Discrepancies between patient recall and the medical record. Potential impact on diagnosis and clinical assessment of chronic disease.

BACKGROUND: During a case-control study, data necessary for fulfilling diagnostic and classification criteria for spondyloarthropathy were collected from 121 patients. OBJECTIVE: To study the potential impact of differences between patient recall and the medical record on diagnosis and clinical characterization of spondyloarthropathy as a model of chronic disease. METHODS: The study was conducted among four Alaskan Eskimo populations served by the Alaska Native Health Service. Two sets of historical data were compiled for each subject, one acquired during the interview and the other derived from the medical record. Paired items from the interview and the medical record were analyzed to determine discrepancies and consequent effects on diagnosis, classification, and disease characterization. RESULTS: Significant differences were observed in the reporting of genitourinary or diarrheal illnesses preceding or associated with arthritis, the occurrence of eye inflammation in association with joint pain, the occurrence of joint pain and back pain together, and the age at onset of back pain all of which are important to the diagnosis and classification of spondyloarthropathy. In contrast, for information needed to establish the probable inflammatory nature of back pain, patient interview was more helpful than the medical records, which did not provide adequate details to differentiate inflammatory from mechanical back pain. CONCLUSIONS: Patient recall bias can substantially affect diagnosis and clinical assessment of chronic disease, as exemplified by spondyloarthropathy. Reliance on records alone, however, may lead to underestimation of features that require subjective appraisal by the patient.

A comparison of patients with spondyloarthropathy seen in specialty clinics with those identified in a communitywide epidemiologic study. Has the classic case misled us?

BACKGROUND: Undiagnosed cases of seronegative spondyloarthropathy (Spa) are often observed during epidemiologic studies. OBJECTIVE: To determine the extent of and the reasons for the underdiagnosis of Spa. METHODS: We studied 2 groups of Alaskan native patients with Spa using a standardized protocol that included an interview, physical examination, medical record review, and radiographic and laboratory examinations. One group consisted of patients identified in a communitywide epidemiologic study; the other group consisted of patients from related but geographically separate populations who had been diagnosed by a specialist in the hospital or a specialty clinic. All cases met the current classification criteria for Spa. The clinical and demographic features of the cases in the 2 groups were compared. RESULTS: Fifty-five (72%) of the 76 community cases that we identified in the epidemiologic study had not been diagnosed previously as Spa. Among the undiagnosed patients were 34 (94%) of the 36 women, 11 (65%) of the 17 patients with ankylosing spondylitis, 12 (36%) of the 33 patients with reactive arthritis, and 24 (100%) of those with undifferentiated Spa. The community and specialty clinic patient groups were similar in age of onset of joint and back pain and in overall symptoms. The specialty clinic group had a higher proportion of men, more severe disease, and a higher frequency of iritis. CONCLUSIONS: The diagnosis of Spa was missed more often than not in the primary care setting, probably because most of the cases were of mild or moderate severity and did not fit the classic descriptions of spondyloarthropathic disorders. The higher proportion of men among the specialty clinic cases probably reflects provider expectation as well as a slightly milder disease course in women.

Arthritis and other rheumatic conditions: who is affected now, who will be affected later? National Arthritis Data Workgroup.

OBJECTIVE: We present national and state estimates for 1990 and projections for the year 2020 of the prevalence of self-reported arthritis and other rheumatic diseases and related activity limitations. We further suggest a research and policy agenda to address this important and growing public health problem. METHODS: Estimates and projections were derived from household interviews conducted for the 1989-1991 National Health Interview Survey, and were applied to United States census population estimates for 1990 and projections for 2020. RESULTS: The prevalence rate of self-reported arthritis and other rheumatic conditions in the United States is projected to increase from 15.0% (37.9 million) of the 1990 population to 18.2% (59.4 million) of the estimated 2020 population. Activity limitation attributed to these conditions is projected to increase from 2.8% (7.0 million) of the 1990 population to 3.6% (11.6 million) of the 2020 population. Prevalence rates were higher for older persons, women, residents of nonmetropolitan areas, and those with less education or lower income. CONCLUSIONS: Arthritis and other rheumatic conditions are frequent and disabling public health problems now, and are projected to become even more so by 2020. Implementing the suggested research and public health agenda could reduce the occurrence and impact of these conditions.

Selective GLC determination of epinephrine, isoproterenol, and phenylephrine in pharmaceutical dosage forms.

A simple, specific GLC analytical procedure for the quantitation of epinephrine, isoproterenol, and phenylephrine in commercial tablets, powders, inhalation solutions, ophthalmic and nasal drops, and injectable preparations is presented. Samples are taken to dryness where required, the dried residue is reacted with an appropriate trimethylsilylating reagent, and the derivatives are eluted from a methyl silicone column using temperature programming. Quantitation of the flame-ionization detector signal is achieved relative to the dibenzyl succinate internal standard by an electric integrator. The results obtained by applying the method to the analysis of each of the three drugs in several simulated decomposed mixtures were in good agreement with theoretical values, even at impurity levels of up to 80% by weight. When applied to commercial formulations, the procedure was feasible for tablets, powders, and solutions at drug concentrations of 0.2% or greater. The commonly incorporated buffering and antioxidant excipients did not interfere.

Simple GLC analysis of anticonvulsant drugs in commercial dosage forms.

A simple, specific GLC procedure is described for the analysis of one sedative and six anticonvulsant drugs in pharmaceutical dosage forms. Sample aliquots of ethotoin, glutethimide, mephenytoin, methsuximide, and phensuximide were shaken with or extracted into ethyl acetate, diluted with the internal standard (diphenyl phthalate) solution, injected into a gas chromatograph, and eluted from a methylsilicon column. Primidone and phenytoin samples (extracted as the free acid) required derivatization with N,O-bis(trimethylsilyl)acetamide prior to chromatography. The same temperature programming conditions and flow rate settings were used for all seven drugs. The GLC results agreed well with those obtained using the pharmacopeial methods.

Routine quality evaluation of benzodiazepine drugs to USP-NF specifications.

A GLC procedure was developed for the evaluation of diazepam, chlordiazepoxide, and flurazepam formulations to USP-NF specifications for drug content, content uniformity, impurities, and identity by retention times and peak areas. The polyimide column, instrument zone temperatures, gas flows, internal standard solution, extraction solvent, and auxiliary equipment were the same for each drug. No derivatization of the samples was required. The GLC assay values (mean of 10 individual dosage units) for diazepam and flurazepam products were in good agreement with the results obtained by the pharmacopeial composite assays. With chlordiazepoxide capsules, when the levels of the two pharmacopeial impurities determined by GLC were added to the GLC assay results (mean of 10), athe aggregate values were consistent wit the drug content results found by the nonspecific USP method. The procedure can be made sensitive to impurity levels of approximately 0.01% for 2-amino-5-chlorobenzophenone and to approximately 0.2% for 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one 4-oxide. With the equipment used, the estimated potential outputs in lots per working day for a complete quality profile (drug content, content uniformity, purity, and identity) were seven for chlordiazepoxide if no impurity test was required, five if such a test was required, eight for diazepam, and seven for flurazepam.

Impurities in drugs V: Meprobamate.

One lot of meprobamate raw material and 28 lots of tablets were examined for impurities by TLC. All lots contained di-(2-methyl-2-propyl-3-carbamoyloxypropyl) carbonate (V) at levels that ranged between 0.1 and 1.0% of the total drug content. Nine lots also contained low levels of a second impurity (approximately 0.1%), and one of these lots contained a third impurity (approximately 0.1%), neither of which was identified. Estimates of the unidentified impurities were based on the assumption of a TLC response with furfural-hydrochloric acid spray equivalent to that of meprobamate. Compound V was identified by mass spectrometry and PMR and IR spectroscopy and by comparison of the TLC Rf value to that of a synthesized sample of V.

Metered dose inhalers III: Metaproterenol sulphate; particle size distribution and dose uniformity.

Three American products and one Canadian product were examined for content uniformity and particle size distribution. The results showed that not all products performed equally well. Some of the products exhibited high sprays early in the canister lifetime and all products demonstrated loss of prime. The particle size distributions were determined using the Andersen cascade impactor (USP Induction Port) and the fine particle fraction was determined using the twin impinger. The results showed that three of the four products had similar particle size distribution profiles. Both the Andersen cascade impactor and the twin impinger yielded the same trends in the amount of drug substance delivered to the fine particle fraction.

Effects of the AMPA receptor modulator S 18986 on measures of cognition and oxidative stress in aged rats.

RATIONALE: Development of cognitive-enhancing drugs that delay or halt mild cognitive impairment progression to Alzheimer's disease would be of great benefit. OBJECTIVES: The aim of this study was to examine the ability of (S)-2,3-dihydro-[3,4]-cyclopentano-1,2,4-benzothiadiazine-1,1-dioxide (S 18986), a positive allosteric modulator of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, to improve behavioral performance and alleviate age-related deficits in oxidative stress status in the prelimbic cortex and hippocampus. MATERIALS AND METHODS: Daily administration of S 18986 (0.1, 0.3, and 1.0 mg/kg) or vehicle was given to separate groups of male rats starting at 12 months of age. Additionally, daily vehicle administration was given to a group of rats starting at 3 months of age. Four months after initiation of drug administration, rats were trained and tested in an operant-delayed alternation task and a reinforcer devaluation task. Upon completion of testing, oxidative stress status was assessed in the prelimbic cortex and hippocampus. RESULTS: S 18986 dose-dependently altered responses in the reinforcer devaluation task such that aged rats came to resemble young rats. There were no age or drug effects in the operant-delayed alternation task. Levels of the lipid peroxidation product 4-hydroxy-nonenal (HNE) were increased, and Cu/Zn-superoxide dismutase (SOD) levels were decreased in prelimbic cortex in aged rats, changes that were reversed by S 18986. Similarly, age-related increases in hippocampal HNE levels were prevented by S 18986. CONCLUSIONS: Positive modulation of AMPA receptor activity may be a therapeutic approach to halt or slow progression of mild cognitive impairment via improvement in oxidative stress status in the hippocampus and prelimbic cortex.

Analysis of selected drug formulations for volatile nitrosamines.

A number of selected drug formulations on the Canadian market were analyzed for N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA) content by using a gas chromatograph interfaced to a thermal energy analyzer (GC/TEA). Of the 34 formulations analyzed, NDMA was found in 21 at levels up to 12 ppb and NDEA was found in 11 at levels up to 0.6 ppb. In many cases, the drug entity in the formulation did not contain the precursors for the observed nitrosamines.

Analysis of piperazine drug formulations for N-nitrosamines.

A quantitative method is described for the measurement of N-mononitrosopiperazine (NPIP) and N,N'-dinitrosopiperazine (DNPIP) in drug formulations containing piperazine, using a gas chromatograph interfaced to a thermal energy analyzer (GC/TEA). The method has detection limits of 20 ppb for NPIP and 12 ppb for DNPIP. In a survey of 6 products available on the Canadian market, all contained NPIP at levels of 0.38-15.3 micrograms NPIP/g piperazine and none contained any detectable amount of DNPIP.

The incorporation of [1-14C] acetate into the methyl ketones that occur in steam-distillates of bovine milk fat.

1. The (14)C-labelling of the fatty acids and the methyl ketones in steam-distillates of milk fat from a lactating cow that had been injected intravenously with [1-(14)C]acetate was determined. 2. The labelling patterns of the C(6)-C(16) fatty acids and the corresponding methyl ketones with one fewer carbon atoms were similar, particularly so for the C(5)-C(10) compounds at 9 and 22hr. after the injection of [1-(14)C]acetate. The isolation of (14)C-labelled methyl ketones in the range C(3)-C(15) is evidence that the beta-oxo acid precursors, which are glyceride-bound in the milk fat, are synthesized in the mammary gland from acetate. The absence of heptadecan-2-one in steam-distillates and the extremely low specific radioactivity of stearic acid are further evidence for this biosynthetic pathway. 3. The specific radioactivities of the C(5)-C(15) methyl ketones were higher (with the exception of C(9) methyl ketone in the second milking) than the specific activities of the corresponding fatty acids with one more carbon atom. This is consistent with the methyl ketone precursors' being formed during the biosynthesis of fatty acids rather than being products of beta-oxidation of fatty acids.

Specific quantitative gas-liquid chromatographic analysis of methyldopa and some foreign related amino acids in raw material and commercial tablets.

A relatively simple gas-liquid chromatographic (GLC) procedure has been designed for the rapid detection and accurate quantitation of some theoretically possible foreign related amino acid contaminants in alpha-methyldopa raw material and commercial tablets. After trimethylsilylation of the drug or drug mixture with N,O-bis(trimethylsilyl)acetamide in acetonitrile at ambient temperature for 90 min, the derivatives are eluted from a methylsilicone column isothermally at 170 degrees. Quantitation of the components is effected by simple computation relative to dibenzyl succinate as the internal standard. The results obtained by applying the GLC procedure to the analysis of a number of multicomponent synthetic mixtures are in good agreement with the theoretical values. The percentage of label claim values obtained by the GLC method for commercial tablets are compared to those measured colorimetrically by the official U.S.P. procedure. No foreign related amino acid impurities were detected in any of the three commercial dosage forms examined.

Production of high titers of enterotoxins for the routine testing of staphylococci.

The cellophane-over-agar technique has been shown to give high titers of enterotoxins A, B, and C for routine testing of staphylococci for enterotoxigenicity.

Production of extracellular enzymes and enterotoxins A, B, and C by Staphylococcus aureus.

Eighty-seven strains of Staphylococcus aureus were examined for their ability to produce enterotoxins A, B, and C, deoxyribonuclease, lysozyme, proteinase, lipase, and alpha-, beta-, and delta-hemolysins. Enterotoxigenic strains showed a significant tendency to be high lipase producers, but none of the other enzymes formed were correlated with the ability of the staphylococci to produce enterotoxins A, B, or C. The conversion of ent(-) to ent(+) strains by lysogenization did not affect significantly the ability of the strains to produce any of the above extracellular enzymes. The formation of enzymes such as deoxyribonuclease and lysozyme by staphylococci is not therefore an indication, necessarily, of their potential enterotoxigenicity.

Titrimetric determination of nonesterified fatty acids in intravenous fat emulsions.

A titrimetric method, suitable for use at a limit of 5 mEq/L, has been developed for the determination of total nonesterified fatty acids in intravenous fat emulsion preparations. The method differentiates titrant consumed by the nonesterified fatty acids from that consumed by egg yolk phospholipids, usually present as an emulsifying agent. The total nonesterified fatty acids in 8 products from 4 manufacturers were in the range from 0.4 to 3.8 mEq/L. The mean standard deviation of the method is 0.09 mEq/L.