Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for CYP3A5 Genotype and Tacrolimus Dosing.

Tacrolimus is the mainstay immunosuppressant drug used after solid organ and hematopoietic stem cell transplantation. Individuals who express CYP3A5 (extensive and intermediate metabolizers) generally have decreased dose-adjusted trough concentrations of tacrolimus as compared with those who are CYP3A5 nonexpressers (poor metabolizers), possibly delaying achievement of target blood concentrations. We summarize evidence from the published literature supporting this association and provide dosing recommendations for tacrolimus based on CYP3A5 genotype when known (updates at www.pharmgkb.org).

Cystatin C is associated with inflammation but not atherosclerosis in systemic lupus erythematosus.

BACKGROUND: Even mild renal impairment is associated with increased atherosclerosis and cardiovascular mortality. Cystatin C, a novel measure of renal function, is more sensitive than conventional creatinine-based measures for the detection of subtle renal impairment. Increased cystatin concentrations are also associated with cardiovascular risk, independently of conventional measures of renal function. This study examined the hypothesis that cystatin C is elevated in systemic lupus erythematosus (SLE) and is associated with coronary atherosclerosis. METHODS: Serum cystatin C, creatinine, tumor necrosis factor (TNF)-α, interleukin (IL)-6, coronary artery calcium score (CACS), Framingham risk score (FRS), Modified Diet in Renal Disease estimated glomerular filtration rate (MDRD-eGFR), and other clinical parameters were measured in 118 patients with SLE and 83 control subjects. The independent association between concentrations of cystatin C and SLE was evaluated using multivariable linear regression models, and the relationship between renal measures and coronary calcium was assessed with multivariable proportional odds logistic regression models. RESULTS: Cystatin C, but not other measures of renal function, was significantly higher in patients with SLE than in controls (1.09 [interquartile range, IQR: 0.85-1.28] mg/l vs. 0.89 [IQR: 0.76-0.99] mg/l; p < 0.001 after adjustment for age, race, sex and MDRD-eGFR). Cystatin C was significantly associated with SLICC (p = 0.04), erythrocyte sedimentation rate (ESR) (p = 0.02), TNF-α (p = 0.008) and IL-6 (p = 0.01) after adjustment for age, race, and sex. Cystatin C was not significantly correlated with coronary calcium score in SLE (rho=0.096, p = 0.31) and the association remained non-significant after adjustment for age, race, sex, and Framingham risk score (p = 0.99). CONCLUSIONS: Cystatin C was higher in patients with SLE than in control subjects even after adjustment for conventional measures of renal function. Cystatin C was significantly correlated with several markers of inflammation in SLE but was not associated with coronary atherosclerosis. Subtle renal dysfunction does not appear to be directly associated with accelerated atherosclerosis in SLE.

Clinical Pharmacogenetics Implementation Consortium guidelines for thiopurine methyltransferase genotype and thiopurine dosing.

Thiopurine methyltransferase (TPMT) activity exhibits monogenic co-dominant inheritance, with ethnic differences in the frequency of occurrence of variant alleles. With conventional thiopurine doses, homozygous TPMT-deficient patients (~1 in 178 to 1 in 3,736 individuals with two nonfunctional TPMT alleles) experience severe myelosuppression, 30-60% of individuals who are heterozygotes (~3-14% of the population) show moderate toxicity, and homozygous wild-type individuals (~86-97% of the population) show lower active thioguanine nucleolides and less myelosuppression. We provide dosing recommendations (updates at http://www.pharmgkb.org) for azathioprine, mercaptopurine (MP), and thioguanine based on TPMT genotype.

Cardiovascular risk scores and the presence of subclinical coronary artery atherosclerosis in women with systemic lupus erythematosus.

The Framingham risk score is widely used to identify patients at increased cardiovascular risk, and women with systemic lupus erythematosus (SLE) have a marked increased prevalence of cardiovascular events. Thus, we examined the hypothesis that cardiovascular risk scores would identify women with SLE who had asymptomatic coronary atherosclerosis. Ninety-three women with SLE and 65 control subjects were studied. The Framingham score and a score for younger populations developed from the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) study were compared in both groups. Coronary atherosclerosis was ascertained by electron beam computed tomography. There were no significant differences in the median (interquartile range) Framingham [5 (2-10) compared to 7 (0-10), P = 0.88] and PDAY [15 (14-18) compared to 16 (13-18), P = 0.99] scores in patients with SLE and controls, respectively. Coronary atherosclerosis was associated with higher Framingham [12 (3-15) compared to 4 (1-8), P = 0.008] and PDAY [17 (15-19 compared to 15 (12-18), P = 0.03)] scores in patients with SLE; however, 99% of patients were classified as low-risk with a 10-year predicted risk of 1% (<1-3%). Our data indicate that cardiovascular risk scores are not adequate for risk stratification in women with SLE. Measurement of coronary calcification may add information to identify asymptomatic women with lupus who might benefit from aggressive preventive measures.

Coadministration of glyburide and minoxidil, drugs with opposing effects on potassium channels.

INTRODUCTION: Adenosine triphosphate (ATP)-sensitive potassium (K+) channels are modulated by drugs, so that they are opened by vasodilators such as minoxidil but are closed by hypoglycemic agents such as glyburide (glibenclamide). Animal studies and in vitro evidence suggests that the coadministration of drugs with opposing effects on K+ channels attenuates their pharmacodynamic effects. METHODS: To investigate whether this important pharmacodynamic interaction occurs in humans, we administered 5 mg minoxidil, 2.5 mg glyburide or both in a double-blind fashion to nine healthy subjects. Glucose and insulin responses during an intravenous glucose tolerance test (0.3 gm/kg) were measured and blood pressure was recorded for 8 hours. In an additional four subjects the effect of 5 mg glyburide on the hypotensive effect of 5 mg minoxidil was examined. RESULTS: None of the parameters of glucose metabolism differed significantly when subjects received glyburide alone, minoxidil alone, or glyburide with minoxidil. Minoxidil or minoxidil in combination with 2.5 mg glyburide resulted in a similar significant decrease in blood pressure compared with the response to glyburide alone. The hypotensive effect of minoxidil was smaller in the four subjects who received the higher dose of glyburide, but significant hypoglycemia (blood glucose concentration < 60 mg/dl) occurred in three of the four subjects. CONCLUSION: We conclude that, in healthy volunteers, the coadministration of 2.5 mg glyburide and 5 mg minoxidil does not result in attenuation of the blood pressure-lowering effect of minoxidil. The smaller hypotensive response in four subjects who received 5 mg glyburide and 5 mg minoxidil suggests the possibility of a dose-related drug interaction. Studies with strict clamping of blood glucose concentrations will be required to address this possibility.

Immunodeficient states and associated rheumatic manifestations.

The molecular mechanisms of the primary immunodeficiencies have been further explored and provide insights into the regulation of the immune response and its role in autoimmune disease, infection, and malignancy. The critical role of CD40-CD40 ligand-mediated effects in T cell-dependent B cell activation, shown through the study of patients with common variable immunodeficiency and hyper IgM syndrome, suggests a potential narrow target for immunomodulatory therapy. A mouse model for chronic granulomatous disease has been developed and promises to be a source of future information. Optimal cost-effective therapy for primary immunodeficiencies continues to be defined, with the results of a large series of patients treated with subcutaneous immunoglobulin infusions reported. Further experience with polyethylene glycol adenosine deaminase and interleukin-2 conjugates is discussed.

Value of the history and stool occult blood test in selection of patients for upper endoscopy in Zimbabwe.

Patients with abdominal pain and no definite diagnosis referred for endoscopy were studied to define discriminating features in the history, and the value of a stool occult blood test, in predicting the presence of upper gastrointestinal disease. Endoscopy was performed in 116 patients; pathology was seen in 32 (duodenal ulcer 17, gastric carcinoma 4, gastric ulcer 3, miscellaneous 8) and no pathology was seen in 84 patients. Features that predicted upper gastrointestinal pathology were, in descending order of rank: a positive pointing sign, a positive stool Fecult test, a history of vomiting, loss of weight, and alcohol intake. Using these discriminating features together it was possible to correctly predict 95% of patients with abnormal endoscopy and 82% of patients with a normal endoscopy. The history and the stool occult blood test are useful predictors of the presence of upper gastrointestinal pathology and may aid rational selection of patients for endoscopy.

Extreme elevation of the erythrocyte sedimentation rate in patients admitted to a general medical ward in Harare, Zimbabwe.

A prospective, 1-year study was performed to determine the causes of an ESR greater than or equal to 100 in patients admitted to a general medical ward in Harare, Zimbabwe. An ESR greater than or equal to 100 was found in 101 (12%) patients. Infection (46 patients) was the commonest cause, followed by malignancy (25), connective tissue disease (17), renal disease (8) and liver disease (5). The frequency of an ESR greater than or equal to 100 in these diagnostic groups was infection (28%), malignancy (44%), connective tissue disease (71%), renal disease (30%) and liver disease (24%). Pneumonia was the commonest infection diagnosed and the commonest cause of a markedly elevated ESR. Although myeloma was only the second commonest malignancy diagnosed it was the commonest malignancy causing an ESR greater than or equal to 100. In the largest group, infection, there was a significantly increased mortality in patients with an ESR greater than or equal to 100.

Systemic lupus erythematosus in Zimbabwe.

Systemic lupus erythematosus (SLE) was diagnosed in 31 black Zimbabweans over a six year period. Renal involvement (71%) was more common and photosensitivity (16%) and serositis (23%) less common than in the United States. Lymphopenia (48%) was the commonest haematological abnormality. Unusual complications included subarachnoid haemorrhage, cardiac rhythm disturbance, portal and superior mesenteric vein thrombosis, and a non-Hodgkin lymphoma. Tuberculosis was a common differential diagnosis that was difficult to exclude. Nine patients (29%) died within one year of diagnosis. SLE is being recognised more commonly in Zimbabwe.

Allopurinol hypersensitivity. A case report.

The allopurinol hypersensitivity syndrome is a rare adverse drug reaction. It usually occurs in patients with impaired renal function or when allopurinol is prescribed with a thiazide diuretic. The recognition of the characteristic features of the syndrome is vital since early aggressive therapy is indicated. A case of allopurinol hypersensitivity, possibly the first in a black African, is reported.

Achalasia in Zimbabwean blacks.

The incidence and clinical features of achalasia in Zimbabwe have not previously been documented. During a 10-year period (1974-1983) 25 cases were seen in Bulawayo and Harare. The estimated incidence is 0,03/100 000 members of the population per year, which is much less than the incidence in Europe and America. Achalasia occurred at any age and there was a preponderance of cases in males. Dysphagia was invariable and its duration varied from 2 weeks to 15 years. Parotid enlargement was found in 2 patients and respiratory infections occurred relatively frequently. The importance of excluding oesophageal carcinoma is emphasized.

Pancreatic calcification not due to alcohol consumption. A case report.

An 18-year-old woman presented with diabetes, pancreatic calcification and evidence of malabsorption. The features of calcific pancreatitis unrelated to alcohol consumption are discussed.