmax was greater (7.4 +/- 0.9 mg/L vs 5.5 +/- 1.7 mg/L, p=0.019) and Tmax was less (2.5 +/- 3.8 vs.14.8 +/- 11.2 hrs, p=0.004) for the sodium solution. The time to 50% fractional absorption (0.33 +/- 0.08 vs 3.2 +/- 2.4 hrs, p=0.004) and 90% fractional absorption (7.9 +/- 6.2 vs 22.3 +/- 17.2 hrs, p=0.021) was also significantly shorter for the sodium solution. CONCLUSION: The absolute bioavailability of the two dosage forms of PHT administered with concomitant enteral feedings were not significantly different, however, the absorption patterns were significantly different, with the sodium solution being more rapidly absorbed.
Assuntos
Anticonvulsivantes/farmacocinética , Nutrição Enteral , Fenitoína/farmacocinética , Adulto , Anticonvulsivantes/administração & dosagem , Disponibilidade Biológica , Feminino , Interações Alimento-Droga , Humanos , Injeções Intravenosas , Masculino , Fenitoína/administração & dosagemRESUMO
This study has examined the changes in tumor interstitial pressure exhibited during and after photodynamic therapy (PDT). The kinetics of these changes are marked by an initial decrease, followed by a rapid rise in tumor interstitial pressure. We have also employed two inhibitory agents to evaluate the different components of the pressure curve. Specially designed pressure chambers were seeded with chondrosarcoma and implanted subcutaneously in rats. Animals were injected with 0-50 mg/kg Photofrin II (i.v.) 7 days post-implantation and tumors were exposed to 0-540 J/cm2 630 nm 24 h later. Interstitial pressure was monitored via a transducer connected to the implanted chamber. Additional groups of animals were injected with either indomethacin (an inhibitor of thromboxane synthesis) or Ketanserin (a serotonin antagonist) before light treatment. Porphyrin doses of 10 mg/kg and above (135 J/cm2), or light doses of 135 J/cm2 and above (25 mg/kg Photofrin II) were effective in modifying interstitial pressure. Porphyrin doses greater than 25 mg/kg, or light doses greater than 270 J/cm2 produced no further increases in interstitial pressure. Animals given indomethacin (10 mg/kg i.p.) exhibited the initial decrease in pressure during light treatment, but showed no increase past baseline levels. Animals given Ketanserin (10 mg/kg i.p.) demonstrated no decrease in pressure during PDT, but showed the same elevations in pressure as controls. This suggests that two independent mechanisms account for the different components of the pressure curve, and that serotonin release may occur during PDT.
Assuntos
Condrossarcoma/tratamento farmacológico , Hematoporfirinas/uso terapêutico , Fotoquimioterapia , Radiossensibilizantes/uso terapêutico , Animais , Condrossarcoma/fisiopatologia , Éter de Diematoporfirina , Espaço Extracelular/fisiologia , Feminino , Técnicas In Vitro , Indometacina/farmacologia , Ketanserina/farmacologia , Lasers , Luz , Pressão , Ratos , Ratos EndogâmicosRESUMO
Vascular stasis and tissue ischemia are known to cause tumor cell death in several experimental models after photodynamic therapy (PDT); however, the mechanisms leading to this damage remain unclear. Because previous studies indicated that thromboxane release is implicated in vessel damage, we further examined the role of thromboxane in PDT. Rats bearing chondrosarcoma were injected with 25 mg/kg Photofrin (intravenously) 24 h before treatment. Light (135 J/cm2, 630 nm) was delivered to the tumor area after injection of one of the following inhibitors: (1) R68070: a thromboxane synthetase inhibitor; (2) SQ-29548: a thromboxane receptor antagonist; and (3) Flunarizine: an inhibitor of platelet shape change. Systemic thromboxane levels were determined. Vessel constriction and leakage were evaluated by intravital microscopy. Tumor response was assessed after treatment. Thromboxane levels were decreased more than 50% with SQ-29548 as compared to controls. Thromboxane levels in animals given R68070 and Flunarizine remained at baseline levels. SQ-29548 and R68070 reduced vessel constriction compared to controls, while Flunarizine totally prevented vessel constriction. R68070 and SQ-29548 inhibited vessel permeability compared to PDT controls; Flunarizine did not. Animals given these inhibitors showed markedly reduced tumor cure. These results indicate that the release of thromboxane is linked to the vascular response in PDT.
Assuntos
Arteríolas/efeitos dos fármacos , Condrossarcoma/tratamento farmacológico , Fotoquimioterapia , Tromboxanos/antagonistas & inibidores , Animais , Arteríolas/fisiologia , Compostos Bicíclicos Heterocíclicos com Pontes , Condrossarcoma/irrigação sanguínea , Ácidos Graxos Insaturados , Feminino , Flunarizina/farmacologia , Flunarizina/uso terapêutico , Hidrazinas/farmacologia , Hidrazinas/uso terapêutico , Ácidos Pentanoicos/farmacologia , Ácidos Pentanoicos/uso terapêutico , Piridinas/farmacologia , Piridinas/uso terapêutico , Ratos , Ratos Sprague-Dawley , Tromboxanos/metabolismo , Vasoconstrição/efeitos dos fármacosRESUMO
Photodynamic therapy (PDT) of malignant tumours may involve the interruption of tumor and peritumor microcirculation. We have studied the effect of light activation of the photosensitizing drug dihematoporphyrin ether (DHE) on rat subcutaneous arterioles and the modulation of these effects by cyclooxygenase inhibitors indomethacin and acetyl salicylic acid (ASA). Animals received DHE 48 h prior to light activation and additionally either indomethacin, ASA or saline 3 h prior to treatment. Light activation (630 nm, 60 J/cm2) resulted in a significant reduction to 62 +/- 2% SEM of initial blood flow. This effect was inhibited by ASA (98 +/- 8% SEM) and indomethacin (87 +/- 8% SEM). Results from the administration of various doses of both compounds indicate that this inhibition is dose related. The data presented here show that PDT causes a significant reduction in blood flow in normal arterioles and that this effect was inhibited by ASA and indomethacin indicating that prostaglandins or thromboxane A2 may play an important role in the microvascular response to PDT.
Assuntos
Microcirculação , Fotoquimioterapia , Prostaglandina-Endoperóxido Sintases/fisiologia , Animais , Aspirina/farmacologia , Indometacina/farmacologia , Masculino , Microcirculação/efeitos dos fármacos , Ratos , Fluxo Sanguíneo Regional/efeitos dos fármacosRESUMO
The effects of four different zinc phthalocyanines were studied during and after photodynamic therapy (PDT). Measurements of vessel constriction, vessel leakage, tumor interstitial pressure, eicosanoid release, and tumor response of chondrosarcoma were made in Sprague-Dawley rats. Animals were injected intravenously with 1 mumol/kg of mono-, di-, or tetrasulfonated zinc phthalocyanine, or 1 mumol/kg of a zinc phthalocyanine substituted with four tertiary butyl groups. Tissues were exposed to 400 J/cm2 670 nm light 24 h after photosensitizer injection. An additional group of animals was given indomethacin before treatment. The use of the monosulfonated and tertiary butyl substituted zinc phthalocyanines in PDT caused the release of specific eicosanoids, caused vessel constriction, and induced venule leakage and increases in tumor interstitial pressure. Tumor cures of 27% and 7% were observed. Photodynamic therapy using the disulfonated zinc phthalocyanine did not induce vessel constriction or the release of eicosanoids, however, tumor cure was 43%. The use of the tetrasulfonated zinc phthalocyanine caused intermediate effects between the mono- and disulfonated compounds. The administration of indomethacin to animals completely inhibited the effects of PDT using the monosulfonated compound but had minimal effects on treatment using the disulfonated compound. This suggests that the monosulfonated and disulfonated compounds act by different mechanisms of destruction.
Assuntos
Arteríolas/efeitos dos fármacos , Condrossarcoma/tratamento farmacológico , Indóis/farmacologia , Indóis/uso terapêutico , Compostos Organometálicos/farmacologia , Compostos Organometálicos/uso terapêutico , Fotoquimioterapia , Vênulas/efeitos dos fármacos , Animais , Arteríolas/fisiologia , Arteríolas/efeitos da radiação , Eicosanoides/sangue , Indometacina/farmacologia , Isoindóis , Luz , Masculino , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/fisiologia , Músculo Liso Vascular/efeitos da radiação , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Vasoconstrição/efeitos dos fármacos , Vênulas/fisiologia , Vênulas/efeitos da radiação , Zinco/farmacologia , Zinco/uso terapêutico , Compostos de ZincoRESUMO
V79 Chinese hamster cells were studied in vitro for modification of cobalt-60 gamma radiation effects by solcoseryl. This treatment did not modify cell survival but did protect against DNA single-strand breaks.
Assuntos
Actiemil/farmacologia , Dano ao DNA , DNA/efeitos da radiação , Protetores contra Radiação , Extratos de Tecidos/farmacologia , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Cricetinae , Raios gama , Técnicas In VitroRESUMO
The clinical application of interleukin-2 (IL-2) for the treatment of certain human malignancies has shown promise. However, the use of IL-2 in immunotherapeutic protocols has been limited due to its associated toxicities. The administration of therapeutic doses of IL-2 results in a vascular leak syndrome with associated multiple system organ edema, hypotension, and respiratory, renal, and hepatic dysfunction. Previous studies suggest that the mechanism of these toxicities involves the activation of both immune effector cells and the microvascular endothelium with resultant leukocyte-vessel wall interaction, endothelial cell injury, and subsequent invasion of normal tissues by activated leukocytes. Recently it has been demonstrated that interleukin-8 (IL-8) will inhibit leukocyte adherence to an activated endothelium. Thus, we hypothesized that IL-8 would ameliorate IL-2-evoked detrimental effects. We also investigated the influence of IL-8 on IL-2-induced antitumor efficacy. Four groups of nontumored, female, C57BL/6 mice and four groups of C57BL/6 mice with pulmonary metastases from a 3-methylcholanthrene-induced fibrosarcoma (MCA-105) were treated every 6 hr for 4 days by intraperitoneal injections of IL-2 alone, IL-2 and IL-8, IL-8 alone, or an equal volume of saline which served as our control. Upon completion of therapy, we found that IL-8 suppressed many of the IL-2-induced effects including multiple organ edema, hepatic dysfunction, leukopenia, and lymphocytic infiltration of normal organs. When the number of pulmonary metastases were counted 20 days after the cessation of therapy. IL-8 was also found to significantly ablate the IL-2-elicited antitumor efficacy.(ABSTRACT TRUNCATED AT 250 WORDS)