Plasmodium vivax malaria requires a 2-week course of primaquine (PQ) for radical cure. Evidence suggests that the hepatic isoenzyme cytochrome P450 2D6 (CYP2D6) is the key enzyme required to convert PQ into its active metabolite.CYP2D6 genotypes and phenotypes of 550 service personnel were determined, and the pharmacokinetics (PK) of a 30-mg oral dose of PQ was measured in 45 volunteers. Blood and urine samples were collected, with PQ and metabolites were measured using ultraperformance liquid chromatography with mass spectrometry.Seventy-six CYP2D6 genotypes were characterized for 530 service personnel. Of the 515 personnel for whom a single phenotype was predicted, 58% had a normal metabolizer (NM) phenotype, 35% had an intermediate metabolizer (IM) phenotype, 5% had a poor metabolizer (PM) phenotype, and 2% had an ultrametabolizer phenotype. The median PQ area under the concentration time curve from 0 to ∞ was lower for the NM phenotype as compared to the IM or PM phenotypes. The novel 5,6-ortho-quinone was detected in urine but not plasma from all personnel with the NM phenotype.The plasma PK profile suggests PQ metabolism is decreased in personnel with the IM or PM phenotypes as compared to those with the NM phenotype. The finding of 5,6-ortho-quinone, the stable surrogate for the unstable 5-hydroxyprimaquine metabolite, almost exclusively in personnel with the NM phenotype, compared with sporadic or no production in those with the IM or PM phenotypes, provides further evidence for the role of CYP2D6 in radical cure.NCT02960568.
ABSTRACT Pharmacogenomics (PGx) plays a fundamental role in personalized medicine, providing an evidence-based treatment approach centered on the relationship between genomic variations and their effect on drug metabolism. Cytochrome P450 (CYP450) enzymes are responsible for the metabolism of most clinically prescribed drugs and a major source of variability in drug pharmacokinetics and pharmacodynamics. To assess the prevalence of PGx testing within the Military Health System (MHS), testing of specific CYP450 enzymes was evaluated. Data were retrospectively obtained from the Military Health System Management Analysis and Reporting Tool (M2) database. Patient demographics were identified for each test, along with TRICARE status, military treatment facility, clinic, and National Provider Identifier. A total of 929 patients received 1,833 PGx tests, predominantly composed of active duty/guard service members (N = 460; 49.5%), with highest testing rates in the army (51.5%). An even distribution in testing was observed among gender, with the highest rates in Caucasians (41.7%). Of the CYP enzymes assessed, CYP2C19 and CYP2D6 accounted for 87.8% of all PGx CYP testing. The majority of patients were tested in psychiatry clinics (N = 496; 53.4%) and primary care clinics (N = 233; 25.1%), accounting for 56.4% and 24.8% of all tests, respectively. Testing was found to be provider driven, suggesting a lack of a standardized approach to PGx and its application in patient care within the MHS. We initially recommend targeted education and revising testing labels to be more uniform and informative. Long-term recommendations include establishing pharmacy-driven protocols and point-of-care PGx testing to optimize patient outcomes.
Abstract Purpose To explore patterns of antimuscarinic medication as a risk factor for type 2 diabetes mellitus (T2DM). Methods This is a retrospective cohort study of females 18 years or older within the Military Health System from 2006 to 2016. Administrative and claims data were used to select patients who initiated therapy with tolterodine, fesoterodine, oxybutynin, darifenacin, solifenacin, or trospium. Patients with no documented history of T2DM were followed for the occurrence of T2DM, the end of the study or loss of eligibility. Rates of T2DM were calculated for the overall population, by duration of therapy and by individual drug s . Crude and adjusted Cox proportional hazards were calculated to assess differences by duration of use and specific muscarinic antagonist. Results Over 2.6 million antimuscarinic prescriptions were dispensed to 241 829 females (mean age/SD, 62 ± 18 years). Patients exposed to M 3 selective antagonists had highest risk of developing T2DM compared to those exposed to nonselective antagonists. Using oxybutynin, a nonselective antagonist as a comparator, adjusted rate ratios of T2DM were 57% (HR 1.57, 95%CI 1.48‐1.67) and 29% (HR 1.29, 95%CI 1.24‐1.35) significantly higher for darifenacin and solifenacin, respectively (both M 3 selective). Conclusions We found exposure to M 3 selective antagonists darifenacin and solifenacin had the highest risk of developing T2DM compared to nonselective antagonist oxybutynin. This is supported by well described physiologic mechanisms and may allow for more informed prescribing decisions, particularly if minimizing risk of T2DM is a priority.
A 32-yr-old woman presented with clinical hypercortisolism, including a 30-lb weight gain, central obesity, oligomenorrhea, hirsutism, and hypertension with hypokalemia. The patient reported easy bruisability, and her surgical history included bilateral breast fibrous adenomas within a myxoid stroma. Labs: K+ 2.9 mmol/liter, 0800-h cortisol 33 μg/dl; 1600-h cortisol 35 μg/dl; and 24-h urine-free cortisol 175 μg. An adrenal computed tomography (CT) revealed bilateral nodularity; a positron emission tomography (PET)-CT demonstrated F18-fluorodeoxyglucose uptake in both adrenals (Fig. 11 and 22).). The patient underwent a two-stage laparoscopic adrenal resection. Pathology revealed primary pigmented nodular adrenocortical disease (PPNAD) (Fig. 33).
Figure 1
F18 fluorodeoxyglucose avid adrenal glands, transverse section, adrenal glands at white arrows. Standardized Uptake Values (SUV):Liver-3.0(range 2.75–3.4), left adrenal-4.45, right adrenal-3.54.
Figure 2
F18 fluorodeoxyglucose avid adrenal glands, coronal section, adrenal glands at white arrows. Standardized Uptake Values (SUV):Liver-3.0(range 2.75–3.4), left adrenal-4.45, right adrenal-3.54.
Figure 3
Left adrenal gland; the white arrows point to pigmented areas of the nodular cells (lipofuscin granules). Magnification 40×.
Carney complex (CNC) is an autosomal dominant multiple neoplasia syndrome associated with hyperfunctioning pituitary, gonads and/or adrenals with hypercortisolism being the most common endocrine finding (1). The diagnosis of Cushing’s syndrome may be elusive: sometimes, abnormal cortisol secretion can only be demonstrated after a dexamethasone-induced stimulation (2), and adrenal CT can be equivocal (3). PET scan of the adrenals has been used to detect cancers, but PET imaging alone may be ambiguous, and the diagnostic capability is increased with PET-CT, allowing for simultaneous anatomical and functional evaluation of adrenal lesions (4).
The presence of breast myxomas, PPNAD, and a PRKAR1A mutation confirmed the diagnosis of CNC in our patient; genetic analysis demonstrated a mutation of the PRKAR1A gene (IVS1–2 A>G), which has been shown before to cause PPNAD and CNC (5). The patient’s only child, a daughter, carries the same PRKAR1A mutation.
This is, to our knowledge, the first report of PET-CT imaging of the adrenal glands in PPNAD. PET-CT imaging may be useful in the evaluation of patients with ACTH-independent hypercortisolism. Apparently, not all F18-fluorodeoxyglucose-avid adrenal glands contain malignancies.
Traumatic brain injury (TBI) causes pituitary dysfunction, mainly featuring GH deficiency. Several mechanisms have been proposed to explain this post-traumatic dyspituitarism, including autoimmunity. We analyzed pituitary antibodies in 100 of US Service Members chosen for a history of TBI and hearing impairment, a concurrence typically seen after blast injuries. Each soldier provided two sera, one before (-1,765 to - 66 days) and one after (10 to 177 days) TBI. All 200 sera were screened by indirect immunofluorescence for binding to a human pituitary gland collected at autopsy. Positive sera were then tested by double indirect immunofluorescence for recognition of cells expressing GH, PRL, ACTH, LH, FSH, TSH, alpha-internexin (INA), vimentin, or glial fibrillary-acidic protein (GFAP). Sera were also tested by ELISA for recognition of native GH or recombinant INA. 63 of 200 sera (31 %) contained pituitary antibodies: of them, 33 (16%) recognized the adenohypophysis, 18 (9 %) the neurohypophysis, and 12 (6%) both lobes. In the adenohypophysis, TSH-secreting cells were the most common target (26 of 45, 58%), followed by INA expressing cells (17 of 45, 37%). In the neurohypophysis, 20 of 30 sera (67 %) recognized INA, 6 (20%) vimentin, and 4 (13%) GFAP-expressing cells. There was no temporal association between pituitary antibodies and TBI: of the sera recognizing TSH-secreting cells, half had antibodies in both the pre- and post-TBI serum (13 of 26, 50%), a quarter (6 of 26, 23%) in the pre-TBI serum, and a quarter (7 of 26, 27%) in the post-TBI serum. Similarly, of the sera recognizing INA-expressing cells, 2 (11.7%) had antibodies in both the pre- and post-TBI serum, 9 (53%) only in the pre-TBI serum, and 6 (35.2%) only in the post-TBI serum. INA antibodies measured by ELISA did not differ between the pre- and post-TBI time points. On the contrary, GH antibodies tended to increase after TBI, although not reaching statistical significance (p= 0.055). The study highlights a preferential recognition of TSH- and INA-expressing cells in TBI patients, which remains to be interpreted in the context of their endocrine dysfunctions. It also suggests that the appearance of GH antibodies after TBI contributes to the GH deficiency typically seen in these patients.
Providing patient-specific clinical care is an expanding focus for medical professionals and researchers, more commonly referred to as personalized or precision medicine. The goal of using a patient-centric approach is to provide safer care while also increasing the probability of therapeutic success through careful consideration of the influence of certain extrinsic and intrinsic human factors in developing the patient care plan. Of increasing influence on patient care is the phenotype and genotype information gathered from employing various next-generation sequencing methods. Guided by and partnered with our civilian colleagues, clinical components within the DoD are embracing and advancing genomic medicine in many facets-from the bench to the bedside-and in many therapeutic areas, from Psychiatry to Oncology. In this PubMed-based review, we describe published clinical research and interventions within the DoD using genome-informed data and emphasize precision medicine efforts in earlier stages of development with the potential to revolutionize the approach to therapeutics.The new PubMed database was searched for articles published between 2015 and 2020 with the following key search terms: precision medicine, genomic, pharmacogenetic, pharmacogenomic, US military, and Department of Defense.Eighty-one articles were retrieved in our initial search. After screening the abstracts for studies that only involved direct testing of (or clinical interaction with) active duty, Reserve, National Guard, or civilian personnel working within the DoD and excluding any epidemiological or microbial isolation studies, seven were included in this review.There are several programs and studies within the DoD, which investigate or use gene-based biomarkers or gene variants to deliver more precise clinical assessment and treatment. These genome-based precision medicine efforts aim to optimize the clinical care of DoD beneficiaries, particularly service members in the operational environment.
Profound hypertriglyceridemia (HTG) is uncommon and often associated with acute pancreatitis. HTG may result from congenital disorders, metabolic diseases, and medications among other causes. The acute management of HTG is not clear, although the combination of insulin and heparin has shown efficacy. Octreotide, a somatostatin analog, has been mildly efficacious in pancreatitis. We present a case of profound HTG and pancreatitis-treated combination of insulin and heparin with octreotide and compare this to previous reports.
