Dipeptidyl peptidase-4 inhibitors and angioedema: a class effect?

BACKGROUND: Dipeptidyl peptidase-4 (DPP-4) inhibitors have been reported to be generally well tolerated. However, angioedema has been reported as one of the rare adverse events of these drugs. CASE REPORT: We report a case in which angioedema induced by vildagliptin disappeared after changing to another DPP-4 inhibitor, alogliptin. DISCUSSION: Our case suggests that there is a difference in the risk of angioedema among DPP-4 inhibitors. To clarify this possibility, further investigation on the risk of angioedema among DPP-4 inhibitors is warranted.

Relationship between fractional pancreatic beta cell area and fasting plasma glucose concentration in monkeys.

AIMS/HYPOTHESIS: We sought to establish the relationship between fasting plasma glucose concentrations and pancreatic fractional beta cell area in adult cynomolgus monkeys (Macaca fascicularis). METHODS: Fasting plasma glucose and pancreatic fractional beta cell area were measured in 18 control and 17 streptozotocin-treated adult primates (17.0 +/- 1.2 vs 15.4 +/- 1.2 years old). RESULTS: Fasting plasma glucose was increased (12.0 +/- 2.0 vs 3.4 +/- 0.1 mmol/l, p < 0.01) and fractional beta cell area was decreased (0.62 +/- 0.13% vs 2.49 +/- 0.35%, p < 0.01) in streptozotocin-treated monkeys. The relationship between fasting plasma glucose and pancreatic fractional beta cell area was described by a wide range of beta cell areas in controls. In streptozotocin-treated monkeys there was an inflection of fasting blood glucose at approximately 50% of the mean beta cell area in controls with a steep increase in blood glucose for each further decrement in beta cell area. CONCLUSIONS/INTERPRETATION: In adult non-human primates a decrement in fractional beta cell area of approximately 50% or more leads to loss of glycaemic control.

Pancreas volumes in humans from birth to age one hundred taking into account sex, obesity, and presence of type-2 diabetes.

Our aims were (1) by computed tomography (CT) to establish a population database for pancreas volume (parenchyma and fat) from birth to age 100 years, (2) in adults, to establish the impact of gender, obesity, and the presence or absence of type-2 diabetes on pancreatic volume (parenchyma and fat), and (3) to confirm the latter histologically from pancreatic tissue obtained at autopsy with a particular emphasis on whether pancreatic fat is increased in type-2 diabetes. We measured pancreas volume in 135 children and 1,886 adults (1,721 nondiabetic and 165 with type-2 diabetes) with no history of pancreas disease who had undergone abdominal CT scan between 2003 and 2006. Pancreas volume was computed from the contour of the pancreas on each CT image. In addition to total pancreas volume, parenchymal volume, fat volume, and fat/parenchyma ratio (F/P ratio) were determined by CT density. We also quantified pancreatic fat in autopsy tissue of 47 adults (24 nondiabetic and 23 with type-2 diabetes). During childhood and adolescence, the volumes of total pancreas, pancreatic parenchyma, and fat increase linearly with age. From age 20-60 years, pancreas volume reaches a plateau (72.4 +/- 25.8 cm(3) total; 44.5 +/- 16.5 cm(3) parenchyma) and then declines thereafter. In adults, total ( approximately 32%), parenchymal ( approximately 13%), and fat ( approximately 68%) volumes increase with obesity. Pancreatic fat content also increases with aging but is not further increased in type-2 diabetes. We provide lifelong population data for total pancreatic, parenchymal, and fat volumes in humans. Although pancreatic fat increases with aging and obesity, it is not increased in type-2 diabetes.

Pneumonitis induced by ou-gon (scullcap).

A 53-year-old Japanese man with recurrent interstitial pneumonia was referred to us. The patient had taken a traditional herb medicine, otsu-ji-to, before the onset of pneumonia. A provocation test for each herbal ingredient contained in otsu-ji-to revealed that the pneumonitis had been induced by ou-gon (scullcap). Lymphocytosis with the CD8+ T-cell subset predominance was found in the bronchoalveolar lavage fluid and lymphocytic alveolitis was noted in the transbronchial lung biopsy specimen after the provocation test. Ou-gon, or scullcap, should be included in the list of drugs with definite causal association with pneumonitis.

Determination of 7alpha-hydroxycholesterol in dog plasma by high-performance liquid chromatography with fluorescence detection.

A new method was developed for the determination of 7alpha-hydroxycholesterol (7-HC) in dog plasma by means of high-performance liquid chromatography (HPLC) with fluorescence detection. 7-HC extracted with organic solvent from plasma was purified with Bond Elut 2OH and converted to a sensitive fluorescent derivative containing double coumarin groups at the C-3 and C-7 positions of the steroid nucleus with 7-methoxycoumarin-3-carbonyl azide. After removal of the excess reagent with Bond Elut NH2, the 7-HC derivative was separated by reverse-phase HPLC method. The detection limit of the authentic 7-HC-3,7-coumarin derivative was 4 pg (S/N = 5), approximately four times less than that of the 7-HC-3-anthroyl derivative yielded by reaction of 7-HC with 1-anthroylcyanide. The newly developed method was used to investigate the effects of consecutive oral administrations of cholestyramine (CA) on 7-HC levels in dog plasma. The plasma 7-HC levels of the CA-treated group were two times greater than those of the control group.

Determination of farnesyl pyrophosphate in dog and human plasma by high-performance liquid chromatography with fluorescence detection.

A nonradioisotopic method has been developed for the determination of all-trans-farnesyl pyrophosphate (FPP), the common intermediate at the branch point of the biosynthesis of cholesterol and nonsterol end products, in dog and human plasma. FPP was cleaved to the parent alcohol, farnesol, by the direct addition of alkaline phosphatase to plasma. Farnesol extracted from plasma was converted into a fluorescent derivative with 9-anthroylcyanide. After the excess reagent was removed using an NH2-bonded phase cartridge, the derivative was separated by a column-switching high-performance liquid chromatographic system, followed by fluorescence detection. A linear response was obtained over the range of 2-18 ng/ml, when FPP was added to dog plasma in which the endogenous FPP concentrations had been lowered to undetectable levels by treatment with an HMG-CoA reductase inhibitor. The endogenous plasma FPP levels in the morning in dog and human detected for the first time by our method were 5.2 and 6.6 ng/ml, respectively. The method was utilized to examine the circadian rhythm of FPP in dog plasma, and different rhythms were observed between feeding and fasting dogs.

A sensitive and selective method for the determination of mevalonic acid in dog plasma by gas chromatography/negative ion chemical ionization-mass spectrometry.

A sensitive and selective method has been developed for the determination of mevalonic acid (MVA), a cholesterol biosynthetic precursor, in dog plasma using solid-phase extraction in combination with gas chromatography/negative ion chemical ionization-mass spectrometry (GC/NICI-MS). MVA extracted from plasma with a phenylboronic acid-bonded phase cartridge was converted to its pentafluorobenzyl (PFB) ester-cyclic boronate derivative to produce a carboxyltate anion [M-PFB]- in the NlCl mode. PFB ester boronate derivatives of MVA and its internal standard, d3-mevalonolactone, were monitored in the selected ion mode at m/z 213 and 216, respectively. The precision and accuracy of within-run and between-run assays were within 8%. This method was used to follow the diurnal variation of MVA levels in plasma of fasted and fed dogs. The diurnal variations of plasma MVA levels observed between the two groups were similar to those reported previously for human and rat plasma.

Studies on steroids. CCLII. Separation and characterization of 3-oxobile acids in serum by high-performance liquid chromatography with fluorescence detection.

The separation of unconjugated and glycine- and taurine-conjugated bile acids with a C-3 oxo group has been carried out by high-performance liquid chromatography on a reversed-phase column. The chromatographic behaviour of these 3-oxobile acids was dependent on the number and positions of hydroxyl groups and the structure of the side-chain. The newly developed method has been applied to the characterization of 3-oxobile acids in biological fluids. The bile acid fraction was obtained from a serum specimen by passing it through a Sep-Pak C18 cartridge. 3-Oxobile acids were derivatized quantitatively to fluorescent oximes through the oxo group by treatment with O-(2-anthrylmethyl)hydroxylamine. The derivatives were separated into the unconjugated and glycine- and taurine-conjugated fractions by ion-exchange chromatography on a lipophilic gel, piperidinohydroxypropyl Sephadex LH-20. Subsequent resolution of each fraction into individual 3-oxobile acids was achieved by chromatography on a Nova-Pak Phenyl column using 3% methanol in 0.3% potassium phosphate buffer (pH 7.0)-acetonitrile (8:5, v/v) as the mobile phase. The derivatized 3-oxobile acids were monitored by fluorescence detection (excitation wavelength 260 nm and emission wavelength 405 nm), the limit of detection being 20 fmol. Glycine- and taurine-conjugated 7 alpha,12 alpha-dihydroxy- and 7 alpha-hydroxy-3-oxo-5 beta-cholanoic acids in human serum were unambiguously idenitified on the basis of their chromatographic behaviour using mobile phases of different pH values.

Continuous monitoring of unbound flomoxef levels in rat blood using microdialysis and its new pharmacokinetic analysis.

Microdialysis sampling method coupled to high-performance liquid chromatography with UV detection was applied to continuous monitoring of in vivo unbound flomoxef concentration in rat blood. By comparison with ultrafiltration method, it was demonstrated that it gave reliable results for the unbound drug monitoring in blood. Furthermore, a new method was presented for the calculation of pharmacokinetic parameters from the data obtained by the microdialysis method.