Physicochemical stability and compatibility testing of levetiracetam in all-in-one parenteral nutrition admixtures in daily practice.

BACKGROUND: Parenteral antiepileptic drugs are frequently used in critically ill patients for seizure control therapy or prevention. Many of these patients require additional parenteral nutrition (PN). Therefore, a parallel infusion of the frequently used antiepileptic drug levetiracetam (LEV) is interesting in terms of the restricted i.v. lines (e.g., neonates). The potential interactions of the complex PN admixture with the drug product and the appropriate admixing of a drug at effective dosages require physicochemical lab assessments to obtain specific and reliable pharmaceutical documentation for the intended admixing. AIM: To assess the of compatibility and stability of LEV, a neutral and hydrophilic drug, in commercial all-in-one (AiO) PN admixtures using simple validated tests to provide necessary data in a timely manner and to allow convenient, documented and safe treatment with PN as the drug vehicle. METHODS: Different concentrations of LEV were injected into two different AiO PN admixtures with no further additives. Stability and compatibility tests for the drug and the PN admixtures were performed over seven days at +4°C, +23±1°C and +37°C without light protection. Stability and sample characteristics were observed by visual inspection and the validated light microscope method. Moreover, the pH level of the admixture was checked, as were the concentrations of LEV over time in the PN admixtures, using an established LC-MS/MS method. RESULTS: The stability controls of LEV at different temperatures were within absolute ±20% of the theoretical value in a concentration range of 98.91-117.84% of the initial value. No changes in pH occurred (5.55±0.04) and no microscopic out of specification data or visual changes were observed. The mean value of the largest lipid droplet in each visual field over seven days was 2.4±0.08µm, comparable to that of the drug-free AiO admixture. Samples stored at +37°C showed yellowish discolorations after 96h of storage. CONCLUSION: LEV showed compatibility and stability over seven days in the selected PN admixtures, and the described methods represented a valuable and timely approach to determine the stability and compatibility of the highly hydrophilic, not dissociated LEV in AiO admixtures under conditions of use. Further studies with clinically relevant and representative examples of physicochemically different drug classes are needed.

Identification of cytochrome P450 forms involved in the 4-hydroxylation of valsartan, a potent and specific angiotensin II receptor antagonist, in human liver microsomes.

Valsartan is known to be excreted largely as unchanged compound and is minimally metabolized in man. Although the only notable metabolite is 4-hydroxyvaleryl metabolite (4-OH valsartan), the responsible enzyme has not been clarified at present. The current in vitro studies were conducted to identify the cytochrome P450 (CYP) enzymes involved in the formation of 4-OH valsartan. Valsartan was metabolized to 4-OH valsartan by human liver microsomes and the Eadie-Hofstee plots were linear. The apparent Km and Vmax values for the formation of 4-OH valsartan were 41.9-55.8 microM and 27.2-216.9 pmol min(-1) mg(-1) protein, respectively. There was good correlation between the formation rates of 4-OH valsartan and diclofenac 4'-hydroxylase activities (representative CYP2C9 activity) of 11 individual microsomes (r = 0.889). No good correlation was observed between any of the other CYP enzyme marker activities (CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4 and CYP4A). Among the recombinant CYP enzymes examined (CYPs 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4, 3A5 and 4A11), CYP2C9 notably catalysed 4-hydroxylation of valsartan. For the specific CYP inhibitors or substrates examined (furafylline, diclofenac, S(+)-mephenytoin, quinidine and troleandomycin), only diclofenac inhibited the formation of 4-OH valsartan. These results showed that CYP2C9 is the only form responsible for 4-hydroxylation of valsartan in human liver microsomes. Although CYP2C9 is involved in valsartan metabolism, CYP-mediated drug-drug interaction between valsartan and other co-administered drugs would be negligible.

In vivo burn depth determination by high-speed fiber-based polarization sensitive optical coherence tomography.

We report the first application of high-speed fiber-based polarization sensitive optical coherence tomography (PS-OCT) to image burned tissue in vivo. Thermal injury denatures collagen in skin and PS-OCT can measure the reduction in collagen birefringence using depth resolved changes in the polarization state of light propagated in, and reflected from, the tissue. Stokes vectors were calculated for each point in a scan and birefringence relative to incident polarization determined using four incident polarization states. Using a high-speed fiber-based PS-OCT system on rat skin burned for varying periods of time, a correlation between birefringence and actual burn depth determined by histological analysis was established. In conclusion, PS-OCT has potential use for noninvasive assessment of burn depth.

[Marginal fit of dental restorations and the periodontium in Swiss army recruits]. / Restaurationsrandschlusse und Parodont bei Schweizer Rekruten.

The present study analyzed the relationship between periodontal health adjacent to filled and unfilled tooth sites in young men (recruits). The status of oral health of 419 Swiss army recruits, aged 19 to 20 years was assessed by determining Plaque Index (PI), Retention Index (RI) and Gingival Index (GI) as well as Pocket Probing Depth (PPD) and Probing Attachment Loss (PAL). In addition, the level of alveolar bone was measured using digitized bite-wing radiographs with an enlargement of 4.5x. Filling margins were assessed and the distance between the alveolar bone crest and the cemento-enamel junction (CEJ) measured to the nearest one tenth of a millimeter. These data were compared with the clinical parameters. A total of 8'050 sites were examined. 765 or 9.5 of the sites in the posterior area were filled. 119 of them showed filling overhangs larger than 0.2 mm. Thus, 1.5 % of the examined sites had a significant overhanging margin. All clinical parameters had greater values at filled than at unfilled sites. The differences were statistically not significant. Even the sites with margins overhanging more than 0.8 mm (n=14) did not show significantly different parameters compared to unfilled sites. The comparison with a similar study involving recruits 11 years earlier assessed that the recruits of 1996 had less and smaller filling overhangs. This, in turn, means that, in Switzerland restorative dentistry in young males has been markedly improved during the 1980's and 1990's.

Determination of fluvastatin and its five metabolites in human plasma using simple gradient reversed-phase high-performance liquid chromatography with ultraviolet detection.

A simple gradient reversed-phase high-performance chromatographic method with ultraviolet detection for the determination of fluvastatin (FV) and its five metabolites, (M-2, M-3, M4, M-5 and M-7) in human plasma was developed and validated. The limit of quantification of FV and its five metabolites in human plasma was 10 ng ml(-1). The assay had satisfactory selectivity, recovery, linearity and precision accuracy. Stability studies showed that FV and its five metabolites were stable in plasma up to at least 1 month of storage at -30 degrees C.

Stable carrier generation and phase-resolved digital data processing in optical coherence tomography.

We present a technique for improved carrier generation by eliminating the instability of a mechanical device in favor of an electro-optical phase modulator in the reference arm of an optical coherence tomography system. A greater than threefold reduction in the phase variance between consecutive A-line scans at a repetition rate of 1 kHz was achieved. Stable and reproducible interference fringe generation permits phase-resolved digital data processing. A correction algorithm was applied to the interferometric signal to compensate for the departure of the source spectrum from an ideal Gaussian shape, resulting in up to 8-dB sidelobe suppression at the expense of a 1-dB increase in the noise floor. In addition, we could eliminate completely the broadening effect of group-delay dispersion on the coherence function by introducing a quadratic phase shift in the Fourier domain of the interferometric signal.

Phase-resolved optical coherence tomography and optical Doppler tomography for imaging blood flow in human skin with fast scanning speed and high velocity sensitivity.

We have developed a novel phase-resolved optical coherence tomography (OCT) and optical Doppler tomography (ODT) system that uses phase information derived from a Hilbert transformation to image blood flow in human skin with fast scanning speed and high velocity sensitivity. Using the phase change between sequential scans to construct flow-velocity imaging, this technique decouples spatial resolution and velocity sensitivity in flow images and increases imaging speed by more than 2 orders of magnitude without compromising spatial resolution or velocity sensitivity. The minimum flow velocity that can be detected with an axial-line scanning speed of 400 Hz and an average phase change over eight sequential scans is as low as 10 microm/s, while a spatial resolution of 10 microm is maintained. Using this technique, we present what are to our knowledge the first phase-resolved OCT/ODT images of blood flow in human skin.

High-speed fiber based polarization-sensitive optical coherence tomography of in vivo human skin.

A high-speed single-mode fiber-based polarization-sensitive optical coherence tomography (PS OCT) system was developed. With a polarization modulator, Stokes parameters of reflected flight for four input polarization states are measured as a function of depth. A phase modulator in the reference arm of a Michelson interferometer permits independent control of the axial scan rate and carrier frequency. In vivo PS OCT images of human skin are presented, showing subsurface structures that are not discernible in conventional OCT images. A phase retardation image in tissue is calculated based on the reflected Stokes parameters of the four input polarization states.

Doppler standard deviation imaging for clinical monitoring of in vivo human skin blood flow.

We used a novel phase-resolved optical Doppler tomographic (ODT) technique with very high flow-velocity sensitivity (10microm/s) and high spatial resolution (10microm) to image blood flow in port-wine stain (PWS) birthmarks in human skin. In addition to the regular ODT velocity and structural images, we use the variance of blood flow velocity to map the PWS vessels. Our device combines ODT and therapeutic systems such that PWS blood flow can be monitored in situ before and after laser treatment. To the authors' knowledge this is the first clinical application of ODT to provide a fast semiquantitative evaluation of the efficacy of PWS laser therapy in situ and in real time.

Effects of axial and radial gradients on Cooke triplets.

This study investigates the role of gradient-index materials in the design of Cooke triplets for use as 35-mm format photographic objectives. Cooke triplet designs are presented with different types of gradient-index profiles. Both linear axial and shallow radial gradients are shown to provide effective control of spherical aberration and astigmatism. In particular, a Cooke triplet with a combination of both linear axial and radial gradients attains performance comparable to a six-element double Gauss lens. In virtually all cases, the use of gradient-index components improves the Cooke triplets' performance significantly.