RESUMEN
Ibogaine is a psychoactive substance that may reduce opioid withdrawal symptoms. This was the first clinical trial of noribogaine, ibogaine's active metabolite, in patients established on methadone opioid substitution therapy (OST). In this randomized, double-blind, placebo-controlled single ascending-dose study, we evaluated the safety, tolerability, and pharmacokinetics of noribogaine in 27 patients seeking to discontinue methadone OST who had been switched to morphine during the previous week. Noribogaine doses were 60, 120, or 180 mg (n = 6/dose level) or matching placebo (n = 3/dose level). Noribogaine was well tolerated. The most frequent treatment-emergent adverse events were noneuphoric changes in light perception â¼1 hour postdose, headache, and nausea. Noribogaine had dose-linear increases for AUC and Cmax and was slowly eliminated (mean t1/2 range, 24-30 hours). There was a concentration-dependent increase in QTcI (0.17 ms/ng/mL), with the largest observed mean effect of â¼16, 28, and 42 milliseconds in the 60-, 120-, and 180-mg groups, respectively. Noribogaine showed a nonstatistically significant trend toward decreased total score in opioid withdrawal ratings, most notably at the 120-mg dose; however, the study design may have confounded evaluations of time to resumption of OST. Future exposure-controlled multiple-dose noribogaine studies are planned that will address these safety and design issues.
Asunto(s)
Ibogaína/análogos & derivados , Adulto , Área Bajo la Curva , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Electrocardiografía/efectos de los fármacos , Femenino , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Ibogaína/administración & dosificación , Ibogaína/efectos adversos , Ibogaína/farmacocinética , Síndrome de QT Prolongado/inducido químicamente , Síndrome de QT Prolongado/fisiopatología , Masculino , Metadona , Narcóticos , Tratamiento de Sustitución de Opiáceos , Trastornos Relacionados con Opioides/tratamiento farmacológico , Síndrome de Abstinencia a Sustancias/tratamiento farmacológicoRESUMEN
INTRODUCTION: Continuous video-electroencephalographic (EEG) monitoring remains the gold standard for seizure liability assessments in preclinical drug safety assessments. EEG monitored by telemetry was used to assess the behavioral and EEG effects of noribogaine hydrochloride (noribogaine) in cynomolgus monkeys. Noribogaine is an iboga alkaloid being studied for the treatment of opioid dependence. METHODS: Six cynomolgus monkeys (3 per gender) were instrumented with EEG telemetry transmitters. Noribogaine was administered to each monkey at both doses (i.e., 160 and 320mg/kg, PO) with an interval between dosing of at least 6days, and the resulting behavioral and EEG effects were evaluated. IV pentylenetetrazol (PTZ), served as a positive control for induced seizures. RESULTS: The administration of noribogaine at either of the doses evaluated was not associated with EEG evidence of seizure or with EEG signals known to be premonitory signs of increased seizure risk (e.g., sharp waves, unusual synchrony, shifts to high-frequency patterns). Noribogaine was associated with a mild reduction in activity levels, increased scratching, licking and chewing, and some degree of poor coordination and related clinical signs. A single monkey exhibited brief myoclonic movements that increased in frequency at the high dose, but which did not appear to generalize, cluster or to be linked with EEG abnormalities. Noribogaine was also associated with emesis and partial anorexia. In contrast, PTZ was associated with substantial pre-ictal EEG patterns including large amplitude, repetitive sharp waves leading to generalized seizures and to typical post-ictal EEG frequency attenuation. INTERPRETATION: EEG patterns were within normal limits following administration of noribogaine at doses up to 320mg/kg with concurrent clinical signs that correlated with plasma exposures and resolved by the end of the monitoring period. PTZ was invariably associated with EEG paroxysmal activity leading to ictal EEG. In the current study, a noribogaine dose of 320mg/kg was considered to be the EEG no observed adverse effect level (NOAEL) in conscious freely moving cynomolgus monkeys.
Asunto(s)
Electroencefalografía/efectos de los fármacos , Ibogaína/análogos & derivados , Síndromes de Neurotoxicidad/psicología , Animales , Conducta Animal/efectos de los fármacos , Convulsivantes , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Femenino , Ibogaína/farmacocinética , Ibogaína/toxicidad , Macaca fascicularis , Masculino , Actividad Motora/efectos de los fármacos , Pentilenotetrazol , Convulsiones/inducido químicamente , TelemetríaRESUMEN
The aim of this study was to switch patients established on methadone opioid substitution therapy (OST) to morphine over 1 week. Subjects established on daily methadone OST (mean dose 60 mg/day) were switched to morphine slow-release capsules, dosed at 4× the previous total daily methadone dose, for 6 days, then given morphine syrup dosed q3h. All 27 subjects enrolled in this study completed the switch from methadone to morphine. Opioid withdrawal symptoms (OWS) peaked within 12-24 hours of starting morphine, and 24/27 subjects required higher daily morphine doses (mean 5.2× multiple). Pharmacokinetic evaluation showed that 91% of methadone was cleared during this time, with a mean elimination half-life of 59 hours. The most frequent treatment-emergent non-OWS adverse events were headache, nausea, constipation, and neck pain. The method described here appears to be a safe and acceptable approach to switch subjects from methadone to morphine.
Asunto(s)
Analgésicos Opioides/administración & dosificación , Sustitución de Medicamentos/métodos , Metadona/administración & dosificación , Morfina/administración & dosificación , Tratamiento de Sustitución de Opiáceos/métodos , Trastornos Relacionados con Opioides/tratamiento farmacológico , Adulto , Analgésicos Opioides/efectos adversos , Analgésicos Opioides/sangre , Método Doble Ciego , Femenino , Cefalea/inducido químicamente , Humanos , Ibogaína/administración & dosificación , Ibogaína/efectos adversos , Ibogaína/análogos & derivados , Ibogaína/sangre , Masculino , Metadona/efectos adversos , Metadona/sangre , Morfina/efectos adversos , Morfina/sangre , Náusea/inducido químicamente , Tratamiento de Sustitución de Opiáceos/efectos adversos , Trastornos Relacionados con Opioides/sangre , Resultado del TratamientoRESUMEN
Development of new drugs is typically thought of as a bottom-up endeavor where basic science identifies a target, various strategies are used to generate drugs that stimulate or inhibit the target, the drugs are first tested for safety and efficacy in animals and finally efficacy and safety are evaluated in a well defined clinical development process. However, this is not the only way that new drug products are developed. Many new products come from re-initiating development of discontinued drugs, finding new uses for existing drugs, creating a new product by obtaining marketing approval in expanded territories, obtaining approvals for new formulations or a single isomer of a previously approved racemic drug, converting products from prescription to over-the- counter use or converting folk medicines or vitamins to modern pharmaceuticals. Based on this long and successful history of contributions to modern therapeutics, these alternative sources of new products should not be neglected.
Asunto(s)
Química Farmacéutica/métodos , Aprobación de Drogas/estadística & datos numéricos , Reposicionamiento de Medicamentos/tendencias , Química Farmacéutica/estadística & datos numéricos , Reposicionamiento de Medicamentos/estadística & datos numéricos , HumanosRESUMEN
Noribogaine is the active metabolite of the naturally occurring psychoactive substance ibogaine, and may help suppress withdrawal symptoms in opioid-dependent subjects. The objectives of this Phase I study were to assess the safety, tolerability, pharmacokinetic, and pharmacodynamic profiles of noribogaine. In this ascending single-dose, placebo-controlled, randomized, double-blind, parallel-group study in 36 healthy drug-free male volunteers, 4 cohorts (n = 9) received oral doses of 3, 10, 30, or 60 mg or matching placebo, with intensive safety and pharmacokinetic assessments out to 216 hours, along with pharmacodynamic assessments sensitive to the effects of mu-opioid agonists. Noribogaine was rapidly absorbed, with peak concentrations occurring 2-3 hours after oral dosing, and showed dose-linear increases of area under the concentration-time curve (AUC) and Cmax between 3 and 60 mg. The drug was slowly eliminated, with mean half-life estimates of 28-49 hours across dose groups. Apparent volume of distribution was high (mean 1417-3086 L across dose groups). No safety or tolerability issues were identified in any cohort. No mu-opioid agonist pharmacodynamic effects were noted in pupillometry or cold-pressor testing. Single oral doses of noribogaine 3-60 mg were safe and well tolerated in healthy volunteers.
Asunto(s)
Ibogaína/análogos & derivados , Adulto , Método Doble Ciego , Glucurónidos/sangre , Voluntarios Sanos , Humanos , Ibogaína/efectos adversos , Ibogaína/sangre , Ibogaína/farmacocinética , Ibogaína/farmacología , Masculino , Adulto JovenRESUMEN
Conventional chemotherapy not only kills tumor cells but also changes gene expression in treatment-damaged tissues, inducing production of multiple tumor-supporting secreted factors. This secretory phenotype was found here to be mediated in part by a damage-inducible cell-cycle inhibitor p21 (CDKN1A). We developed small-molecule compounds that inhibit damage-induced transcription downstream of p21. These compounds were identified as selective inhibitors of a transcription-regulating kinase CDK8 and its isoform CDK19. Remarkably, p21 was found to bind to CDK8 and stimulate its kinase activity. p21 and CDK8 also cooperate in the formation of internucleolar bodies, where both proteins accumulate. A CDK8 inhibitor suppresses damage-induced tumor-promoting paracrine activities of tumor cells and normal fibroblasts and reverses the increase in tumor engraftment and serum mitogenic activity in mice pretreated with a chemotherapeutic drug. The inhibitor also increases the efficacy of chemotherapy against xenografts formed by tumor cell/fibroblast mixtures. Microarray data analysis revealed striking correlations between CDK8 expression and poor survival in breast and ovarian cancers. CDK8 inhibition offers a promising approach to increasing the efficacy of cancer chemotherapy.
Asunto(s)
Antineoplásicos/farmacología , Quinasa 8 Dependiente de Ciclina/fisiología , Regulación Neoplásica de la Expresión Génica , Neoplasias/tratamiento farmacológico , Animales , Línea Celular Tumoral , Nucléolo Celular/metabolismo , Senescencia Celular , Quinasa 8 Dependiente de Ciclina/metabolismo , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Genómica , Humanos , Ratones , Ratones Endogámicos C57BL , Trasplante de Neoplasias , Neoplasias/metabolismo , Análisis de Secuencia por Matrices de Oligonucleótidos , Regiones Promotoras Genéticas , Proteínas Quinasas Asociadas a Fase-S/metabolismo , Transcripción Genética , Resultado del TratamientoRESUMEN
To gather preliminary evidence in Alzheimer's disease (AD) for the efficacy of phenserine, a non-competitive acetylcholinesterase inhibitor that has independent modulatory effects on amyloid-ß generation, a 12-week comparison of patients receiving phenserine (10 and 15 mg BID) or placebo was conducted under double-blind conditions. Patients who completed 12 weeks of the double-blind before others were continued in the double-blind to determine longer-term treatment effects. At 12 weeks, mean ADAS-cog (AD assessment scale-cognitive) changes from baseline were -2.5 and -1.9 for high-dose phenserine (n=83) and placebo (n=81) groups, respectively, a non-statistically significant improvement for the high-dose phenserine group relative to placebo. CIBIC+ (clinician's interview based impression of change + caregiver's input) values for the high-dose and placebo groups were similar at 12 weeks. For patients who received more than 12 weeks of therapy, the ADAS-cog changes were -3.18 and -0.66 for the high-dose phenserine (n=52) and placebo (n=63) groups, respectively, a difference achieving statistical significance (p=0.0286). After 12 weeks, CIBIC+ values were 3.59 and 3.95 for the high-dose (n=54) and placebo (n=66) groups respectively (p=0.0568). These results from this short-term study are consistent with phenserine potentially benefiting mild to moderate Alzheimer's disease symptomatically but do not address possible amyloid metabolic mediated effects on disease processes in AD.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Inhibidores de la Colinesterasa/uso terapéutico , Fisostigmina/análogos & derivados , Anciano , Anciano de 80 o más Años , Análisis de Varianza , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Fisostigmina/uso terapéutico , Resultado del TratamientoRESUMEN
The pharmacokinetics and dose-exposure relationship of an extended-release formulation of metformin (ER-metformin) was investigated in a randomized, single-dose, four-period crossover study in 24 healthy male volunteers. During each study period, subjects received a randomly assigned dose containing 1000, 1500, 2000 or 2500 mg metformin. Blood samples were drawn 0-72 h after dosing for pharmacokinetic and dose-proportionality assessment. Although several pairwise comparisons between dose groups were significant (p<0.05) with respect to dose-normalized C(max), AUC(0-72 h), and AUC( infinity ), the magnitude of the difference across the dose range was <20% for AUC(0-72 h) and AUC( infinity ), and was < or = 30% for C(max). The results indicate a consistent and predictable increase in metformin exposure with an extended-release formulation of metformin over 1000 to 2500 mg.
Asunto(s)
Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/farmacología , Metformina/administración & dosificación , Metformina/farmacocinética , Administración Oral , Área Bajo la Curva , Cromatografía Líquida de Alta Presión , Estudios Cruzados , Preparaciones de Acción Retardada , Relación Dosis-Respuesta a Droga , Humanos , Hipoglucemiantes/sangre , Masculino , Metformina/sangreRESUMEN
The purpose of this study was to evaluate pharmacokinetics and dose proportionality of lovastatin extended-release dosage form (ER-lovastatin) in the dosage levels of 10, 20 and 40 mg in 9 healthy male subjects. Each subject was randomized to receive a single oral dose of ER-lovastatin either 10, 20 or 40 mg in a three-way crossover design with a washout period of 7 days between the treatments. Subjects were served dinner at approximately 5:30 PM followed by dosing at approximately 10:00 PM in each study period. Serial plasma samples were collected up to 48 h after dosing and assayed for lovastatin and its active metabolite lovastatin acid using an LC/MS/MS method. The plasma concentration-time profiles of lovastatin and its active metabolite lovastatin acid exhibited delayed- and extended-release characteristics at each dose. Mean (+/-) values for the C(max) of lovastatin were 1.04+/-0.43, 2.03+/-0.65 and 4.03+/-3.02 ng/ml for the 10, 20 and 40 mg dosage, respectively. The corresponding values for the AUC(0-48 h) of lovastatin were 14.6+/-7.8, 34.1 +/-13.7, and 53.9+/-35.6 ng h/ml. The same tendency was also found for C(max) and AUC(0-48 h) values of lovastatin acid. Results from this study demonstrated as the dose of ER-lovastatin increased from 10 to 40 mg, the C(max) and AUC(0-48 h) values of lovastatin as well as lovastatin acid appeared to increase linearly.
Asunto(s)
Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacocinética , Lovastatina/farmacocinética , Adulto , Área Bajo la Curva , Disponibilidad Biológica , Estudios Cruzados , Preparaciones de Acción Retardada , Relación Dosis-Respuesta a Droga , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/administración & dosificación , Inhibidores de Hidroximetilglutaril-CoA Reductasas/sangre , Lovastatina/administración & dosificación , Lovastatina/sangre , MasculinoRESUMEN
Epidemiological studies demonstrate that hypercholesterolemia is a risk factor for Alzheimer's disease (AD). As the generation and accumulation of the beta-amyloid peptide (Abeta) in the brain appears to be significant for the initiation and progression of AD, it is possible that cholesterol levels regulate Abeta formation and/or clearance. To test the effects of altering cholesterol on Abeta formation, we incubated cells with or without lovastatin acid, the active metabolite of the HMG-CoA reductase inhibitor lovastatin, and measured the fraction of Abeta formed from its precursor under each condition. We observed that treatment with lovastatin acid led to a profound decrease in the levels of Abeta formed. This effect was observed at concentrations of 0.05-5 microM, ranges where this compound is effective at inhibiting HMG-CoA reductase. To examine the effects of lovastatin on Abeta in vivo, human subjects who had elevated low-density lipoprotein cholesterol were treated during a double-blind, randomized study with 10-60-mg once-daily doses of a controlled-release formulation of lovastatin, or matching placebo. Serum Abeta concentrations were measured before and after up to 3 months of treatment. Mean and median changes from baseline in serum Abeta concentrations showed a significant (p < 0.0348), dose-dependent decrease. Differences between the 40- and 60-mg dose groups and placebo were statistically significant (Dunnett's p< 0.05). Our results suggest a mechanism by which hypercholesterolemia may increase risk for AD and indicate that lovastatin reduces Abeta formation and may thereby be effective in delaying the onset and/or slowing the progression of AD.
Asunto(s)
Péptidos beta-Amiloides/metabolismo , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Lovastatina/farmacología , Adulto , Anciano , Enfermedad de Alzheimer/etiología , Péptidos beta-Amiloides/sangre , Animales , Células CHO , Línea Celular , Colesterol/metabolismo , Cricetinae , Perros , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Humanos , Hipercolesterolemia/sangre , Hipercolesterolemia/complicaciones , Hipercolesterolemia/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Fragmentos de Péptidos/sangre , Fragmentos de Péptidos/metabolismoRESUMEN
The pharmacokinetics of lovastatin and its active metabolite lovastatin acid was evaluated in 9 healthy subjects in a three-period crossover study following a single oral dose of lovastatin extended-release (ER) tablets and lovastatin immediate-release (IR) tablets. Participants were dosed with lovastatin IR 40 mg tablets following a standard breakfast, lovastatin ER 40 mg tablets following a standard breakfast, and lovastatin ER 40 mg tablets underfasting conditions. Serial plasma samples were collected for up to 48 hours postdose and assayed for lovastatin and lovastatin acid using a liquid chromatography/mass spectroscopy/mass spectroscopy method. Lovastatin ER tablets, unlike lovastatin IR tablets, exhibited delayed- and extended-release characteristics. The relative bioavailability, in terms of area under the curve values, of lovastatin (156%) and lovastatin acid (124%) was greater from lovastatin ER tablets as compared with lovastatin IR tablets when given with breakfast. An even greater increase in the bioavailability of lovastatin (261%) and lovastatin acid (231%) was observed when the lovastatin ER tablets were administered under fasting conditions. Thus, greater gastrointestinal tract drug absorption of lovastatin from lovastatin ER tablets was demonstrated. Ingestion of a standard breakfast prior to administration of lovastatin ER tablets decreased absorption of lovastatin by approximately 40%, relative to lovastatin ER tablets under fasting conditions.
Asunto(s)
Anticolesterolemiantes/farmacocinética , Lovastatina/farmacocinética , Adulto , Anticolesterolemiantes/administración & dosificación , Área Bajo la Curva , Estudios Cruzados , Preparaciones de Acción Retardada , Interacciones Alimento-Droga , Semivida , Humanos , Lovastatina/administración & dosificación , Masculino , Método Simple CiegoRESUMEN
BACKGROUND: Because lovastatin is efficiently extracted by the liver and because its administration in divided doses is associated with increased efficacy, an extended-release (ER) formulation may have the potential for a dose-sparing advantage relative to the immediate-release (IR) formulation in the treatment of hypercholesterolemia. OBJECTIVE: This study compared the short-term pharmacodynamics, safety, and pharmacokinetics of multiple doses of lovastatin ER with those of lovastatin IR in patients with fasting low-density lipoprotein cholesterol (LDL-C) levels between 130 and 250 mg/dL and fasting triglyceride levels < 350 mg/dL. METHODS: The study had a randomized, single-blind, positive-controlled, 2-way crossover design, with a 4-week diet/placebo run-in period and two 4-week active-treatment periods. During period 1, patients received either lovastatin ER or lovastatin IR (both 40 mg OD). After 4 weeks of the initial study treatment and a 2-week washout period, patients were switched to the alternate treatment (period 2). Pharmacodynamic parameters (LDL-C, high-density lipoprotein cholesterol, total cholesterol, and triglyceride levels) were evaluated by combining data from weeks 3 and 4 of treatment. In a pharmacokinetic substudy, maximum plasma concentrations (C(max)) and area under the plasma concentration-time curve from zero to 24 hours (AUC(024)) were determined for lovastatin, lovastatin acid, and total and active inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase on days 1 and 28 of active treatment. The geometric mean ratio of AUC(0-24) (lovastatin ER/lovastatin IR) was also calculated for each of these substances. RESULTS: Of 76 patients who entered the run-in period, 26 (12 men, 14 women; mean age, 56.2 years) were randomized to receive active treatment and 24 were included in the efficacy analysis; 13 patients were included in the pharmacokinetic substudy, 12 of whom had complete pharmacokinetic data. Compared with lovastatin IR, lovastatin ER produced a 3.9% greater reduction in LDL-C (P = 0.044). Changes in other lipid parameters were not statistically significant. In the pharmacokinetic substudy, C(max) values for lovastatin, lovastatin acid, and in hibitors of HMG-CoA reductase were lower at day 28 with lovastatin ER than with lovastatin IR. The AUC(0-24) ratio for lovastatin was 1.91 (90% CI, 1.77 - 3.35), reflecting higher bioavailability of the prodrug with lovastatin ER; in contrast, the ratios for lovastatin acid and active and total inhibitors of HMG-CoA reductase were < 1. CONCLUSIONS: In this short-term study in a small number of patients, lovastatin ER 40 mg produced significantly greater LDL-C lowering than did an equal dose of lovastatin IR, with a relatively low C(max) and comparable systemic exposure to lovastatin acid and active and total inhibitors of HMG-CoA reductase. Lovastatin ER was well tolerated, with no discontinuations due to adverse events.
Asunto(s)
Anticolesterolemiantes/uso terapéutico , Hidroximetilglutaril-CoA Reductasas/administración & dosificación , Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Hipercolesterolemia/tratamiento farmacológico , Lovastatina/administración & dosificación , Lovastatina/uso terapéutico , Adulto , Anciano , Anticolesterolemiantes/administración & dosificación , Anticolesterolemiantes/efectos adversos , Área Bajo la Curva , Colesterol/sangre , Preparaciones de Acción Retardada , Femenino , Humanos , Hidroximetilglutaril-CoA Reductasas/efectos adversos , Hipercolesterolemia/sangre , Pruebas de Función Hepática , Lovastatina/efectos adversos , Masculino , Persona de Mediana Edad , Cooperación del Paciente , Método Simple CiegoAsunto(s)
Anticolesterolemiantes/uso terapéutico , Hipercolesterolemia/tratamiento farmacológico , Lovastatina/uso terapéutico , Adulto , Anciano , Anticolesterolemiantes/administración & dosificación , Preparaciones de Acción Retardada , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Humanos , Lovastatina/administración & dosificación , Masculino , Persona de Mediana Edad , Resultado del TratamientoRESUMEN
Epidemiological studies have demonstrated that hypercholsterolemia is a significant risk factor for Alzheimer's disease (AD). The mechanism by which increased cholesterol may contribute to AD is unknown. However, as the generation and accumulation of the amyloid Abeta peptide in the brain appears to be significant for the initiation and progression of AD, it is possible that cholesterol levels can regulate Abeta formation and/or clearance. To test the effects of altering cholesterol on Abeta formation, we incubated cells in the presence of lipid depleted serum, with or without the active metabolite of the HMG-CoA reductase inhibitor lovastatin. After confirming that cholesterol was depleted in the cells, we then measured the fraction of Abeta formed from its precursor betaPP under each condition. We observed that cholesterol depletion led to a profound decrease in the levels of Abeta released from the cells. This effect of lovastatin acid was observed at concentrations of 0.05-5 &mgr;M, ranges where this compound is effective at inhibiting HMG-CoA reductase, thereby inhibiting cholesterol synthesis. In contrast, the release of an additional AbetaPP fragment, AbetaPPs, was only modestly reduced by cholesterol treatment. In further studies, we determined that the decreased release of Abeta was not due to its accumulation in the cell, but rather due to decreased formation of Abeta. Finally, we were able to exclude decreased maturation (glycosylation and sulfation) of newly synthesized AbetaPP as a cause for the effects of lovastatin acid on betaPP processing and Abeta formation. Our results demonstrate that reducing cellular cholesterol by the use of an HMG-CoA reductase inhibitor regulates Abeta formation. This effect may involve alterations in the trafficking of AbetaPP and/or alterations in the activity of the proteases that cleave AbetaPP. The results suggest a mechanism by which hypercholesterolemia may increase risk for AD and indicate that reduction in cholesterol may delay the onset and/or slow the progression of AD.