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Biomedical subjects

R E Johnson

Publications and source records attributed to R E Johnson.

At least 73 records · Page 4Linked to original sources
PubMed1998

Identification of APN2, the Saccharomyces cerevisiae homolog of the major human AP endonuclease HAP1, and its role in the repair of abasic sites.

Abasic (AP) sites arise in DNA through spontaneous base loss and enzymatic removal of damaged bases. APN1 encodes the major AP-endonuclease of Saccharomyces cerevisiae. Human HAP1 (REF1) encodes the major AP endonuclease which, in addition to its role in DNA repair, functions as a redox regulatory protein. We identify APN2, the yeast homolog of HAP1 and provide evidence that Apn1 and Apn2 represent alternate pathways for repairing AP sites. The apn1Delta apn2Delta strain displays a highly elevated level of MMS-induced mutagenesis, which is dependent on the REV3, REV7, and REV1 genes. Our findings indicate that AP sites are highly cytotoxic and mutagenic in eukaryotes, and that the REV3, REV7-encoded DNA polymerase zeta mediates the mutagenic bypass of AP sites.

Amino Acid Sequence↗
PubMed1998

Induction with levomethadyl acetate: safety and efficacy.

BACKGROUND: Levomethadyl acetate hydrochloride (known as LAAM) is a mu-opioid agonist approved for the treatment of opioid dependence. Clinical trials comparing LAAM and methadone have reported lower patient retention rates during LAAM induction; however, this may reflect dose and schedule differences. Few studies have systematically examined LAAM dose induction. This study compared induction with 3 different LAAM dosage levels. METHODS: In a randomized, double-blind trial, male and female opioid-dependent patients (N = 180) were assigned to 1 of 3 LAAM doses. The low-dose (25 mg) induction was constant from the onset of treatment, the medium-dose (50 mg) induction lasted 7 days, and the high-dose (100 mg) induction lasted 17 days. Safety and efficacy were assessed on retention, urinalysis and self-reported drug use, symptoms, and patient ratings of medication adequacy. RESULTS: The high-dose group had significantly fewer illicit opioid-positive urine samples in weeks 3 and 4 as compared with the low-dose group. The high-dose group had significantly lower self-reported heroin craving in weeks 2 and 3. All groups demonstrated significant decreases in illicit drug use, withdrawal symptoms, and depression. There were no between-group differences in retention; however, there was a trend (P = .08) for lower retention and a greater number of agonist adverse effects were observed in the high-dose group. Overall, LAAM doses were well tolerated by most patients. CONCLUSION: Induction with low and medium LAAM doses can be safely and effectively achieved within 7 days. Induction with higher LAAM doses can be safely achieved within 17 days, but may result in greater rates of patient dropout and opioid agonist adverse effects. Therefore, higher doses should be approached more slowly.

Adult↗
PubMed1998

Comparing the use of short-acting and long-acting calcium channel blockers in an HMO.

One of the questions surrounding the controversy over the risks of MI among hypertensives taking calcium channel blockers (CCBs) is the dosage form, and whether the short-acting form may be more likely than the long-acting to increase the risk of MI. This preliminary study compared HMO members receiving the two dosage forms by sociodemographic and clinical characteristics, and by utilization (hospital, office visits, emergency room, outside of HMO services) prior to and during CCB use. The sampling frame was members with one or more dispensings for a CCB 1990 through 1994. Incident users were those who received one or more CCB dispensings and no cardiovascular disease-related drugs the year prior to their first dispensing of a CCB. CCB users were those who had at least 90 days of continuous CCB use. Short-acting outnumbered long-acting users by eight to one. Few incident users of long-acting CCBs were found. Among incident users, diagnoses and comorbidities were similar. In general, short-acting users appeared to have less risk of exposure to heart-related medications, but similar risks of exposure to non-heart-related drugs and to utilization of the various services during the year prior to first use. The odds of being exposed to heart-related medications and non-heart related medications and use of services during periods of use of CCBs were similar in general, but where differences were observed, the odds of being exposed were less among short-acting users. Users of the two dosage forms in this setting prior to reports questioning the safety of short-acting CCBs were different quantitatively and qualitatively making a retrospective comparative study difficult, perhaps not possible, due to substantial selection bias among users. Further patient selection bias has also undoubtedly occurred subsequent to the reports. The final answer to the relative safety and effectiveness of the different dosage forms of calcium channel blockers is likely to have come from randomized clinical trials.

Journal Article↗
PubMed1998

Toxicokinetics of inhaled 2-butoxyethanol and its major metabolite, 2-butoxyacetic acid, in F344 rats and B6C3F1 mice.

2-Butoxyethanol (2BE) is used extensively in the production of cleaning agents and solvents. It is primarily metabolized in the liver to 2-butoxyacetic acid (2BAA), which is believed to be responsible for 2BE toxicities associated with hemolysis of red blood cells. The objective of the study was to characterize the systemic disposition of 2BE and 2BAA in rats and mice during 2-year 2BE inhalation toxicity studies. Male and female F344 rats and B6C3F1 mice (6-7 weeks old) were exposed to target 2BE concentrations of 0, 31.2, 62.5, or 125 ppm (rats), or 0, 62.5, 125, or 250 ppm (mice), by whole-body inhalation for 6 h/day, 5 days/week for up to 18 months. Postexposure blood samples were collected after 1 day, 2 weeks, and 3, 6, 12, and 18 months of exposure. Postexposure 16-h urine samples were collected after 2 weeks and 3, 6, 12, and 18 months of exposure. A separate set of mice was kept in the control chamber and exposed to 2BE for 3 weeks when they were approximately 19 months old. Postexposure blood samples were collected after 1 day and 3 weeks of exposure and 16-h urine samples were collected after 2 weeks of exposure from these aged mice. Blood samples were analyzed for both 2BE and 2BAA and urine samples were analyzed for 2BAA using GC/MS, and their kinetic parameters were estimated through the curve-fitting method using SAS. Systemically absorbed 2BE was rapidly cleared from blood (t1/2-RAT < 10 min; t1/2-MOUSE < 5 min after the 1-day exposure) independent of exposure concentration. Proportional increases in AUC2BE relative to increases in exposure concentration indicated linear 2BE kinetics. In contrast, the rate of 2BAA elimination from blood decreased as the exposure concentration increased. Nonproportional increases in AUC2BAA also indicated that 2BAA is eliminated following dose-dependent, nonlinear kinetics. Overall, mice eliminated both 2BE and 2BAA from blood faster than rats. Sex-related differences in 2BAA elimination were most significant with rats, in that females were less efficient in clearing 2BAA from the blood. Differences in renal excretion of 2BAA are possibly responsible for the sex-related difference in the 2BAA blood profiles in rats. As exposure continued, the rates of elimination for both 2BE and 2BAA decreased in both species, resulting in longer residence times in the blood. When 19-month-old naive mice were exposed to 125 ppm, 2BE was rapidly cleared from the systemic circulation, exhibiting clearance profiles similar to young mice. However, old mice eliminated 2BAA from blood > 10 times slower than young mice after 1-day of exposure. This delayed elimination of 2BAA in old mice was less obvious after 3 weeks of exposure, suggesting that there might be other factors in addition to the age of animals that could influence the apparent difference in 2BAA kinetics between old and young mice. It was concluded that the elimination kinetics of 2BE and 2BAA following repeated 2BE exposure appear to be dependent on species, sex, age, time of exposure, as well as the exposure concentration.

Administration, Inhalation↗
PubMed1998

Role of yeast Rth1 nuclease and its homologs in mutation avoidance, DNA repair, and DNA replication.

The RTH1(RAD27) gene of Saccharomyces cerevisiae encodes a structure-specific endonuclease that cleaves 5'-ended single-stranded DNA at its junction with duplex DNA. Genetic and biochemical studies have indicated a role of Rth1 nuclease in the removal of RNA primers formed during DNA replication. The rth1Delta mutation confers temperature-sensitive lethality, and increases sensitivity to alkylating agents. The instability of repetitive DNA is greatly enhanced in the rth1Delta mutant. The conditional lethality of the rth1Delta mutation indicates that another nuclease can function in DNA replication in the absence of RTH1. RAD2, a homolog of RTH1, is required for nucleotide-excision repair. Here, we examine three other homologs of RTH1/RAD2 - YEN1, EXO1, and DIN7. Deletion of any of these genes in the rth1Delta strain has no effect on cell viability, suggesting the involvement of another, and as yet unidentified, nuclease in the maturation of Okazaki fragments. Our data also indicate that only RTH1 functions in the repair of alkylation damage. Deletions of YEN1, EXO1, DIN7, or RAD2, either singly or when combined with one another and with the rth1Delta mutation, have no effect on the rate of instability of dinucleotide repeats or on the rate of formation of large duplications in the CAN1 gene. These data provide evidence of a high degree of specificity for the role of RTH1 in DNA replication and in base-excision repair, and for the requirement of RAD2 in nucleotide-excision repair. The possibility that both Rth1 and Exo1 function in DNA mismatch repair is discussed.

Alkylation↗
PubMed1998

Relationship of plasma buprenorphine and norbuprenorphine to withdrawal symptoms during dose induction, maintenance and withdrawal from sublingual buprenorphine.

AIMS: Examine the relationship between buprenorphine and norbuprenorphine plasma concentrations with subject-reported withdrawal symptomatology during buprenorphine dose induction, maintenance treatments (daily and alternate-day dosing) and withdrawal. DESIGN: Two groups of randomly assigned subjects inducted onto buprenorphine and maintained on 8 mg daily by the sublingual route for 18 days. Group 1 continued to receive daily buprenorphine to day 36. Group 2 subjects received alternate-day dosing of buprenorphine and placebo on days 19 to 36. Both groups received placebo on days 37 to 52. SETTING: Inpatient facilities at the Addiction Research Center, Intramural Research Center, NIDA, Baltimore, MD. PARTICIPANTS: Eleven male, heroin-dependent volunteers participating in a research study. INTERVENTION: Medications for treatment of withdrawal symptoms were prescribed as needed after day 39 (72 hours after the last dose of buprenorphine). MEASUREMENTS: Plasma concentrations of buprenorphine and norbuprenorphine, withdrawal symptomatology and pupil diameter. FINDINGS: The mean steady-state buprenorphine plasma concentration (24 hours) after daily administrations of sublingual buprenorphine for study days 21-35 was 0.80 ng/ml, and the mean alternate day steady-state buprenorphine plasma concentration (24 hours) was 0.77 ng/ml. Daily and alternate day steady-state norbuprenorphine plasma concentrations were 1.10 and 0.90 ng/ml, respectively. Predicted alternate day steady-state buprenorphine and norbuprenorphine plasma concentrations at 48 hours were 0.49 ng/ml and 0.57 ng/ml, respectively. Withdrawal scores varied inversely with plasma concentration. There were no significant differences between Groups 1 and 2 during steady-state (days 21-35) with regard to withdrawal scale scores or pupillary diameter. The overall, mean terminal elimination half-lives for buprenorphine and norbuprenorphine were 42 and 57 hours, respectively. CONCLUSIONS: during daily buprenorphine maintenance, plasma concentrations greater than 0.7 ng/ml of buprenorphine and norbuprenorphine were associated with minimal withdrawal symptoms. The long elimination half-life of buprenorphine suggested that increasing the buprenorphine dose with alternate-day administration may provide an effective, flexible therapy regimen for the treatment of opioid dependence.

Administration, Sublingual↗
PubMed1998

Laboratory testing for Neisseria gonorrhoeae by recently introduced nonculture tests: a performance review with clinical and public health considerations.

Since 1992 two new nucleic acid-based tests (Gen-Probe Pace 2 and Abbott LCR) for the diagnosis of Neisseria gonorrhoeae infection have been approved by the U.S. Food and Drug Administration. We systematically assessed the quality of 21 studies that evaluated these tests' performance compared with that of culture for diagnosis of gonorrhea, on the basis of established criteria. We estimated overall test sensitivity and specificity by the testing method, sex, and anatomic site. None of the studies optimally fulfilled all quality criteria; few studies adequately used reference tests or described blinding. The sensitivity and specificity of nucleic acid hybridization (approximately 85%, approximately 98%) and amplification tests (approximately 95%, approximately 99%) were high and did not appear to differ substantially by sex or anatomic site. When proficiency in the performance of culture is high, the new tests are comparable to culture and may not offer a substantial advantage; in settings where optimization of culture is difficult, nucleic acid amplification may detect more infections than nucleic acid probe or culture.

Bacteriological Techniques↗
PubMed1998

Prevalence variations in psychotropic treatment of children.

This study was undertaken to clarify several aspects of the estimation of prevalence of three commonly use pediatric psychotropic agents, namely, methylphenidate, desipramine, and imipramine. The study aims are threefold: (1) to show the variability of drug prevalence by comparing estimates from three data sources; (2) to show the misleading impression that can be created by reporting drug prevalence estimates based on counts of prescriptions rather than persons; (3) to show the utility of gender-by-age-specific prevalence of drug use as a marker for diagnosis. Two data sources that yield population-based prescription estimates were available: 1991 Medicaid administrative claims data for prescriptions from a mid-Atlantic state and 1991 prescription records of the northwest region of Kaiser Permanente, a staff-model health maintenance organization (HMO). Another source of data consists of the 1991 National Ambulatory Medical Care Survey, which records medication information reported during physician office visits. Data analysis consists of quantitative estimates of (1) drug prevalence from each source; (2) the ratio of prescription claims to persons; and (3) the proportion of drug use according to age and gender. Methylphenidate and desipramine prevalence had a twofold greater use among state Medicaid enrollees compared with HMO enrollees. Average claims-to-person ratios of 5:1 suggest better accuracy using persons with medication rather than prescription counts. Gender-by-age-specific prevalence rates showed that 75% of the drug use for desipramine among those less than 15 years old was found among males, whereas 75% of the desipramine use among those 15 or older was found among females, suggesting its use for the treatment of attention deficit-hyperactivity disorder among young males and for depression among older females. The variability of community physician decision making in pediatric psychopharmacology is better understood by observing drug prevalence rates from different settings. National sampling efforts should be undertaken to verify regional and setting-specific prevalence findings and to learn the reasons for their fluctuation.

Adult↗
PubMed1998

Recent patterns of hormone replacement therapy use in a large managed care organization.

Rates of hormone replacement therapy (HRT) in women have varied substantially over the last 25 years. Data on the impact of recent recommendations for widespread use to prevent cardiovascular disease and osteoporosis and factors that influence use are needed. We attempted to (1) describe recent trends in HRT use, (2) investigate the relationship between HRT use and prepaid drug benefit, and (3) detail prescribing frequencies by provider specialty. We conducted a cross-sectional analysis of annual HRT pharmacy dispensings from 1986 to 1995 in a large HMO to all female HMO members aged 45 years and older. HRT rates increased among all age categories, although the magnitude of change varied by age. Highest rates of use were found in those 50-59 years old. Although combined estrogen-progestin use increased, 57% of all estrogen users did not receive progestin in 1995. Unopposed estrogen use was largely limited to hysterectomized women. Women of all ages with no prepaid drug benefit as part of their HMO coverage had the lowest HRT rates. Internal medicine, obstetrics/gynecology, and family practice providers prescribed over 90% of HRT, and prescriber specialty varied with user age. HRT use increased in the HMO from 1986 to 1995, especially among younger women. In 1995, about half of women aged 50-64 years received one or more HRT dispensings. As the benefits, risks, and cost effectiveness of HRT depend on the duration of use, additional information on current use duration is needed. Combined estrogen-progestin use increased and appeared appropriate to hysterectomy status. Research is needed to determine if lower HRT use rates among women without a prepaid drug benefit indicate less prophylactic HRT use, particularly among younger women, for whom this lack of coverage was relatively common.

Age Factors↗
PubMed1998

Information about barriers to planned change: a randomized controlled trial involving continuing medical education lectures and commitment to change.

PURPOSE: To determine whether practicing physicians receiving only clinical information at a traditional continuing medical education (CME) lecture (control group) and physicians receiving clinical information plus information about barriers to behavioral change (study group) would alter their clinical behaviors at the same rate. METHOD: In a randomized controlled trial, the investigators matched 13 pairs of U.S. and Canadian medical schools, assigning one school from each pair to study or control conditions. Following the commitment-to-change model, the investigators asked the primary care physicians attending control or study lectures on the management of cardiovascular risks whether they intended to make behavioral changes as a result of participating in the lectures and, if so, to indicate the specific changes. Thirty to 45 days later, the investigators surveyed the responding physicians to learn whether they had implemented those changes. RESULTS: Information about barriers to change did not increase the likelihood that physicians in the study group would report successful changes; they were no more likely to change than those in the control group. However, the physicians in both study and control groups were significantly more likely to change (47% vs 7%, p < .001) if they indicated an intent to change immediately following the lecture. CONCLUSIONS: Successful change in practice may depend less on clinical and barriers information than on other factors that influence physicians' performances. To further develop the commitment-to-change strategy in measuring the effects of planned change, it is important to isolate and learn the powers of individual components of the strategy as well as their collective influence on physicians' clinical behaviors.

Behavior↗
PubMed1998

A pilot study of the prevalence of chlamydial infection in a national household survey.

BACKGROUND: The prevalence of Chlamydia trachomatis genital infection in the United States population is unknown. Using a new urine test for C. trachomatis, we conducted a pilot survey as part of the National Health and Nutrition Examination Survey III (NHANES III). GOAL: To determine whether the prevalence of chlamydial infection in a convenience sample of NHANES participants was high enough to justify testing for C. trachomatis in a national survey. STUDY DESIGN: NHANES III, conducted from 1988 to 1994, was based on a stratified multistage probability sample of the United States population. Non-Hispanic blacks and Mexican-Americans were oversampled. Using the ligase chain reaction assay for C. trachomatis, we tested urine from participants 12 to 39 years of age from 10 of the 89 sites of NHANES III. The prevalence of infection was calculated by racial or ethnic group. RESULTS: We tested 1,144 study participants, of whom 65% were female, 30% were non-Hispanic blacks, and 30% were Mexican-American. Prevalence was higher for non-Hispanic blacks (7%) than for Mexican-Americans (3%) and non-Hispanic whites (2%). Prevalence was higher for women than men in non-Hispanic blacks (7% vs. 6%), Mexican-Americans (5% vs. 2%), and non-Hispanic whites (2% vs. 1%). In 15- to 19-year-old women, prevalence was 13% in non-Hispanic blacks, 11% in Mexican-Americans, and 5% in non-Hispanic whites. CONCLUSION: The prevalence of C. trachomatis genital infection was high enough to suggest that a reliable national prevalence estimate could be obtained in a national probability sample survey.

Adolescent↗
PubMed1998

Benzodiazepine exposure and functional status in older people.

OBJECTIVE: To determine the association between benzodiazepine exposure and functional status in older patients. DESIGN: A nonexperimental, observational study design. SETTING: Kaiser Permanente, Northwest Division, a health maintenance organization (HMO) providing prepaid, comprehensive inpatient and outpatient care for more than 410,000 persons. PATIENTS: Patients were the 4192 Social HMO Project members 65 years of age and older, enrolled for 1 full year, who returned their annual health status survey during 1990. MEASUREMENTS: Functional status was measured using self-reported activities of daily living and instrumental activities of daily living. Predictor variables were self-reported medical conditions and benzodiazepine exposure during the previous 12 months. RESULTS: Age, gender, and living status were associated with functional status. Severe memory loss, stroke, Parkinson's disease, circulation problems, lung problems, hip fracture, urinary problems, arthritis, heart trouble, diabetes, stomach/bowel problems, and cancer were associated independently with functional status. Persons exposed to a benzodiazepine scored lower on the functional status measure. Benzodiazepine exposure added significantly to the prediction of functional status after controlling for patients' socio-demographic characteristics and medical conditions. CONCLUSIONS: Age and medical conditions were the most significant predictors of functional status. Benzodiazepine exposure was associated with functional status to the same extent as several chronic medical conditions. When prescribing benzodiazepines for older people, caution should be taken to minimize the possibility of iatrogenic-functional limitations.

Activities of Daily Living↗
PubMed1998

Evaluation of bias in diagnostic-test sensitivity and specificity estimates computed by discrepant analysis.

When a new diagnostic test is potentially more sensitive than the reference test used to classify persons as infected or uninfected, a substantial number of specimens from infected persons may be reference-test negative but new-test positive. Discrepant analysis involves the performance of one or more additional tests with these specimens, reclassification as infected those persons for whom the new-test-positive results are confirmed, and recalculation of the estimates of new-test sensitivity and specificity by using the revised classification. This approach has been criticized because of the bias introduced by the selective use of confirmation testing. Under conditions appropriate for evaluating a nucleic acid amplification (NAA) test for Chlamydia trachomatis infection with cell culture as the reference test, we compared the bias in estimates based on the discrepant-analysis classification of persons as infected or uninfected with that in estimates based on the culture classification. We concluded that the bias in estimates of NAA-test specificity based on discrepant analysis is small and generally less than that in estimates based on culture. However, the accuracy of discrepant-analysis-based estimates of NAA-test sensitivity depends critically on whether culture specificity is equal to or is slightly less than 100%, and it is affected by competing biases that are not fully taken into account by discrepant analysis.

Bacteriological Techniques↗
PubMed1998

Beta-blockers and depression: the more the murkier?

OBJECTIVE: To review the literature regarding the purported association between oral ingestion of beta-blocker drugs and depressed mood. DATA SOURCE: MEDLINE was searched for published articles using the key words propranolol, atenolol, metoprolol, nadolol, timolol, beta-blocker, beta-adrenergic antagonist, or beta-adrenergic blocker in combination with the key words depression, depressive symptomatology, major depressive disorder, or depressed mood from January 1966 through December 1996. DATA SYNTHESIS: Findings regarding the association are equivocal. Plausible explanations include study design, case definition, and confounding disease states. Most of the evidence supporting an association has used case series and case reports. Findings from cross-sectional observational studies and case-control studies are equivocal. Case definition and measurement instruments may partially explain these inconsistencies. Studies using a diagnosis of depression generally do not support the relationship. Trials using depressive symptoms are about evenly split, but they have generally enrolled a small number of patients and have questionable statistical power. Studies defining antidepressant prescriptions dispensed as a marker for depression generally support the association. Evidence exists both for and against the hypothesis that lipophilic beta-blockers cause more depression than do hydrophilic beta-blockers. CONCLUSIONS: beta-Blockers may have been unjustly associated with depression and their use avoided for that reason. Future studies into the association between depression and beta-blocker use should evaluate whether the association is affected by case definition and study design characteristics, including disease, dose-response, bias, measurement error, or ability to precisely measure the length of the exposure.

Adrenergic beta-Antagonists↗
PubMed1998

The effects of linear acceleration on distortion product otoacoustic emissions in human ears.

BACKGROUND: The effect of high levels of linear acceleration (G) on the cochlea has never been studied prospectively. HYPOTHESIS: Linear acceleration at high levels has no effect on the human cochlea as demonstrated by a comparison of pre- and post-exposure measurements. METHODS: There were 22 healthy volunteers who underwent exposure to up to 9 G in a military aviation training centrifuge. Prior to exposure they were screened for cochleovestibular disorders and underwent tympanometry, audiometry and distortion product otoacoustic emissions testing (DPOAE). Immediately after exposure, they underwent serial testing of each of these parameters until they returned to baseline. RESULTS: There was no significant change in tympanometry in any subject. Audiometry revealed a temporary threshold shift of 30 db at 6 kHz in one ear of a single subject. This was accompanied by a complete loss of DPOAE at the same frequency. DPOAE did not return to baseline at 2 weeks even though the audiogram had reverted to baseline by 8 d. Four other ears displayed significant losses of emissions at single frequencies without an accompanying change on the audiogram. CONCLUSIONS: This study demonstrates that accelerative stress may cause transient injury to the cochlea. The mechanism of injury due to acceleration is probably ischemia, although a purely mechanical effect on the outer hair cells cannot be precluded. These data also reinforce a growing body of evidence that demonstrates the greater sensitivity of DPOAE over psychoacoustic testing in detecting early or subclinical cochlear damage.

Acceleration↗
PubMed1998

Intravenous and oral l-alpha-acetylmethadol: pharmacodynamics and pharmacokinetics in humans.

Levo-alpha-acetylmethadol (LAAM) is a long-acting opioid agonist approved for use as a maintenance treatment for opioid dependence. Previous clinical studies report that the onset of the effects of LAAM is slower after parenteral administration than oral administration; however, preclinical studies suggest otherwise. This study examined the pharmacodynamic and pharmacokinetic profile of LAAM when given orally and intravenously to humans. Opioid-experienced volunteers (n = 6), who were not physically dependent on opioids, received LAAM (20 and 40 mg/70 kg i.v. and p.o.) and placebo under double-blind, double-dummy conditions during five weekly experimental sessions. Behavioral, physiological, subjective and pharmacokinetic measures were collected before and for 96 hr after drug administration. Intravenous LAAM produced significant subjective and physiological effects that appeared within 5 min, whereas the effects of oral LAAM appeared more slowly within 1 to 2 hr after drug administration. Pharmacokinetic data indicate that the immediate effects of intravenous LAAM are largely attributable to the parent drug rather than the active metabolites, nor-LAAM and dinor-LAAM. LAAM produced prototypic opioid agonist effects (i.e., miosis, subjective ratings of high, nodding) that were of equal magnitude across routes, dose-related and of long duration (up to 60 hr). These data are in contrast to previous clinical reports and indicate that LAAM produces effects of immediate onset when administered parenterally, which suggests that intravenous LAAM possesses greater abuse potential than previously believed.

Administration, Oral↗
PubMed1998

Dose-response analysis of opioid cross-tolerance and withdrawal suppression during LAAM maintenance.

Levo-alpha-acetylmethadol (LAAM) currently is approved as an opioid maintenance treatment. This double-blind study was designed to characterize withdrawal suppression and opioid blockade produced by two different LAAM maintenance doses. Outpatient opioid-dependent volunteers were stabilized (5-7 weeks) on 25 (n = 8) or 75 mg (n = 8) LAAM administered every-other-day with placebo administered on intervening days. After stabilization, four inpatient, randomly ordered experimental sessions were conducted at 24, 48, 72 and 96 hr after LAAM dosing; the timing of these sessions corresponds to intervals that occur during typical thrice-weekly treatment and after a missed dose. During each session, after baseline assessments, ascending doses of hydromorphone (0, 6 and 12 mg i.m.) were administered 45 min apart; physiological, subjective and observer-rated effects were recorded throughout the session. Physiological and subjective indices of opioid withdrawal measured at session base lines increased with time since the last LAAM dose, but did not depend on the maintenance dose. Withdrawal symptoms were mild in both groups, even at 96 hr after LAAM dosing. Hydromorphone produced dose-related opioid agonist effects at all intervals in the 25 mg LAAM group; these effects were attenuated substantially in the 75 mg LAAM group. Time since last LAAM dose had little influence on hydromorphone effects in either group. Thus, 75 mg LAAM provides opioid blockade and withdrawal suppression for up to 96 hr, whereas 25 mg LAAM is relatively ineffective at producing significant opioid blockade.

Adult↗