Glycogenic hepatopathy is an under-recognised cause of hepatomegaly and elevated liver transaminases in type 1 diabetes mellitus.

Glycogenic hepatopathy (GH) is an under-recognised complication of type 1 diabetes mellitus (T1DM) not controlled to target resulting in hepatomegaly and elevated liver transaminases. We report the case of a 19-year-old man with T1DM not controlled to target who presented with abdominal pain, hepatomegaly and deranged liver transaminases. He was subsequently diagnosed with GH on liver biopsy, with the mainstay of treatment being reduction in caloric intake and insulin.

Non-adherence to statin therapy: a major challenge for preventive cardiology.

BACKGROUND: Hypercholesterolemia is a major risk factor for atherosclerosis and cardiovascular disease, the leading cause of death worldwide. In the last twenty years, effective lipid-lowering therapies, particularly statins, have become widely available to prevent and reverse the progression of disease. However, there is a significant gap between expected and actual benefits; this may be attributed to poor adherence to statin therapy. OBJECTIVE: To define the extent, causes (including psychological aspects), consequences and management of non-adherence to statins. METHODS: Literature using PubMed and Medline up to and including 30 July 2009. RESULTS: Adherence to statin therapy is suboptimal in both primary and secondary prevention of cardiovascular disease. Causes vary, and include patient factors (e.g., comorbidities, financial constraints, psychological issues), practitioner factors (e.g., poor knowledge of adherence, time constraints, poor communication skills and patient-doctor working alliance) and system factors (e.g., medication costs, lack of clinical monitoring, drug side effects). Non-adherence is associated with adverse health outcomes and increased costs of healthcare. A framework, based on a multidisciplinary approach, for addressing non-adherence, including managing the statin-intolerant patient, is presented. CONCLUSIONS: Non-adherence to statins is a significant issue for the prevention and treatment of cardiovascular disease. Increased awareness of the causes and solutions for overcoming non-adherence, including safer prescribing, improvement in physician-patient alliance and reduction in drug costs, will enhance the cost-effectiveness of the use of statins and significantly improve patient care and outcomes.

Plant growth and phosphorus accumulation of wild type and two root hair mutants of Arabidopsis thaliana (Brassicaceae).

Arabidopsis thaliana root hairs grow longer and denser in response to low-phosphorus availability. We tested the hypothesis that wild-type Arabidopsis would acquire more phosphorus under phosphorus-limiting conditions than mutants that do not have the root hair response. The growth and phosphorus acquisition of wild-type Arabidopsis (WS) were compared to two root hair mutants (rhd6 and rhd2) under eight phosphorus treatments ranging from 0.4 mmol/m to 54 mmol/m phosphorus. At the lowest phosphorus treatment, all plants were small and showed severe phosphorus stress symptoms. At 1.5 mmol/m phosphorus, WS plants had greater shoot biomass, absolute growth rate, total phosphorus, and specific phosphorus absorption than the two root hair mutants. At the highest phosphorus treatment, there was no difference between genotypes in any of the parameters measured. We conclude that the response of increased root hair growth under low phosphorus availability in Arabidopsis is important in increasing phosphorus acquisition under phosphorus-limiting conditions.

The efficiency of Arabidopsis thaliana (Brassicaceae) root hairs in phosphorus acquisition.

Arabidopsis thaliana root hairs grow longer and denser in response to low-phosphorus availability. In addition, plants with the root hair response acquire more phosphorus than mutants that have root hairs that do not respond to phosphorus limiting conditions. The purpose of this experiment was to determine the efficiency of root hairs in phosphorus acquisition at high- and low-phosphorus availability. Root hair growth, root growth, root respiration, plant phosphorus uptake, and plant phosphorus content of 3-wk-old wild-type Arabidopsis (WS) were compared to two root hair mutants (rhd6 and rhd2) under high (54 mmol/m) and low (0.4 mmol/m) phosphorus availability. A cost-benefit analysis was constructed from the measurements to determine root hair efficiency. Under high-phosphorus availability, root hairs did not have an effect on any of the parameters measured. Under low-phosphorus availability, wild-type Arabidopsis had greater total root surface area, shoot biomass, phosphorus per root length, and specific phosphorus uptake. The cost-benefit analysis shows that under low phosphorus, wild-type roots acquire more phosphorus for every unit of carbon respired or unit of phosphorus invested into the roots than the mutants. We conclude that the response of root hairs to low-phosphorus availability is an efficient strategy for phosphorus acquisition.

Effect of miconazole on warfarin disposition in rabbits.

To elucidate the mechanism underlying the reported potentiation of warfarin anticoagulant action after initiation of miconazole therapy, the effects of acute and chronic miconazole administration on warfarin disposition were examined in six adult New Zealand male rabbits. The rabbits received a 3.5 mg/kg iv dose of warfarin either alone, 1 hr after a single 100 mg/kg ip miconazole dose, or on day 5 of a 6-day 50 mg/kg/12 hr ip miconazole dosing regimen. Acute miconazole administration decreased the elimination rate constant of warfarin, but other warfarin disposition parameters were not altered. Chronic miconazole administration caused a 47% increase in warfarin plasma-free fraction (probably caused by competitive or noncompetitive protein binding displacement by miconazole metabolites) and a 42% decrease in warfarin intrinsic clearance (probably caused by a miconazole-induced inhibition in warfarin metabolism). As a consequence of these quantitatively similar but opposite changes, the total body clearance of warfarin (a low clearance drug) was marginally decreased. A significant decrease in the elimination rate constant and an increase in the tissue-free fraction of warfarin were also observed during chronic miconazole treatment. These results suggest that chronic miconazole administration should not significantly affect the steady-state plasma concentrations of total warfarin, but should increase the steady-state plasma concentrations of free warfarin. The expected increases in the steady-state plasma concentrations of free, pharmacologically active warfarin may account for the reported potentiation of the pharmacological action of warfarin when coadministered with chronic miconazole. Measurement of total plasma concentrations, and estimation of total body clearance might be misleading, and inadequate in identifying certain drug interactions involving low clearance drugs.

Existence of a flip-flop kinetic model for zidovudine (AZT) after oral administration.

Using a three-way crossover experimental design, the effects of food and propantheline bromide on the pharmacokinetics of orally administered zidovudine (AZT; 3'-azido-3'-deoxythymidine) were assessed in six adult male Sprague-Dawley rats by the urinary excretion rate method. Accordingly, a single-10 mg/kg oral dose of AZT was administered as an aqueous solution to either fasting (F) rats, nonfasting (NF) rats or fasting rats pretreated with a 5 mg/kg oral dose of propantheline bromide (P; an inhibitor of GI motility). Quantitative urine collections were made at predetermined intervals for 24-32 hr after AZT administration, and each urine specimen was assayed for unmetabolized AZT by a sensitive and specific high-performance liquid chromatographic method. The mean extent of AZT absorption, as reflected by mean total urinary excretion values expressed as % of AZT dose, ranged from 72.9% to 75.2% and was unaffected by study condition. Kinetic interpretation of the terminal linear phase of the urinary excretion rate vs. time data yielded mean (+/- SD) half-lives of 4.35 +/- 2.1 hr for NF and 3.42 +/- 0.86 hr for P, which were significantly greater than the mean 1.58 +/- 0.63 hr half-life observed for F. The reported mean biological half-life of AZT after a 10 mg/kg intravenous dose to the same strain of rats is 0.76 +/- 0.35 hr (n = 6). After intravenous AZT administration, the terminal half-life reflects drug elimination. However, after oral AZT administration, the observed terminal half-lives reflect drug absorption rather than drug elimination (i.e., a flip-flop kinetic model is operable). There is some evidence to suggest that the disappearance of AZT from the blood of orally dosed AIDS patients may also be controlled by drug absorption.

Liquid chromatographic determination of propoxyphene and norpropoxyphene in plasma and breast milk.

A sensitive and specific high-performance liquid chromatographic (HPLC) procedure was developed for determination of propoxyphene and norpropoxyphene in plasma and breast milk. The compounds were isolated from the biological specimen by extraction, the organic phase was evaporated to dryness, and the residue was redissolved in mobile phase [acetonitrile: 0.002 M H2SO4 (1:1)]. The resultant solution was then injected into an HPLC system utilizing a C18 reversed-phase analytical column and a variable-wavelength detector set at 205 nm. Under these conditions the method has a sensitivity of 20 ng/mL using 1 mL of plasma or milk. The within-run coefficient of variation for both compounds varied between 6.2 and 8.9% within the concentration range tested. Applicability of the method was demonstrated in a nursing mother who received multiple oral doses of propoxyphene.

Pharmacokinetics of erythromycin in normal and alcoholic liver disease subjects.

The objective of this study was to compare the pharmacokinetic behavior of erythromycin in normal volunteers with that in subjects with alcoholic liver disease. Six normal volunteers received 500 mg erythromycin as an intravenous infusion or as two 250-mg enteric-coated tablets in a crossover fashion. The pharmacokinetics of erythromycin after intravenous administration was best described as a two-compartment model. The elimination half-life was 1.6 +/- 0.7 hours (mean +/- S.D.) after the intravenous dose and 2.0 +/- 0.7 hours after the oral dose. In patients with alcoholic liver disease the elimination half-life after oral administration of two 250-mg enteric-coated tablets was 3.2 +/- 0.5 hours, significantly different from that in normal subjects, probably due to impaired metabolism. The difference in half-life does not require dosage adjustment in this patient population. The systemic availability of erythromycin was 33.5 per cent (range 10.5 to 79.3 per cent).

Trimethoprim-sulfamethoxazole therapy of experimental Escherichia coli meningitis in rabbits.

We used two strains of ampicillin-susceptible Escherichia coli to produce meningitis in rabbits and utilized these models (i) to compare the killing effects of parenteral trimethoprim-sulfamethoxazole (TMP-SMZ) and ampicillin on E. coli in cerebrospinal fluid after 8 h of treatment and (ii) to measure the penetration of TMP-SMZ and ampicillin into cerebrospinal fluid and the brain. At 16 h after intracisternal inoculation with a test strain, rabbits were treated with TMP (6 mg/kg per h) and SMZ (30 mg/kg per h), ampicillin (40 mg/kg per h), or saline intravenously for 8 h. TMP-SMZ levels were measured by high-pressure liquid chromatography, and ampicillin levels were measured by microbiological assay. Mean +/- standard deviation concentrations of TMP, SMZ, and ampicillin in cerebrospinal fluid (mean percent penetration) at the completion of 8 h of therapy were 0.80 +/- 0.41 (18%), 15.7 +/- 21.1 (27.2%), and 2.6 +/- 1.7 (8.9%) microgram/ml, respectively. TMP, SMZ, and ampicillin levels in brain homogenate after 8 h of therapy were 0.23 +/- 0.07 (6.6%), 3.31 +/- 3.3 (5.5%), and 0.6 +/- 4.53 (1.9%) microgram/g, respectively. TMP-SMZ infusion for 8 h produced a significant reduction in mean bacterial counts in cerebrospinal fluid in both models of meningitis compared with saline controls. The decrease in mean bacterial counts with TMP-SMZ therapy was equivalent to that produced by ampicillin.

Chlorothiazide absorption from solution and tablet dosage forms in dogs.

The bioavailability of an aqueous solution of chlorothiazide and three commercially available chlorothiazide tablets was assessed in adult mongrel dogs. In two crossover urinary excretion studies, six fasting dogs received single 500-mg doses of chlorothiazide as an aqueous solution, one 500-mg originator tablet on two separate occasions (Tablets A-1 and A-2), two 250-mg originator tablets (Tablet B), or one 500-mg generic tablet (Tablet C). 6-Amino-4-chlorobenzene-1,3-disulfonamide )chloraminophenamide), a pharmacologically active hydrolysis product of chlorothiazide was not detected in any urine sample. Urinary recoveries of chlorothiazide after oral administration, expressed as the mean (range) percent of the dose, was only 22.0 (8.41-33.9), 15.7 (10.2-25.0), 20.7 (7.25-31.0), 18.5 (8.72-33.2), and 21.9% (6.69-41.1%) for the aqueous solution and Tablets A-1, A-2, B, and C, respectively. Considerable interindividual variation and some intraindividual variation were observed. No statistically significant difference in bioavailability existed among the aqueous solution and Tablets A-2 and B, between Tablets A-1 and C, and between Tablets A-1 and A-2.

Factors affecting the plasma protein binding of verapamil and norverapamil in man.

The in vitro and vivo binding of the antiarrhythmic agent verapamil and its active metabolite norverapamil to human plasma proteins was determined under different conditions at 37 degrees C by equilibrium dialysis. The binding of verapamil was considerable (free fraction of about 0.10) and was independent of plasma concentration over the range of 50 ng/ml to 1500 ng/ml. Norverapamil was also extensively bound to plasma proteins. Verapamil binding was reduced significantly upon plasma dilution and upon addition of three of its major metabolites (norverapamil and metabolites A and B). Therapeutic concentrations of several drugs including disopyramide (12 micrograms/ml), diazepam (2 micrograms/ml), lidocaine (4 micrograms/ml), propranolol (150 ng/ml), and salicylate (250 microgram/ml) also significantly increased the free fraction of verapamil. The results of in vivo protein binding studies using plasma samples collected during a steady-state dosing interval from a patient receiving 80 mg of verapamil orally every 6 hr were similar to those obtained from vitro binding studies.

Capacity-limited gut wall metabolism of 5-aminosalicylic acid, a therapeutically active metabolite of sulfasalazine, in rats.

The metabolic fate of 5-aminosalicylic acid (reported to be the active therapeutic moiety of sulfasalazine) was assessed in fasting rats as a function of dose (25-200 mg/kg) and administration route (oral, intraperitoneal, and intravenous). 5-Aminosalicylic acid is subject to both capacity-limited presystemic (apparently during first passage through the intestinal epithelium) and systemic acetylation. The possibility exists that 5-aminosalicylic acid also is acetylated presystemically after oral sulfasalazine administration to patients with inflammatory bowel disease. Any alteration in the absorption activity if N-acetyl-5-aminosalicylic acid is inactive or less active than 5-amino-salicylic acid.

Apparent dose-dependent absorption of chlorothiazide in dogs.

The purpose of this study was to determine the effect of oral dose on the absorption of chlorothiazide in the dog. Chlorothiazide was quantitatively excreted in the urine after administration of 50-mg and 250-mg intravenous doses. In contrast, the urinary recovery of chlorothiazide after oral administration showed appreciable interanimal variation and decreased from 70.4% to 26.7% on the average as the oral dose was increased from 125 mg to 750 mg. Oral administration of a single 15-mg dose of propantheline bromide (a potent inhibitor of gastric emptying and intestinal motility) at--1 hr increased the absorption of a 250 mg oral dose of chlorothiazide in three out of four dogs. These results suggest that chlorothiazide absorption is dose dependent and apparently site specific.