History Of Drug Exposure Research Articles

Understanding drug allergies

At this time, the incidence of adverse drug reactions can only be estimated because the intensive monitoring and documenting that is required to make this determination does not exist at most hospitals and clinics. Despite these limitations, a meta-analysis of prospective studies has estimated the incidence of serious adverse drug reactions in hospitalized patients to be 6.7% and the incidence of fatal adverse drug reactions to be 0.32%. When evaluating and managing the condition of a patient who has experienced an adverse drug reaction, the physician first obtains an accurate history and performs a careful physical examination to determine whether the reaction was immunologic in nature. Drug reactions that are immunologically mediated (1) require a period of sensitization, (2) occur in a small proportion of the population, (3) are elicited at drug doses far below the therapeutic range, and (4) subside after drug discontinuation in most instances. All possible culprit drugs should be identified, with dosages and dates of administration and discontinuation, and the patient should be asked about any previous drug exposure history. Although immunodiagnostic tests for allergic drug reactions are limited, several tests do exist and may be useful in the identification of drug-specific antibodies, drug-specific T lymphocytes, or mediators from activated cells. If the reaction was not consistent with an IgE-mediated event and if it did not involve serious organ damage, cautious rechallenge may be considered. For those reactions that appear to be IgE-mediated and for which there is no reliable skin test reagent, drug desensitization may be performed by allergists who are trained in this procedure. (J Allergy Clin Immunol 2000;105:S637-44.)

Diet Drug-Related Cardiac Valve Disease: The Mayo Clinic Echocardiographic Laboratory Experience

To describe the prevalence of diet drug-related valvular disease among our referral population and the association of valvular disease with duration of exposure to fenfluramine and phentermine in combination and to dexfenfluramine alone. In this retrospective review of clinical and echocardiographic data, charts of patients referred for treatment of toxic effects of diet drugs were reviewed, and telephone interviews were conducted. Between June and December 1997, 191 patients (164 women, 27 men; mean age, 47 years) were referred for possible diet drug-related valvular disease. Twenty-eight (28%) of the 99 asymptomatic patients and 40 (43%) of the 92 symptomatic patients had abnormal echocardiographic findings. Valvular lesions among the 68 patients with abnormal echocardiographic findings included mild (or greater) aortic regurgitation in 55 patients (81%), moderate (or greater) mitral regurgitation in 12 (18%), and moderate (or greater) tricuspid regurgitation in 7 (10%). The Food and Drug Administration case definition of diet drug-related valvulopathy was noted in 31 % of this referral population. Of patients with valvulopathy, mean duration of therapy with fenfluramine and phentermine in combination and dexfenfluramine alone was 9 months and 5 months, respectively. Duration of therapy was not associated with presence or absence of disease. Five patients had surgical intervention for severe valvulopathy: 3 had mitral valve repair, 1 had mitral valve replacement, and 1 had aortic valve replacement. Pulmonary hypertension (>40 mm Hg) was found in 24 patients (13%), and 17 (71 %) had pulmonary hypertension in association with valvulopathy. This study demonstrated a 31% (60/191) prevalence of valvulopathy in patients with a history of diet drug exposure who were referred for echocardiographic evaluation. The most common finding was mild aortic regurgitation. Twenty-eight percent of asymptomatic patients had abnormal echocardiographic findings. This study emphasizes the spectrum of diet drug-related cardiac disease and the potential for valvulopathy in asymptomatic patients.

Anorexigens and Pulmonary Hypertension in the United States

The use of appetite suppressants in Europe has been associated with the development of primary pulmonary hypertension (PPH). Recently, fenfluramine appetite suppressants became widely used in the United States but were withdrawn in September 1997 because of concerns over adverse effects. We conducted a prospective surveillance study on patients diagnosed with pulmonary hypertension at 12 large referral centers in North America. Data collected on patients seen from September 1, 1996, to December 31, 1997, included the cause of the pulmonary hypertension and its severity. Patients with no identifiable cause of pulmonary hypertension were classed as PPH. A history of drug exposure also was taken with special attention on the use of antidepressants, anorexigens, and amphetamines. Five hundred seventy-nine patients were studied, 205 with PPH and 374 with pulmonary hypertension from other causes (secondary pulmonary hypertension [SPH]). The use of anorexigens was common in both groups. However, of the medications surveyed, only the fenfluramines had a significant preferential association with PPH as compared with SPH (adjusted odds ratio for use > 6 months, 7.5; 95% confidence interval, 1.7 to 32.4). The association was stronger with longer duration of use when compared to shorter duration of use and was more pronounced in recent users than in remote users. An unexpectedly high (11.4%) number of patients with SPH had used anorexigens. The magnitude of the association with PPH, the increase of association with increasing duration of use, and the specificity for fenfluramines are consistent with previous studies indicating that fenfluramines are causally related to PPH. The high prevalence of anorexigen use in patients with SPH also raises the possibility that these drugs precipitate pulmonary hypertension in patients with underlying conditions associated with SPH.

Histologic Changes in Three Explanted Native Cardiac Valves Following Use of Fenfluramines

Use of fenfluramines, either alone or co-administered with phentermine (“fen-phen”) as anorexic agents in obesity, has been associated with the development of clinically significant cardiac valve disease. We present the macroscopic and histologic findings in cardiac valves explanted from three patients who presented with valvular disease after fenfluramine or fenfluramine-phentermine use and underwent single valve replacement surgery. Paraffin sections were prepared with hematoxylin and eosin, trichrome, elastic–van Gieson, and Giemsa stains, as well as immunostains using antibody to CD3 and CD20. All three patients (two females, ages 37 and 43, and a 49-year-old male) developed progressively symptomatic mitral (2 patients) or aortic (1 patient) valvular insufficiency following dexfenfluramine (2 patients) or fenfluramine-phentermine (1 patient) use. Macroscopic changes included irregular leaflet thickening, accompanied by chordal fusion in the mitral valves, but without vegetations, commissural fusion, or evidence of annular dilation. Histologically, fibromyxoid plaques and nodules just below the valve surface, superficial to a generally intact elastic fiber layer, were associated with CD3-positive lymphocytes. Valves from all three patients had central myxoid degenerative changes, which were focal/mild in one mitral valve, diffuse/moderate in one mitral valve, and diffuse/marked in one aortic valve. Focal areas of superficial fibromyxoid change or intimal thickening may also be seen in cardiac valves from patients with drug-unrelated processes leading to symptomatic or asymptomatic valvulopathy. Therefore, when valve tissue is available for histopathologic examination, valvular disease can be attributed to use of fenfluramines only if the following criteria are satisfied: (i) the macroscopic and microscopic features are consistent with fenfluramine-related valvulopathy, (ii) clinical, echocardiographic, and intraoperative findings support the diagnosis, and (iii) the history of drug exposure predates the development or exacerbation of valvular dysfunction.

Study of the association between cytochromes P450 2D6 and 2E1 genotypes and the risk of drug and chemical induced idiosyncratic aplastic anaemia.

A genetic susceptibility to drug or chemical toxicity may provide a basis for an increased risk of idiosyncratic aplastic anaemia (AA). The cytochrome P450 enzymes are responsible for the metabolism of many drugs, some of which have been linked to AA. Mutations in the cytochrome P450 CYP2D6 gene result in absent or impaired enzyme activity in about 7% of Caucasians, whereas a specific mutation in the 5'-regulatory region of the CYP2E1 gene causes overexpression of the gene. We evaluated the frequency of allelic variants of CYP2D6 and CYP2E1 using allele-specific PCR amplification and restriction enzyme analysis of blood mononuclear cell DNA among 54 Caucasian AA patients. CYP2D6 and CYP2E1 were chosen because of the link between AA and the antipsychotic drug remoxipride (CYP2D6 substrate) and benzene (CYP2E1 substrate), respectively. Results were compared with 53 controls matched for age, sex and ethnicity. The percentage of AA patients homozygous for the CYP2D6*3, CYP2D6*4 alleles (poor metabolizer phenotype) and the CYP2E1 mutant allele (overexpression) was 0%, 4% and 0%, respectively, and the percentage of heterozygotes was 2%, 28% and 15%, respectively. For normal controls the corresponding results for homozygous mutants were 0%, 4% and 0% and for heterozygotes 4%, 25% and 6%, respectively. We concluded that there were no major differences in the frequencies of the genetic polymorphisms between this series of AA patients and controls, but due to the low number of cases with the poor metabolizer phenotype and those with a history of drug exposure, the power of the study was too low to disprove an interaction.

Recognizing cutaneous drug eruptions

PREVIEWConsidering the thousands of drugs prescribed every day and the large number of over-the-counter drugs available to patients, it is not surprising that cutaneous drug eruptions are a significant problem. In this review, Drs Daoud, Schanbacher, and Dicken focus on recognition of drug reactions, analysis of the history of drug exposure, confirmation of the diagnosis, and identification of clinical entities that require dermatologic consultation.

Controlling confounding when studying large pharmacoepidemiologic databases: a case study of the two-stage sampling design.

Large drug databases have been the source of interesting developments for pharmacoepidemiologic research, because they provide relatively accurate drug exposure histories. An important limitation of these databases is the lack of information on potential confounders. One solution, developed more than a decade ago but not widely used, is "two-stage sampling," in which stage 1 is the collection of information on drug exposure and outcomes, and stage 2 is the collection of confounder data on a subset of the stage 1 sample. The balanced design, wherein an equal number of individuals is selected from each drug exposure/disease category, is usually the most efficient strategy by which to select the stage 2 sample. We illustrate the efficiency of the balanced design in two-stage sampling using data from a provincial health organization and a simulation. We also evaluate the relative importance of factors affecting the precision of the effect estimate of the exposure of interest.

Controlling Confounding When Studying Large Pharmacoepidemiologic Databases

Large drug databases have been the source of interesting developments for pharmacoepidemiologic research, because they provide relatively accurate drug exposure histories. An important limitation of these databases is the lack of information on potential confounders. One solution, developed more than a decade ago but not widely used, is “two-stage sampling,” in which stage 1 is the collection of information on drug exposure and outcomes, and stage 2 is the collection of confounder data on a subset of the stage 1 sample. The balanced design, wherein an equal number of individuals is selected from each drug exposure/disease category, is usually the most efficient strategy by which to select the stage 2 sample. We illustrate the efficiency of the balanced design in two-stage sampling using data from a provincial health organization and a simulation. We also evaluate the relative importance of factors affecting the precision of the effect estimate of the exposure of interest. (Epidemiology 1998;9:309–315)

ERYTHROID PROGENITORS IN CHILDHOOD PURE RED CELL APLASIA 102

To determine the utility of marrow cultures in defining the pathophysiology and therapeutic response of pure red cell aplasia (PRCA) in children we have studied 22 patients. Patients were evaluated before specific therapies (n=20) or at the time of treatment failure (n=2). Evaluation included a medical and drug exposure history, a physical examination, marrow morphology and cytogenetics, a serological screen for autoimmune diseases, serial measurements of human parvovirus B19 specific IgM and IgG antibodies, and marrow progenitor cell cultures. Clinical follow-up was obtained to document therapeutic responses. Among 22 patients with PRCA the distribution of diseases was as follow: Transient Erythroblastopenia of Childhood (TEC) 9, Diamond-Blackfan Anemia (DBA) 4, acquired PRCA 3, PRCA combined with autoimmune hemolytic anemia 2, refractory anemia with ring sideroblasts (RARS) 2 and unclassified cases 2.

Standardized test performance of children with a history of prenatal exposure to multiple drugs/cocaine

Twenty-four children, age 14 to 50 months, with a history of prenatal exposure to multiple drugs including cocaine, were matched by adjusted birth age and sex to 24 children with no history of drug exposure. All children had been living in stable, drug-free environments from at least the age of 11 months. Tests administered included the Sequenced Inventory of Communicative Development—Revised ( SICD), the Bayley Scales of Infant Development, and the Peabody Picture Vocabulary Test—Revised ( PPVT-R). Results indicated significant differences between groups and genders on the SICD when age was covaried and between groups on the Bayley. No groups or genders differed on the PPVT-R. Many (45.8%) of the children in the drug-exposed group qualified for intervention services according to Washington state criteria. Subject characteristics, other than age, did not play a significant role in the findings of group differences. It is concluded that, due to the cumulative effects of prenatal history, these children should be considered at risk for language delay.

The Pathophysiology of Pure Red Cell Aplasia: Implications for Therapy

To determine the utility of marrow culture in defining the natural history and therapeutic response of pure red cell aplasia we have studied 37 patients. Patients were evaluated at the University of Washington before specific therapies (n = 21) or at the time of treatment failure in = 16). Evaluation included a medical and drug exposure history, a physical examination, a chest x-ray or computed tomography to rule out thymoma, lymphocyte immunophenotype studies, anti-nuclear antibody and rheumatoid factor determinations, marrow cytogenetics, and marrow progenitor cell cultures. Retrospective Southern analyses to detect human parvovirus B19 was performed in the 27 patients for whom sera was stored. Clinical follow-up was obtained to document therapeutic responses. Normal burst forming unit-erythroid (BFU-E) growth (>30 bursts/10(5) marrow mononuclear cells [MMNC]) in culture proved an outstanding predictor of clinical response, as 27 of 29 individuals with normal frequencies of erythroid bursts in culture responded to immunomodulating therapies (sensitivity 96%, specificity 78%, predictive value 93%, P = .0001 with two-tailed chi square analysis). Overall, 28 patients responded to either immunomodulating therapies or drug withdrawal. Twenty-four patients obtained a normal hematocrit (complete response [CR] and 4 additional patients became transfusion independent (partial response). Although responding patients often required several therapies, 20 of 24 (83%) patients who obtained a CR have sustained a normal hematocrit without maintenance therapy at the time of last follow-up (median 5 years). In contrast, of 8 patients with poor in vitro BFU-E growth (<6 bursts/10(5) MMNC), 7 failed to respond to any therapy and all died (median survival time 17 months). Our data suggest that in individuals, from whom BFU-E mature appropriately in culture, immunosuppressive drugs should be used sequentially until a CR is obtained and a durable remission is the expected outcome.

HOSPITALIZATION OF CHILDREN EXPOSED TO ILLICIT DRUGS IN UTERO. 617

Illicit drug use has been spiraling in United States and this leads to increased environmental and intrauterine exposure of children. We retrospectively identified 190 children born in 1988, 1991 and 1990 with positive maternal drug screen and or maternal drug history. They were 5, 3, and 1 year old respectively at the time of the study. 95 of the drug exposed children were included in the subject group. There was no follow up for the rest. 95 children with no history of drug exposure were randomly matched for age, sex, gender, socioeconomic status and gestational age as control group. Besides hospital admissions and child abuse, diagnosis of developmental delays and seizure disorders were also recorded. Out of 95 drug exposed children 3 were diagnosed with seizure disorder and 5 with developmental delay. The difference from the control group was not statistically significant for both diagnosis; (x=0.29; p=0.59) and (x=0.15; p=0.69) respectively. This was attributed to the small sample size. Even though there was no statistically significant difference in the number of outpatient clinic visits (mean of drug exposed group=0.87, mean of control=1.1; t=0.71, p=0.47), there was a significant difference in hospitalization rate (x=14.6; p<0.0001). Drug exposed children were more likely to have a history of hospitalization (50%) than the control group (22%). Furthermore, drug exposed children were more likely to be hospitalized for accidents, injuries and burns (28%) when compared to control group (5%); (x=3.2; p=0.07). Child abuse and or neglect was reported for 30% of the drug exposed children. These data suggest that children exposed to drugs in utero need to be followed more closely by the pediatrician and interventions in this group may decrease hospital admissions.

Using ofloxacin as a time marker in hair analysis for monitoring the dosage history of haloperidol.

Hair samples were obtained 1-5 months after ingestion of the antimicrobial ofloxacin, which had been given for 1 or 3 days at the commencement of haloperidol administration, or when its dosage was reduced. The axial distribution of ofloxacin, haloperidol and its active metabolite, reduced haloperidol, was analysed in segments from single strands of hair. Ofloxacin was detected where the content of haloperidol and reduced haloperidol along the hair shaft showed a sharp change, corresponding to the change in dose. When we matched the time scale of the dosage history to the growth rate, which was estimated using ofloxacin as the time marker, the distribution of the haloperidol and reduced haloperidol precisely coincided with the rise and fall in the dose of haloperidol. These findings demonstrate that ofloxacin can serve as a time marker when drug distribution along the hair shaft is used to obtain the drug exposure history of an individual.

Transient Dystonia in an Infant With Prenatal Drug Exposure

The purpose of this case report is to describe the occurrence of transient dystonia in an infant with a history of prenatal drug exposure. Although the term transient dystonia has been used repeatedly in reports describing infants of low birth weight, this terminology has not been specifically used in describing infants at risk for neurological problems because of prenatal drug or alcohol exposure. The male infant who was the subject in this case report outgrew what had seemed to be cerebral palsy during his first year of life but went on to develop borderline cognitive delays, expressive speech delays, and behavioral problems as a toddler. Physical therapists should be aware of the possibility of encountering transient neurological signs in infants with histories of prenatal drug exposure.

Otoacoustic emissions in full‐term newborns at risk for hearing loss

Distortion product otoacoustic emissions (DPOEs) and click-evoked otoacoustic emissions (CEOEs) characteristics of the normal newborn population have been previously reported in the literature. There is little information about DPOE evaluations in the newborn population at risk for hearing loss. The authors now report the DPOE and/or CEOE data from six full-term subjects at risk for hearing loss or with highly suspected hearing loss. These subjects were less than 1 year of age and at risk for hearing loss secondary to a history of hereditary hearing loss, meningitis, hyperbilirubinemia, and ototoxic drug exposure. Audiometric evaluation included auditory brainstem responses (ABR), behavioral observation audiometry, and tympanometry. The CEOEs and DPOEs were found to be decreased or absent in the subjects with suspected hearing loss secondary to cochlear pathology; they were found to be normal in a subject with a suspected central hearing loss. This study's data suggest that otoacoustic emissions when combined with ABR can provide a frequency-specific evaluation of cochlear function and help determine the anatomic site of a pathologic lesion.

Intensive Chemotherapy and Bone Marrow Transplantation for Myelodysplastic Syndromes

In myelodysplastic syndromes (MDS), complete remission rates of acute myelogenous leukemia (AML)-type chemotherapeutic regimens vary widely, ranging from 15% in patients with myelodysplasia after previous cytotoxic therapy to 61% in patients with refractory anemia with an excess of blasts in transformation without previous exposure to leukemogenic chemicals. The duration of remission is usually short, and those that exceed 24 months are unusual. Results of treatment are identical in the different types of MDS. No sufficient data on aggressive therapy are available for refractory anemia and refractory anemia with ringed sideroblasts. Prognostically favorable subgroups of patients are defined by age (below 45 or 50 years), no prior history of cytotoxic drug exposure, and absence of cytogenetic aberrations, especially of chromosomes 5 and/or 7. In contrast to AML-type chemotherapy, allogeneic bone marrow transplantation following high-dose (radio) chemotherapy offers a significantly greater chance of cure with a long-term relapse-free survival rate of 30% to 60%.

Historical factors in the development of ETOH-conditioned place preference

Three groups of male Sprague-Dawley rats were conditioned with ethanol (ETOH) and water in a Conditioned Place Preference task. to assess the contribution of prior drug/behavioral history on the relative hedonic valence of ETOH, the three groups differed in the task demands and degree of prior ETOH exposure. One group was trained to self-administer 20% w/v ETOH in a home-cage self-administration task using a “Samson sucrose-fading” procedure prior to place conditioning trials (Group SA/CPP). A second group was initially trained in a two-choice ETOH-Saline drug discrimination (DD) task and subsequently conditioned in the place preference paradigm (Group DD/CPP). The third group of rats had no history of drug exposure and were experimentally naive prior to the place learning task (Group NH/CPP). Group SA/CPP developed a significant conditioned place preference; Group DD/CPP failed to demonstrate either a preference or aversion, whereas the Group NH/CPP demonstrated a significant place aversion. Data suggest that both present and past contingencies contribute to the algebraic summation of ETOH's hedonic valences.

Sudden infant death syndrome in infants of substance-abusing mothers

A population-based study was performed to determine whether substance abuse during the perinatal period may be a risk factor for sudden infant death syndrome (SIDS). The incidence of SIDS was studied in 2143 infants of substance-abusing mothers (ISAM) born in Los Angeles County during 1986 and 1987 who were reported to the Los Angeles County Department of Health Services because of a history of drug exposure or positive urine test results in the mother, infant, or both. By comparing the ISAM birth reports with records of autopsy-proven SIDS in Los Angeles County, we found 19 SIDS cases in the population of 2143 ISAM, a SIDS rate of 8.87 cases per 1000 ISAM (95% confidence interval 5.3 to 13.8). This was significantly higher than the SIDS rate for the non-ISAM general population: 396 SIDS deaths among 325,372 live births, an incidence rate of 1.22 cases per 1000 births, p less than 0.00001. The age of ISAM at death was 99 +/- 63 (mean +/- SD) days compared with 91 +/- 52 days for the non-ISAM population (not significant). The incidence of SIDS was significantly greater in male infants, during the winter months, in black infants, and in non-Hispanic white infants in the non-ISAM population. Such differences were not observed in the ISAM group. A greater incidence of symptomatic apnea was reported before SIDS for the ISAM than for the non-ISAM population (22% vs 5.4%, p = 0.022). We conclude that ISAM have a higher incidence of SIDS than the non-ISAM general population. However, it was not possible to separate maternal substance abuse from other confounding variables that may also have had an impact on SIDS risk in the ISAM group.

Lifetime antipsychotic-drug exposure, dyskinesia and related movement disorders in the developmentally disabled

The relationship between dyskinesia and related movement disorders was examined as a function of cumulative exposure to antipsychotic drugs (APD). Lifetime drug-exposure histories were obtained for 162 developmentally disabled (DD) persons; drug-exposed groups were compared to nondrug-exposed groups. There were no statistically significant relationships between dyskinesia and the amount of lifetime APD exposure, nor between dyskinesia and the number of long-term APDs, mean exposure, peak exposure, recency of exposure, duration of exposure, changes in medication levels, number of drug interruptions, age, gender, cerebral palsy, epilepsy, or IQ. Of the other movement disorders, a positive relationship was noted only between akathisia and long-term APD exposure; the increased prevalence of akathisia persisted beyond four years after APD withdrawal.

Aversive property of opioid receptor blockade in drug-naive mice.

The motivational effect of naloxone administration in the non-dependent laboratory mouse was examined with taste and place conditioning procedures. Thus, male CD1 mice without any history of drug exposure avoided a cue paired with three SC injections of as little as 0.1 mg/kg naloxone HCl. The aversive effect of naloxone was also seen in DBA/2 and C57BL/6 mice. In addition, it only occurred with the minus isomer and not the plus isomer, and it was potentiated by implantation, 3 days prior to training, of a morphine-containing (37.5 mg) but not a placebo pellet. Naloxone injection, therefore, acts as an aversive stimulus in naive mice and this is probably produced by decreases in activity of endogenous opioid peptide systems. Together with other data, the present results support the conclusion that the aversive effect of opioid receptor blockade in the opiate non-dependent organism may be general to a wide range of species including primates. The importance of training and testing variables for observing the naloxone aversive effect is discussed. Advantages of studying preference conditioning with mice are also given.