Most Thyroid Cancers Detected by Sonography Lack Intranodular Vascularity on Color Doppler Imaging: Review of the Literature and Sonographic-Pathologic Correlations for 698 Thyroid Neoplasms.

OBJECTIVES: This study investigated the controversy of whether hypervascularity on color Doppler sonography correlates with thyroid malignancy by reviewing the literature and sonographic-pathologic correlation. METHODS: Over a 20-year period, 698 thyroid nodules had color Doppler and histopathologic data. Intranodular vascularity was graded 0 to 3+, and histopathologic findings were recorded. RESULTS: The data were collected from 698 patients (557 women and 141 men) with a mean age of 48 years (range, 16-87 years). Of the 698 neoplasms, 425 were malignant (mean size, 1.7 cm; range, 0.4-9 cm; 150 ≤1 cm), and 273 were benign. The carcinomas included 391 papillary, 12 Hürthle cell, 9 medullary, 6 follicular, 5 poorly differentiated, and 2 anaplastic. The grading of intranodular vascularity was 0 in 63.3%, 1+ in 12.9%, 2+ in 6.6%, and 3+ in 17.4%. Among thyroid carcinomas, follicular carcinoma and the encapsulated subtype of the follicular variant of papillary carcinoma had significantly higher intranodular vascularity than the rest (P < .0001). Benign neoplasms included 226 follicular adenoma/adenomatoid nodules (mean size, 3.2 cm; range, 1.2-8.0 cm), 42 Hürthle cell adenoma/adenomatoid nodules (mean size, 2.6 cm; range, 0.8-5.5 cm), and 5 hyalinizing trabecular adenomas (mean size, 2.4 cm; range, 0.6-6.0 cm; 4 ≤1 cm). The grading of intranodular vascularity was 0 in 6.9%, 1+ in 12.1%, 2+ in 2.6%, and 3+ in 78.4%. Intranodular hypervascularity was associated with adenoma/adenomatoid thyroid nodules, whereas a lack of vascularity was related to thyroid carcinomas (P < .0001). CONCLUSIONS: Most sonographically detected thyroid cancers lack intranodular vascularity, and most hypervascular thyroid nodules are adenoma/adenomatoid nodules, the encapsulated subtype of the follicular variant of papillary carcinoma, or follicular carcinomas.

Encapsulated follicular variant of papillary thyroid carcinoma: fine-needle aspiration with ultrasound and histologic correlation of 41 cases.

OBJECTIVE: The encapsulated follicular variant of papillary carcinoma (FVPC) was recently reported to have genetic alterations and biological behavior closer to follicular adenoma/carcinoma than classic papillary carcinoma and unencapsulated FVPC. The objective of this study is to alert cytologists to this new subtype and to report our experience. STUDY DESIGN: Cytology of 41 cases of surgery-proven encapsulated FVPC was reviewed and correlated with histopathology and ultrasound findings. These cases were collected over 19 years from 188 aspirates reported as 'suspicious or atypical, cannot exclude FVPC' and from 245 aspirates reported as follicular neoplasm. RESULTS: Thirteen aspirates had diffusely atypical nuclei, 20 aspirates had mixed normal and atypical nuclei, and 8 aspirates had no atypical nuclei. On histology, papillary nuclei were distributed focally in the second and third groups. Crowded, oval, clear nuclei occurred in nearly 80% of the cases, nuclear grooves occurred in 12.2%, and nuclear pseudoinclusions occurred in 4.9%. Capsular invasion without angioinvasion was present in 30% of encapsulated FVPCs, with angioinvasion in 17.5% and lymph node metastasis in 7.5%. Most encapsulated FVPCs were benign-appearing on ultrasound with round-to-oval, circumscribed nodules with a hypoechoic rim. CONCLUSIONS: Encapsulated FVPC is more difficult to recognize on fine-needle aspiration and ultrasound than unencapsulated FVPC.

Can cytology and the Thyroid Imaging, Reporting, and Data System (TI-RADS) identify noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) before surgery?

INTRODUCTION: In 2017, the American College of Radiology (ACR) created the Thyroid Imaging, Reporting, and Data System (TI-RADS) to select thyroid nodules for fine-needle aspiration (FNA). The objective of this study is to find out whether ACR TI-RADS is useful in triaging thyroid follicular cells with papillary-like nuclear features obtained by FNA to determine the extent of surgery. MATERIAL AND METHODS: The grayscale ultrasound of 76 noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP), 41 encapsulated (E), and 79 infiltrative (I) follicular variant (FV) of papillary thyroid carcinoma (PTC) were reviewed and assigned TI-RADS points and then suspicion levels. RESULTS: Of the 39 tumors with high suspicion level, 32 were IFVPTC, and seven were EFVPTC. Of the 137 tumors with moderate suspicion level, 47 were IFVPTC, 34 were EFVPTC, and 56 were NIFTP. Of the 19 tumors with mild suspicion level, all were NIFTP. The only tumor with no suspicion was an NIFTP. IFVPTC had a significantly higher suspicion level than EFVPTC and NIFTP (P < 0.0001). The difference in suspicion level between EFVPTC and NIFTP is not statistically significant. None of the cases of NIFTP in the study had a high suspicion level. CONCLUSIONS: The study demonstrates that cytology interpreted in the context of ACR TI-RADS suspicion levels can separate NIFTP from many IFVPTC and a few EFVPTC with overt invasion. PTC could be diagnosed in cytology if cells with papillary-like nuclear features derived from TR5 nodules. The nodules with TR4 or less that yield similar cells require surgical pathology to diagnose FVPTC with microscopic capsular or vascular invasions.

Communication with general practitioners: a survey of spinal cord injury physicians' perspectives.

Study design: An online questionnaire. Objectives: To gauge spinal cord injury (SCI) specialists' assessment of their communications with general practitioners (GPs). To determine whether economic or health-care system-related factors enhance or inhibit such communication. Setting: A collaboration of co-authors from a health-care system. Methods: An online survey interrogating a number of aspects of communication between SCI specialists and GPs was developed, distributed, and made available for 4 months. Responses were analyzed for the entire cohort then according to descriptions of participants' home nations' economies and the type of health-care delivery systems in which they work. Results: A total of 88 responses were submitted. The majority (64%) were from nations with developed economies, a plurality (47.1%) were from countries that offer universal health coverage, and half used a combination of paper and electronic health records. A majority of respondents (61.8%) reported routinely communicating with their patients' GPs, but most (53.4%) rated those communications as only "fair". The most commonly listed barriers to communication with GPs were lack of time (46.3%) and a perceived lack of receptivity by GPs (26.9%). Nearly all respondents (91.6%) believed that the care they provide would be enhanced by improved communication with GPs. Participants who used electronic means of communication were more likely to communicate with GPs and to describe those interactions as "positive". Conclusions: Although there are a number of barriers to communication between SCI specialists and GPs, most SCI specialists are eager for such inter-physician communication and believe it would enhance their care they deliver.

Pharmacokinetics of sertraline across pregnancy and postpartum.

Insufficient data inform dosing of antidepressants and clinical monitoring for major depressive disorder (MDD) during the perinatal period. The objectives were to assess the pharmacokinetics of sertraline (SER) across pregnancy and postpartum. Participants treated with SER for MDD underwent serial sampling to measure steady-state concentrations of SER and norsertraline during the second and third trimesters and postpartum (total of 3 assessments). Blood was drawn before observed SER administration and 0.5, 1, 2, 4, 6, 8, 10, 12, and 24 hours after administration. A sensitive high-performance liquid chromatography/mass spectrometric method for simultaneous determination of serum concentrations of SER and norsertraline was developed and validated. For each sampling period for SER, area under the serum concentration versus time curve, maximal serum concentration (Cmax), and the time at which Cmax occurred (Tmax) were determined. Of 11 women initially enrolled, 6 completed second- and third-trimester assessments, and 3 completed all 3 assessments (including the postpartum assessment). Mean changes on all pharmacokinetic parameters were nonsignificant between assessments, although there was a marked heterogeneity among individuals. Results were not significantly altered by incorporation of body weights into the analyses. The range of pharmacokinetic changes between individuals was broad, indicating heterogeneity regarding the impact of pregnancy on SER metabolism. Overall, lowest observed SER area under the curve and Cmax occurred in the third trimester (observed in 5 of 6 participants). Despite nonsignificant mean pharmacokinetic changes, the range of pharmacokinetic changes across pregnancy warrants careful monitoring of depressive symptoms in women with MDD in late pregnancy and further study.

Pathologic basis of the sonographic differences between thyroid cancer and noninvasive follicular thyroid neoplasm with papillary-like nuclear features.

Ultrasonography is pivotal in triage thyroid biopsy in the era after the identification of noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). This pictorial essay illustrates the pathologic basis of the sonographic features that distinguish NIFTP from thyroid cancers. In this study, we present the correlations of ultrasonography to ×1 histopathology to assess shape and margin characteristics. Markedly hypoechoic nodules correlate to microfollicular/solid nodules, while isoechoic/hyperechoic thyroid nodules correlate to normofollicular/macrofollicular nodules. The ultrasound findings of NIFTP and minimally invasive encapsulated thyroid cancers are similar. Both are well-circumscribed, oval-to-round nodules with regular margins. Blurred or microlobulated margins indicate infiltrating tumors, while lobulated margins are characteristic of expansile tumors. Overtly invasive encapsulated tumors are characterized by oval-to-round nodules with irregular or lobulated margins. The ultrasound findings for infiltrative thyroid cancers show at least one of the following malignant features: marked hypoechoicity, taller-than-wide shape, microcalcifications, and blurred or microlobulated margins.

Sonographic and cytologic differences of NIFTP from infiltrative or invasive encapsulated follicular variant of papillary thyroid carcinoma: A Review of 179 Cases.

We reclassified 179 cases of the follicular variant (FV) of papillary thyroid carcinoma (PTC) into 72 (40.2%) noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP), 37 (20.7%) encapsulated FVPTC with invasion (EFVPTC), and 70 (39.1%) infiltrative FVPTC (IFVPTC) without a capsule. In the NIFTP group, 5.6% cytology were hypercellular and the remainder low to moderate cellularity. PTC nuclei were absent in 18%, focally present in 37.5%, and diffusely present in 44.4%. In the EFVPTC group, 8.1% cytology were hypercellular and the reminder low to moderate cellularity. PTC nuclei were absent in 24.3%, focally present in 29.7% and diffusely present in 45.9%. In IFVPTC group, 24.3% cytology were hypercellular and the reminder low to moderate cellularity. PTC nuclei were diffusely present in 88.6% and focally present in 11.4%. The ultrasound findings for NIFTP and minimally invasive EFVPTC typically demonstrated a circumscribed oval/round nodule with a hypoechoic rim, and the Doppler was mostly hypervascular. The ultrasound findings for overtly invasive EFVPTC typically showed a round/oval nodule with irregular margins and the Doppler was mostly hypervascular. The ultrasound findings for IFVPTC group showed at least one of the malignant gray-scale features: markedly hypoechoic, taller-than-wide, microcalcifications or blurred margins. The Doppler in this group was mostly avascular. An algorithm is proposed to triage thyroid FNA based on different scenarios of the sampled cells, interpreted in the context of ultrasound features with histology outcomes. Five composite ultrasound-cytology-histology figures illustrate NIFTP, IFVPTC, and IFVPTC with intratumoral fibrosis, microfollicular EFVPTC and normofollicular EFVPTC. Diagn. Cytopathol. 2017;45:533-541. © 2017 Wiley Periodicals, Inc.

Distinguishing parathyroid and thyroid lesions on ultrasound-guided fine-needle aspiration: A correlation of clinical data, ancillary studies, and molecular analysis.

BACKGROUND: Differentiating parathyroid and thyroid lesions can be challenging because of considerable morphologic overlap and anatomic proximity. Therefore, the authors sought to identify characteristic morphologic patterns and useful adjunct tests to distinguish these 2 entities. METHODS: A search was conducted in the study institution database for clinically indeterminate thyroid nodules from 2000 through 2016 with an emphasis on confirmed parathyroid nodules. Pathology reports, slides, ancillary studies, molecular analysis, and clinical and radiologic data were retrieved. RESULTS: A total of 143 cases of clinically indeterminate thyroid nodules were identified; 34 of these were confirmed parathyroid nodules. Three cytologic patterns were identified: 1) oncocytic cell pattern (9 cases; 26%); 2) follicular lesion of undetermined significance-like/papillary-like pattern (14 cases; 41%); and 3) nonspecific endocrine cell clusters (11 cases; 32%). Bare oval nuclei (100%), nuclear overlap (88%), crowded sheets (88%), and intracytoplasmic vacuoles (62%) were observed. Ten cases (29%) demonstrated positive immunostaining for parathyroid hormone (PTH), 7 cases (21%) demonstrated a positive PTH assay, and 9 cases (26%) had PTH detected by ThyroSeq v.2. The remaining 8 cases were morphologically either indeterminate or suggestive of parathyroid origin. The cytologic diagnosis was confirmed clinically (20 cases) or surgically (14 cases). Based on cytology alone, 8 cases initially were diagnosed as thyroid tissue and amended to parathyroid lesion after ancillary studies were performed, including 5 cases based on ThyroSeq v.2 results alone. CONCLUSIONS: Lesions with follicular lesion of undetermined significance-like or oncocytic features are prone to misdiagnosis. The current study identified distinct cytologic patterns in parathyroid lesions suggestive of parathyroid origin, which, together with PTH immunostains or assay, molecular studies, or sestamibi scans, aid in distinguishing parathyroid from thyroid lesions. Cancer Cytopathol 2017;125:674-82. © 2017 American Cancer Society.

Bazett and Fridericia QT correction formulas interfere with measurement of drug-induced changes in QT interval.

BACKGROUND: The QT interval on the ECG is prolonged by more than 50 marketed drugs, an effect that has been associated with syncope and/or sudden cardiac death due to an arrhythmia. Because changes in heart rate also change the QT interval, it has become standard practice to use a correction formula, such as the Bazett formula, to normalize the QT interval to a heart rate of 60 bpm, that is, the rate-corrected QT or QTc. Numerous other formulas have been devised to make this correction, including the Fridericia, Hodges, and Framingham formulas. OBJECTIVES: The purpose of this study was to investigate how the Bazett formula and three other formulas influence assessment of the QT-prolonging effect of the potassium channel-blocking drug ibutilide. METHODS: Using a standardized physical activity protocol, the QT interval was assessed over a broad range of heart rates before and after an infusion of ibutilide (4.75 microg/kg) that produced a stable 15- to 20-ms QT prolongation in consenting normal subjects (9 men and 9 women). The QT interval was measured digitally over a range of heart rates from 60 to 120 bpm, and then four correction formulas (Bazett, Fridericia, Framingham, or Hodges) were applied. The uncorrected change in QT interval due to ibutilide was compared with the change using each of the formulas by repeated measures analysis of variance. RESULTS: At heart rates from 60 to 120 bpm, the Bazett and Fridericia correction formulas overestimated the change in QT in both men and women (P <.001). However, the Framingham and Hodges formulas did not alter the accuracy of the assessment of QT interval change. CONCLUSION: Rate correction of QT intervals using the standard Bazett and Fridericia formulas can introduce significant errors in the assessment of drug effects on the QT interval. This has implications for the clinical assessment of drug effects and for the safety assessment of new drugs under development.

Medical Therapy for Inappropriate Sexual Behaviors in a Teen With Autism Spectrum Disorder.

Teens with autism spectrum disorder often exhibit sexual behaviors in public that are disturbing to parents, teachers, and peers. Some have proposed that such behaviors can be curtailed with hormonal suppression. There is information on the Internet suggesting that such medications work, and some reports in the peer-reviewed medical literature support these claims. Such medications can have serious side effects. In this paper, we present a case in which parents requested such treatment of their teenage son with autism spectrum disorder.

The enantioselective determination of chlorpheniramine and its major metabolites in human plasma using chiral chromatography on a beta-cyclodextrin chiral stationary phase and mass spectrometric detection.

A sensitive enantioselective high-performance liquid chromatographic (HPLC) method has been developed for the simultaneous determination of plasma concentrations of (-)(R)- and (+)(S)-chlorpheniramine (CP) and their metabolites, desmethyl-chlorpheniramine (DCP), didesmethyl-chorpheniramine (DDCP) and chlorpheniramine N-oxide (CPNO). Enantioselective separations were achieved on a beta-cyclodextrin chiral stationary phase (CYCLOBOND I 2000) with a mobile phase consisting of diethylamine acetate (0.25%, pH 4.4):methanol:acetonitrile [85:7.5:7.5, (v/v/v)]and a flow-rate of 0.5 ml/min. For CP, the enantioselectivity (alpha) of the separation was 1.12 with a resolution factor (R(s)) of 1.17. The method was validated for CP by using mass spectroscopy detection (MSD). Concentrations of each enantiomer could be measured down to 125 pg/ml from a 1-ml plasma sample. Extracted calibration curves were linear from 0.13 to 50.00 ng/ml for each enantiomer. The method was applied to samples from two clinical studies.

Spinal cord injury and use of botulinum toxin in reducing spasticity.

Spasticity is commonly seen after spinal cord injury, and a large percentage of patients with spinal cord injury will need treatment to control it. Although oral medications do a fair job of controlling spasticity in most patients, some patients will need additional forms of treatment. In many cases, oral medications alone do not adequately control spasticity or the patient cannot tolerate the side effects. In these instances, botulinum toxin may help control the spasticity for approximately 3 months after injection. The amount of botulinum toxin and the injection sites can be tailored to meet individual patient needs. Botulinum toxins can reduce spasticity, improve function, and reduce the amount of needed assistance.

Aspiration biopsy of mammary analogue secretory carcinoma of accessory parotid gland: another diagnostic dilemma in matrix-containing tumors of the salivary glands.

Mammary analogue secretory carcinoma (MASC) is a newly described rare salivary gland tumor, which shares morphologic features with acinic cell carcinoma, low-grade cystadenocarcinoma, and secretory carcinoma of the breast. This is the first reported case of MASC of an accessory parotid gland detected by aspiration biopsy with radiologic and histologic correlation in a 34-year-old patient. Sonographically-guided aspiration biopsy showed cytologic features mimicking those of low-grade mucoepidermoid carcinoma, including sheets of bland epithelial cells, dissociated histiocytoid cells with intracytoplasmic mucinous material, and spindle cells lying in a web-like matrix. Histologic sections showed a circumscribed tumor with microcystic spaces lined by bland uniform epithelial cells and containing secretory material. The tumor cells expressed mammaglobin and BRST-2. The cytologic features, differential diagnosis, and pitfalls are discussed. The pathologic stage was pT1N0. The patient showed no evidence of disease at 1 year follow-up.

Cytological features of clear cell thyroid tumors, including a papillary thyroid carcinoma with prominent hobnail features.

Primary thyroid tumors with extensive clear cell changes are extremely rare. More than 10,000 ultrasound-guided thyroid fine needle aspirations examined over a period of 17 years by the first author, only one of the 530 (<0.2%) papillary thyroid carcinomas (PTCs) and three of the 42 (7.1%) follicular thyroid carcinomas (FTCs) had extensive cytoplasmic clearing. Thyroidectomies were performed for these cases at four different hospitals in New York City. Final pathology was available for review in each of the four cases. Histology showed a 1.5-cm PTC with prominent hobnail features and clear cell change in a 31-year-old woman, a 4.3-cm FTC without angioinvasion in a 31-year-old woman, a 4.5-cm angioinvasive FTC in a 45-year-old man, and a 2-cm FTC with extensive angioinvasion in a 41-year-old woman with McCune-Albright syndrome (previously published). On ultrasound, the FTCs were solid circumscribed nodules and the PTC had an irregular margin. In these cases, the etiology for the cytoplasmic clearing included accumulation of glycogen in the PTC, accumulation of vesicles in two of the FTCs, and accumulation of lipid droplets in a FTC with extensive angioinvasion. Review of the cytologic literature showed 17 cases of follicular-derived thyroid tumors with extensive clear cell change. To the best of our knowledge, this is the first cytologic report of PTC with hobnail features and extensive clear cell change.

Orally active alpha-tocopheryloxyacetic acid suppresses tumor growth and multiplicity of spontaneous murine breast cancer.

We recently demonstrated the antitumor efficacy of orally administered alpha-tocopheryloxyacetic acid (alpha-TEA), a redox silent and nonhydrolyzable derivative of naturally occurring vitamin E. In order to move alpha-TEA closer to the clinic to benefit patients with breast cancer, the present study had two goals. First, to determine the minimal effective treatment dose; and second, to test the efficacy of dietary administration of alpha-TEA in the clinically relevant MMTV-PyMT mouse model of spontaneous breast cancer that more closely resembles human disease. The minimal effective dose of alpha-TEA was evaluated in the transplantable 4T1 tumor model and we show a dose-dependent decrease of primary tumor growth and reduction of metastatic spread to the lung. Six-week-old MMTV-PyMT mice were treated with oral alpha-TEA for 9 weeks, with no apparent signs of drug toxicity. The alpha-TEA treatment delayed tumor development and significantly slowed tumor progression, resulting in a 6-fold reduction of the average cumulative tumor size. In addition, oral alpha-TEA caused an 80% reduction in spontaneous metastases. In situ analysis of tumor tissue identified apoptosis as an important mechanism of alpha-TEA-mediated tumor suppression in addition to inhibition of tumor cell proliferation. This study shows, for the first time, the ability of orally administered alpha-TEA to delay tumor onset and to inhibit the progression and metastatic spread of a clinically relevant model of spontaneous breast cancer. Our finding of the high efficacy in this tumor model highlights the translational potential of oral alpha-TEA therapy.

Rates of malignancy in incidentally discovered thyroid nodules evaluated with sonography and fine-needle aspiration.

OBJECTIVE: The purpose of this study was to compare the rate of malignancy in thyroid nodules discovered incidentally on magnetic resonance imaging, computed tomography, and sonography with the rate of malignancy in nonincidentally discovered nodules. METHODS: All thyroid sonographic and fine-needle aspiration (FNA) procedures performed during a 6-month period were retrospectively reviewed. Study indications were categorized as incidental (thyroid nodules found on magnetic resonance imaging, computed tomography, or sonography performed for nonthyroid indications) or nonincidental (studies prompted by abnormal physical examination findings or laboratory values or signs or symptoms suggestive of thyroid disease). Rates of malignancy in patients with incidentally discovered nodules were compared with rates in patients with nonincidental thyroid abnormalities by the Fisher exact test. RESULTS: Of 225 thyroid sonographic studies, 35 (16%) were performed for incidentally discovered thyroid nodules, and 190 (84%) were performed for evaluation of nonincidental thyroid abnormalities. A total of 21 patients (60%) in the incidental group and 90 patients (47%) in the nonincidental group underwent FNA. The rate of malignancy in nodules examined by biopsy in the incidental group was 17% compared with 3% in the nonincidental group (P = .020). Patient sex, multiplicity of nodules, nodule size, echo texture, and presence of calcifications did not differ significantly between the groups. The mean age of patients in the incidental group was significantly higher (61 versus 51 years; P = .007); however, advanced age was not associated with a greater rate of malignancy. CONCLUSIONS: This study identified an unexpectedly high rate of malignancy in incidentally discovered thyroid nodules, suggesting that incidentally discovered thyroid nodules should be evaluated with follow-up thyroid sonography and FNA.

Polyorchidism: report of 3 cases and review of the literature.

OBJECTIVE: To describe the embryologic, clinical, sonographic, and magnetic resonance imaging features of polyorchidism and to review the literature on similar cases. METHODS: Over a 5-year period, we encountered 3 patients who were found to have polyorchidism on scrotal sonography. All 3 patients had a painless scrotal mass. Two patients also had magnetic resonance imaging of the scrotum, and the results were correlated with the sonograms. We also performed a literature search for other reports of polyorchidism. RESULTS: One patient had 2 right testicles and a single left testicle. The second patient had 3 left testicles and 1 right testicle. In the third patient, who had 2 left testicles and 1 right testicle, microlithiasis was found in all 3 testes. The supernumerary testes were within the scrotum in all cases. All testicles were identified by sonography. Magnetic resonance imaging in 2 cases provided confirmatory data regarding the presence of an extra testicle but did not add other relevant information. Conservative treatment was chosen in all cases. CONCLUSIONS: Polyorchidism is a rare congenital anomaly. There are characteristic sonographic features of polyorchidism, and the diagnosis is often made on the basis of sonography. Magnetic resonance imaging can be used for confirmation but may be more helpful in cases complicated by cryptorchism or neoplasia. Conservative treatment is advised in uncomplicated cases.

The roles of CYP2D6 and stereoselectivity in the clinical pharmacokinetics of chlorpheniramine.

AIMS: To examine the stereoselective disposition of chlorpheniramine and to evaluate the role of CYP2D6 in chlorpheniramine pharmacokinetics in humans. METHODS: Eight healthy volunteers (six extensive metabolizers with respect to CYP2D6 and two poor metabolizers) received a single 8 mg oral dose of rac-chlorpheniramine either given alone or following administration of quinidine 50 mg every 6 h for 2 days prior to the study day and every 6 h thereafter until the end of the study. Plasma concentrations of (S)-(+)- and (R)-(-)-enantiomers of chlorpheniramine were determined using liquid chromatography/mass spectrometry. RESULTS: In extensive metabolizers, mean Cmax was greater (12.55+/-1.51 ng ml-1vs 5.38+/-0.44 ng ml-1) and CLoral was lower (0.49+/-0.08 l h-1 kg-1vs 1.07+/-0.15 l h-1 kg-1) for (S)-(+)- than for (R)-(-)-chlorpheniramine (P<0.005). For (S)-(+)-chlorpheniramine, administration of quinidine, an inhibitor of CYP2D6, resulted in an increase in Cmax to 13.94+/-1.51 (P<0.01), a reduction in CLoral to 0.22+/-0.03 l h-1 kg-1 (P<0.01), and a prolongation of elimination half-life from 18.0+/-2.0 h to 29.3+/-2.0 h (P<0.001). Administration of quinidine decreased CLoral for (R)-(-)-chlorpheniramine to 0.60+/-0.10 l h-1 kg-1 (P<0.005). In CYP2D6 poor metabolizers, systemic exposure was greater after chlorpheniramine alone than in extensive metabolizers, and administration of quinidine resulted in a slight increase in CLoral. CONCLUSIONS: Stereoselective elimination of chlorpheniramine occurs in humans, with the most pharmacologically active (S)-(+)-enantiomer cleared more slowly than the (R)-(-)-enantiomer. CYP2D6 plays a role in the metabolism of chlorpheniramine in humans.