RESUMEN
STUDY OBJECTIVE: To compare 24-hour blood pressure control and adverse effects in patients with essential hypertension who were switched from amlodipine to nisoldipine. DESIGN: Open-label, one-way crossover study. SETTING: Cardiac clinic and patients' homes. PATIENTS: Twenty-five patients with stage I or II essential hypertension stabilized with amlodipine for at least 3 months, of whom 21 patients completed the study. INTERVENTION: All patients underwent 24-hour ambulatory blood pressure monitoring while receiving amlodipine 5 or 10 mg/day. Patients then were switched to nisoldipine 10 mg/day (> or = 65 yrs old) or 20 mg/day (< 65 yrs old) and returned to the clinic at 2-week intervals to assess cuff blood pressure, heart rate, adverse effects, and compliance. No adverse effects were experienced in 15 of the 25 patients. Lower extremity edema was the most commonly reported adverse effect (four patients). Two patients discontinued treatment because of pulmonary edema in one and chest pain in the other. Two patients were lost to follow-up. After a mean of 10.6 weeks, repeat 24-hour ambulatory monitoring was performed to evaluate blood pressure control with nisoldipine. Systolic and diastolic ambulatory results for daytime, nighttime, and total 24 hours were calculated. For amlodipine versus nisoldipine, no significant differences existed in any of the blood pressure parameters (p>0.05) in the 21 patients who completed the study, except for 24-hour diastolic pressure (p<0.05); however, this latter difference was only 2 mm Hg (nisoldipine 77 mm Hg, amlodipine 75 mm Hg). CONCLUSION: Both amlodipine and nisoldipine have similar 24-hour ambulatory blood pressure profiles. The frequency of lower extremity edema was no different after the switch to nisoldipine than when the patients were taking amlodipine.
Asunto(s)
Amlodipino/uso terapéutico , Presión Sanguínea/efectos de los fármacos , Bloqueadores de los Canales de Calcio/uso terapéutico , Hipertensión/tratamiento farmacológico , Nisoldipino/uso terapéutico , Adulto , Anciano , Amlodipino/efectos adversos , Amlodipino/economía , Monitoreo Ambulatorio de la Presión Arterial , Bloqueadores de los Canales de Calcio/efectos adversos , Bloqueadores de los Canales de Calcio/economía , Estudios Cruzados , Femenino , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Masculino , Persona de Mediana Edad , Nisoldipino/efectos adversos , Nisoldipino/economía , Cooperación del Paciente , Factores de TiempoRESUMEN
BACKGROUND: Recent hypertension trials have demonstrated the importance of achieving goal blood pressures to reduce the risk of target organ damage. In patients with moderate to severe hypertension, the use of high-dose monotherapy and/or combinations of drugs are necessary to achieve these goals. Fixed-dose combination products may be useful in these patients by reducing the number of daily doses required to control blood pressure. OBJECTIVE: The objective of the present study was to evaluate the efficacy and safety of a therapeutic interchange between high-dose calcium channel blocker therapy and a fixed-dose combination of amlodipine/ benazepril (Lotrel; Novartis Pharmaceuticals, USA) in patients with moderate to severe hypertension. METHODS: A total of 75 patients were switched from amlodipine (n = 25), felodipine (n = 25), and nifedipine-GITS (n = 25) to amlodipine/benazepril. Twenty-eight of the 75 patients (37%) were taking either a beta-blocker or a diuretic in addition to the high-dose calcium channel blocker prior to the switch. Blood pressure control, side effects and the cost of the therapeutic interchange were evaluated in the year following the therapeutic interchange. RESULTS: Sixty-six of the 75 (88%) patients were successfully switched with maintenance of blood pressure control and without the development of new dose-limiting side effects. Reasons for treatment failure after the therapeutic interchange included loss of blood pressure control in five patients and the development of new dose-limiting side effects in four patients. These side effects included cough in three patients and rash in one patient. After accounting for differences in drug acquisition cost and costs related to the switch (clinic and emergency room and laboratory tests), a cost savings of $16030 for all 75 patients was realised in the first year. The per patient-per year cost savings was $214. CONCLUSIONS: Our data indicate that a therapeutic interchange from selected high-dose calcium channel blockers to a fixed-dose combination of amlodipine/ benazepril can be successfully accomplished in the majority of patients.
Asunto(s)
Amlodipino/uso terapéutico , Antihipertensivos/uso terapéutico , Benzazepinas/uso terapéutico , Bloqueadores de los Canales de Calcio/uso terapéutico , Hipertensión/tratamiento farmacológico , Adulto , Anciano , Amlodipino/efectos adversos , Amlodipino/economía , Antihipertensivos/efectos adversos , Antihipertensivos/economía , Benzazepinas/efectos adversos , Benzazepinas/economía , Presión Sanguínea/efectos de los fármacos , Bloqueadores de los Canales de Calcio/efectos adversos , Bloqueadores de los Canales de Calcio/economía , Costos y Análisis de Costo , Relación Dosis-Respuesta a Droga , Quimioterapia Combinada , Felodipino/efectos adversos , Felodipino/economía , Felodipino/uso terapéutico , Femenino , Humanos , Hipertensión/economía , Masculino , Persona de Mediana Edad , Nifedipino/efectos adversos , Nifedipino/economía , Nifedipino/uso terapéutico , Resultado del TratamientoRESUMEN
STUDY OBJECTIVE: To evaluate short-term outcomes when atorvastatin was substituted for pravastatin or simvastatin in patients with coronary artery disease. DESIGN: Open-label, fixed-dosage, one-way crossover from pravastatin and simvastatin to atorvastatin. SETTING: University-affiliated hospital and outpatient clinics. PATIENTS: Eighty patients with coronary artery disease with a minimum baseline low-density lipoprotein (LDL) above 130 mg/dl: 20 were treated with pravastatin 20 mg/day, 20 with pravastatin 40 mg/day, 20 with simvastatin 20 mg/day, and 20 with simvastatin 40 mg/day for a minimum of 6 months, with a prescription refill rate of 80% or greater. Intervention. Before crossover, patients had a fasting lipid profile determined and were questioned about side effects of pravastatin and simvastatin. All patients were switched to atorvastatin 10 mg/day. After 12 weeks of atorvastatin therapy, a repeat fasting lipid profile was obtained and patients were questioned about side effects with the drug. MEASUREMENTS AND MAIN RESULTS: Baseline demographic and clinical characteristics of the treatment groups were not significantly different with the exception of a lower baseline LDL in patients receiving pravastatin 20 mg/day. Baseline LDL values were as follows: pravastatin 20 mg/day, 158+/-26 mg/dl; pravastatin 40 mg/day, 176+/-22 mg/dl; simvastatin 20 mg/day, 177+/-27 mg/dl; and simvastatin 40 mg/day, 177+/-27 mg/dl. Reductions in LDL after treatment with pravastatin or simvastatin were as follows: pravastatin 20 mg/day, 22%; pravastatin 40 mg/day, 32%; simvastatin 20 mg/day, 33%; and simvastatin 40 mg/day, 38%. Patients achieving LDL goal with initial therapy were as follows: pravastatin 20 mg/day, 5%; pravastatin 40 mg/day, 5%; simvastatin 20 mg/day, 20%; and simvastatin 40 mg/day, 30%. After the switch to atorvastatin 10 mg/day, reductions in LDL were as follows: pravastatin 20 mg/day, 39% (p<0.001); pravastatin 40 mg/day, 38% (p<0.01); simvastatin 20 mg/day, 39% (p=0.04); and simvastatin 40 mg/day, 38% (p=0.83). Patients achieving LDL goals with atorvastatin 10 mg/day were as follows: pravastatin 20 mg/day, 60%; pravastatin 40 mg/day, 30%; simvastatin 20 mg/day, 25%; and simvastatin 40 mg/day, 30%. The frequency of side effects was similar for all three statins. Based on annual average wholesale price, atorvastatin 10 mg/day was more cost-effective than all pravastatin and simvastatin regimens. CONCLUSIONS: Therapeutic interchange from pravastatin 20 and 40 mg/day and simvastatin 20 mg/day to atorvastatin 10 mg/day was associated with both cost savings and significant reductions in LDL. The change from simvastatin 40 mg/day to atorvastatin 10 mg/day was associated with cost savings and an equivalent reduction in LDL.
Asunto(s)
Enfermedad Coronaria/tratamiento farmacológico , Ácidos Heptanoicos/uso terapéutico , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Pravastatina/uso terapéutico , Pirroles/uso terapéutico , Simvastatina/uso terapéutico , Atorvastatina , LDL-Colesterol/sangre , Estudios de Cohortes , Análisis Costo-Beneficio , Estudios Cruzados , Esquema de Medicación , Femenino , Ácidos Heptanoicos/administración & dosificación , Ácidos Heptanoicos/economía , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/administración & dosificación , Inhibidores de Hidroximetilglutaril-CoA Reductasas/economía , Masculino , Persona de Mediana Edad , Pravastatina/administración & dosificación , Pravastatina/economía , Pirroles/administración & dosificación , Pirroles/economía , Simvastatina/administración & dosificación , Simvastatina/economía , Resultado del TratamientoRESUMEN
BACKGROUND: Supraventricular tachyarrhythmias are common after open heart surgery. Possible causative factors for these arrhythmias include operative trauma, atrial ischemia, electrolyte imbalances, pericardial irritation, and excess catecholamines. Two agents commonly used to control ventricular rate in atrial fibrillation or atrial flutter (AF/AFL) are beta-blockers and calcium channel blockers. METHODS AND RESULTS: This randomized study was designed to compare the safety and efficacy of intravenous diltiazem versus intravenous esmolol in patients with postoperative AF/AFL after coronary bypass surgery and/or valve replacement surgery. A comparative cost analysis was also performed. Thirty patients received either esmolol (n = 15) or diltiazem (n = 15) for AF/AFL. During the first 6 hours of treatment, 66.6% of esmolol-treated patients converted to sinus rhythm compared with 13.3% of the diltiazem-treated patients (P <.05). At 24 hours, 66.6% of the diltiazem group converted to SR compared with 80% of the esmolol group (not significant). Drug-induced side effects, time to rate control (<90 beats/min), number of patients requiring cardioversion, and length of hospitalization were similar for the two groups. The drug cost/successfully treated patient for esmolol versus diltiazem was $254 versus $437 at 6 hours and $529 versus $262 at 24 hours. CONCLUSIONS: Although this is a small study, it suggests that esmolol is more effective in converting patients to normal sinus rhythm than diltiazem during the initial dosing period. No differences in conversion rates were observed between the two groups after 24 hours. Additional studies are needed to confirm whether esmolol is the initial drug of choice in patients with postoperative AF/AFL after coronary bypass surgery.
Asunto(s)
Fibrilación Atrial/tratamiento farmacológico , Aleteo Atrial/tratamiento farmacológico , Puente de Arteria Coronaria/efectos adversos , Diltiazem/administración & dosificación , Propanolaminas/administración & dosificación , Antagonistas Adrenérgicos beta/uso terapéutico , Adulto , Anciano , Fibrilación Atrial/etiología , Fibrilación Atrial/mortalidad , Aleteo Atrial/etiología , Análisis Costo-Beneficio , Diltiazem/economía , Femenino , Humanos , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Complicaciones Posoperatorias/tratamiento farmacológico , Probabilidad , Pronóstico , Propanolaminas/economía , Valores de Referencia , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
Outpatient transesophageal echocardiography was performed in a 69-year-old man with a history of aortic valve repair. During the procedure the patient became markedly cyanotic and hypotensive. Oxygen saturation measured by pulse oximetry decreased from 97% to the mid-80s. The man's condition continued to deteriorate. On transfer to a critical care unit, blood analysis by co-oximetry showed methemoglobin saturation of 67.8%. The patient's condition improved significantly after intravenous administration of methylene blue 1 mg/kg. With increasing numbers of outpatient procedures performed under topical anesthesia, measures should be in place to deal with a potential life-threatening adverse event such as methemoglobinemia.
Asunto(s)
Anestésicos Locales/efectos adversos , Benzocaína/efectos adversos , Metahemoglobinemia/inducido químicamente , Anciano , Ecocardiografía Transesofágica , Humanos , Masculino , Pacientes AmbulatoriosRESUMEN
Fixed-dose combination antihypertensive therapy has received interest since the publication of the JNC-VI report. Relatively few head-to-head comparative studies between fixed-dose combinations and first-line monotherapies for hypertension have been published. The objective of this study was to conduct a meta-analysis of various first-line monotherapies and the fixed-dose combination of amlodipine/benazepril. The results of the meta-analysis were used to compare the efficacy and safety of the first-line monotherapies with amlodipine/benazepril. The meta-analysis included 82 studies that included 110 treatment groups (cohorts). The study compared nine different monotherapies and one combination therapy (amlodipine/benazepril). Of the 82 studies, 22 were placebo-controlled and 60 were active treatment controlled. The mean absolute decrease in supine diastolic blood pressure (BP) ranged from 9.7 to 13.3 mm Hg with verapamil showing the greatest effect and captopril the least (13.3 +/- 3.0 mm Hg; 9.7 +/- 2.9 mm Hg, respectively). When studies were weighted by sample size, atenolol, verapamil, lisinopril and amlodipine/benazepril showed the greatest BP effect. When studies were weighted by variance, amlodipine/benazepril and atenolol showed the greatest BP effect. The percentage of patients controlled on therapy ranged from 54% to 79%. Lisinopril and amlodipine/benazepril showed the greatest percent controlled. The overall incidence of adverse effects ranged from 12.1% to 41.8% with lisinopril having the lowest and nifedipine having the highest incidence. The overall incidence of adverse effects resulting in drug discontinuance ranged from 1.3% to 10.7%, with amlodipine/benazepril having the lowest and nifedipine having the highest incidence. The results of the meta-analysis indicate that amlodipine/benazepril produces above average reductions in BP with a lower than average incidence of overall side effects and the lowest incidence of adverse effects resulting in drug discontinuance. The fixed-dose combination of amlodipine/benazepril achieves its goal of effective BP lowering with a minimum of significant side effects.
Asunto(s)
Hipertensión/tratamiento farmacológico , Amlodipino/administración & dosificación , Amlodipino/efectos adversos , Amlodipino/uso terapéutico , Antihipertensivos/efectos adversos , Antihipertensivos/uso terapéutico , Benzazepinas/administración & dosificación , Benzazepinas/efectos adversos , Benzazepinas/uso terapéutico , Combinación de Medicamentos , Humanos , Lisinopril/efectos adversos , Lisinopril/uso terapéutico , Resultado del Tratamiento , Verapamilo/efectos adversos , Verapamilo/uso terapéuticoRESUMEN
STUDY OBJECTIVE: To evaluate 24-hour blood pressure control and frequency of adverse effects in patients with mild to moderate hypertension switched from nifedipine gastrointestinal therapeutic system (Nif-GITS) to nifedipine coat core (Nif-CC). DESIGN: Open-label, prospective, switch study SETTING: University-affiliated outpatient cardiology clinic. SUBJECTS: Twenty patients with mild to moderate essential hypertension, who were taking Nif-GITS 30, 60, or 90 mg/day for 8 weeks or longer. INTERVENTIONS: Patients stabilized with Nif-GITS 30, 60, or 90 mg were monitored over 24 hours with an ambulatory blood pressure monitor and were then switched to an equivalent dosage of Nif-CC. After 8 weeks+/-1 week taking Nif-CC, they were again monitored with a 24-hour blood pressure monitor. The 24-hour blood pressure load (percentage of values > 135/85 mm Hg for 24 hrs), daytime blood pressure load (percentage of values > 140/90 mm Hg from 7:00 A.M.-10:00 P.M.), nighttime blood pressure load (percentage of values > 120/80 mm Hg from 10:00 P.M.-7:00 A.M.), diurnal blood pressure variation, average 24-hour blood pressure, daytime blood pressure, nighttime blood pressure, mean blood pressure for the first 4 hours, and last 8 hours of the dosing interval were measured. Adverse effects such as headache, dizziness, and edema were also reported. MEASUREMENTS AND MAIN RESULTS: No differences in average 24 hour-blood pressure readings were observed but significant differences in blood pressure control during the first 4 and last 8 hours of the dosing interval were seen. Systolic and diastolic blood pressures were higher after approximately 16 hours in patients switched from Nif-GITS to Nif-CC. Although Nif-CC caused a greater initial response, it was less effective than Nif-GITS after 16 hours. This could explain the lack of differences in average 24-hour blood pressure values between formulations. Of the 20 patients, 20% experienced increased headaches, 20% showed signs of increased peripheral edema, and 10% reported occasional dizziness after switching agents. Three patients discontinued Nif-CC, two as ordered by their primary care physician and one on his own due to headache. CONCLUSION: This study suggests that patients switched from Nif-GITS to Nif-CC could experience increased blood pressure during the night or toward the end of the dosing interval. They could also experience adverse effects such as headache, edema, and dizziness, which could result in more physician visits and put patients with other disease states such as coronary heart disease at increased risk.
Asunto(s)
Monitoreo Ambulatorio de la Presión Arterial , Bloqueadores de los Canales de Calcio/administración & dosificación , Hipertensión/tratamiento farmacológico , Nifedipino/administración & dosificación , Adulto , Anciano , Bloqueadores de los Canales de Calcio/efectos adversos , Bloqueadores de los Canales de Calcio/farmacocinética , Formas de Dosificación , Femenino , Humanos , Hipertensión/metabolismo , Masculino , Persona de Mediana Edad , Nifedipino/efectos adversos , Nifedipino/farmacocinética , Estudios ProspectivosRESUMEN
Coronary angioplasty is widely performed for the management of symptomatic coronary artery disease. With improvements in technique, operator experience, and tools, more complex lesions are being treated. Unfortunately, luminal renarrowing continues to limit the long-term success of the procedure, resulting in the need for repeat revascularization in approximately 30% of patients within 6 months. As the pathophysiologic process of restenosis is better defined, various pharmacologic and mechanical interventions have been tried to attenuate the process. Some agents are antithrombotics, antiplatelets, angiotensin-converting enzyme inhibitors, lipid-lowering drugs, and calcium channel blockers. Improvement has been noted with the newer glycoprotein IIb- and IIIa-blocking agents, mechanical stents, and radioactive materials. Whether these new compounds will withstand the test of time is unknown.
Asunto(s)
Angioplastia , Enfermedad Coronaria/terapia , Enfermedad Coronaria/patología , Vasos Coronarios/patología , Humanos , Inhibidores de Agregación Plaquetaria/uso terapéutico , Complejo GPIIb-IIIa de Glicoproteína Plaquetaria/antagonistas & inhibidores , Prevención Secundaria , StentsAsunto(s)
Presión Sanguínea/efectos de los fármacos , Bloqueadores de los Canales de Calcio/administración & dosificación , Nifedipino/administración & dosificación , Vasodilatadores/administración & dosificación , Anciano , Monitoreo Ambulatorio de la Presión Arterial , Estudios Cruzados , Preparaciones de Acción Retardada , Femenino , Humanos , Masculino , Persona de Mediana Edad , Nifedipino/efectos adversosRESUMEN
The detection of abnormal DNA base pairing arrangements and conformations is chemically probed in synthetic 32P-end-labeled deoxyribonucleotide oligomers using N-methyl-N-nitrosourea (MNU) and 2,12,-dimethyl-3,7,11,17-tetraazabicyclo-[11.3.1]heptadeca-1 -[17],2,11,13,15 pentaene-Ni (II) (Ni-complex) with KHSO5. The DNA targets studied are single-stranded (s-s) DNA, double-stranded (d-s) DNA, d-s DNA with G-G, G-A and G-T mismatches, d-s DNA with a single bulged G and d-s DNA with two bulged G's. The effect of the non-Watson--Crick structures on the formation of N7-methylguanine (N7-MeG) by MNU and the oxidation of G by Ni-complex is reported along with the Tm's and circular dichroism spectra of the different duplex oligomers. The results for MNU and Ni-complex show that the qualitative and quantitative character of the cleavage patterns at a G3 run change with the nature of the abnormal base pairing motif. Based on the DNA substrates studied, the results indicate that a combination of reagents which report electronic and steric perturbations can be a useful approach to monitor DNA mismatches and bulges.
Asunto(s)
ADN de Cadena Simple/efectos de los fármacos , ADN/efectos de los fármacos , Guanina/química , Metilnitrosourea/farmacología , Ácidos Nucleicos Heterodúplex/efectos de los fármacos , Autorradiografía , Secuencia de Bases , Dicroismo Circular , ADN/metabolismo , ADN de Cadena Simple/metabolismo , Calor , Metilación , Datos de Secuencia Molecular , Ácidos Nucleicos Heterodúplex/química , Ácidos Nucleicos Heterodúplex/metabolismoRESUMEN
The syntheses of N-2-chloroethyl-N-nitrosoureas (Cl-ENU) that are covalently linked to a series of minor groove binding lexitropsins related to distamycin A are reported. The lexitropsins of 2-Cl-ENU show a sequence specificity for alkylating an adenine toward the ends of its DNA affinity binding domains. The reaction of DNA with 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea does not yield these products. Therefore, the linking of the 2-Cl-ENU to the minor groove binder qualitatively and quantitatively alters the DNA observed.
Asunto(s)
Antineoplásicos/metabolismo , ADN/metabolismo , Netropsina/análogos & derivados , Compuestos de Nitrosourea/metabolismo , Alquilación , Secuencia de Bases , Datos de Secuencia Molecular , Netropsina/metabolismo , Radioisótopos de FósforoRESUMEN
The synthesis and characterization of a series of compounds that contain an N-alkyl-N-nitrosourea functionality linked to DNA minor groove binding bi- and tripeptides (lexitropsins or information-reading peptides) based on methylpyrrole-2-carboxamide subunits are described. The lexitropsins (lex) synthesized have either a 3-(dimethylamino)propyl or propyl substituent on the carboxyl terminus. The preferred DNA affinity binding sequences of these compounds were footprinted in 32P-end-labeled restriction fragments with methidiumpropyl-EDTA.Fe(II), and in common with other structural analogues, e.g., distamycin and netropsin, these nitrosoureas recognize A-T-rich runs. The affinity binding of the compound with the dimethylamino terminus, which is ionized at near-neutral pH, appeared stronger than that observed for the neutral dipeptide. The sequence specificity for DNA alkylation by (2-chloroethyl)nitrosourea-lex dipeptides (Cl-ENU-lex), with neutral and charged carboxyl termini, using 32P-end-labeled restriction fragments, was determined by the conversion of the adducted sites into single-strand breaks by sequential heating at neutral pH and exposure to base. The DNA cleavage sites were visualized by polyacrylamide gel electrophoresis and autoradiography. The alkylation of DNA by Cl-ENU-lex was compared to that by N-(2-chloroethyl)-N'-cyclohexyl-N-nitrosourea (CCNU), which has no DNA affinity binding properties. While all the Cl-ENU compounds generate DNA breaks as a consequence of the formation of N7-alkyl-guanine, the Cl-ENU-lex compounds induced, in a time- and dose-dependent fashion, intense DNA cleavage bands at adenine, cytosine, and thymine residues associated with affinity binding sites. These non-G cleavages induced by Cl-ENU-lex were inhibited by the coaddition of distamycin at concentrations that did not affect G alkylation break sites. CCNU, even at much higher concentrations, does not generate any similar detectable lesions at non-G sites. Therefore, linking the Cl-ENU moiety to minor groove binders is a viable strategy to qualitatively and quantitatively control the delivery and release of the ultimate DNA alkylating agent in a sequence-dependent fashion.
Asunto(s)
Etilnitrosourea , Guanidinas , Netropsina , Alquilación , Secuencia de Bases , Sitios de Unión , Cationes , ADN , Enzimas de Restricción del ADN , Distamicinas , Etilnitrosourea/síntesis química , Guanina , Datos de Secuencia Molecular , Estructura Molecular , Netropsina/análogos & derivadosRESUMEN
The synthesis and characterization of an N-methyl-N-nitrosourea (MNU) analogue that is covalently linked to a methidium nucleus is described. At 37 degrees C in pH 8.0 buffer 9 hydrolyzes via pseudo-first-order kinetics, with a calculated t1/2 = 77 min. By use of polyacrylamide sequencing gels the formation of piperidine-labile N7-methylguanine adducts from the reaction of 9 and MNU with 5'-32P-end-labeled DNA restriction fragments is reported. DNA methylation by 9 in 10 mM Tris buffer is enhanced with increasing ionic strength (50-200 mM NaCl), which contrasts to the inhibition of MNU-induced cleavage with increasing salt. In addition, 9 methylates all G sites equally, while MNU shows a clear preference for d(G)n (n greater than or equal to 3) runs and an asymmetrical methylation pattern within these G-rich regions. The results are discussed in terms of the delivery of the MNU moiety to the DNA target by a non-sequence-specific intercalation process and the subsequent hydrolytic generation of a nondiffusible alkylating intermediate.