A Novel Method to Optimize Drug Delivery for Parenteral Products Involving New Therapies and Unmet Needs.

Healthcare trends continue to move from hospital to home and many targeted therapies and precision medicines are now being designed to be self-administered by patients or delivered in a home setting. In the case of long acting injectables and bio-therapeutics, the importance of optimal drug/biologic-device combination in terms of user needs becomes critical for successful clinical outcomes. The risk especially increases for novel therapies due to unknowns and uncertainties surrounding new formulation flow behavior, delivery methods, new injection sites and therapeutic optimization. Other risk factors include patient tolerability and acceptability. The success of the clinical outcome is now dependent on the optimal delivery in these situations for a consistent pharmacokinetics (PK) response. In addition, the complexity of formulations and challenging delivery needs have brought to light some of the limitations of existing legacy device technology, which may not be suited for these novel applications. The formulation itself may not be an exact fit to deliver with existing standard device technologies and may need to be designed to deliver the specific formulation appropriately. Formulations may have to be optimized both for delivery and for the therapeutic outcome creating many iterative development cycles. Rapid development of the therapies requires simultaneous development of drug and device and thus the importance of early-stage characterization. We present a novel integrated approach that includes drug delivery optimization via an autoinjector simulator in pre-clinical and clinical studies to assess the PK performance and potential to establish path to device early on and reduce time to the clinic.

Exploring predictors of first appointment attendance at a pain management service.

BACKGROUND: Individual characteristics such as gender, employment and age have been shown to predict attendance at pain management services (PMS). The characteristics of those who drop out of pain management programmes have also been explored, but as yet no studies have analysed the characteristics of those who do not attend the service following referral. PURPOSE: To explore the characteristics and predictors of those who attend and those who do not attend their first appointment with a PMS. METHOD: Predictive factors in the two groups - attenders (n = 425) and non-attenders (n = 69) - were explored using logistic regression. RESULTS: Non-attendance was significantly predicted by the patient being a smoker and the appointment being in the morning. Non-attenders also scored higher on the Modified Somatic Perception Questionnaire, indicating higher levels of somatic pain. DISCUSSION: Predictors of non-attendance were different from those for individuals who drop out of pain services. Implications and recommendations are made for PMS.

Vulnerable atherosclerotic plaque detection by resonance Raman spectroscopy.

A clear correlation has been observed between the resonance Raman (RR) spectra of plaques in the aortic tunica intimal wall of a human corpse and three states of plaque evolution: fibrolipid plaques, calcified and ossified plaques, and vulnerable atherosclerotic plaques (VPs). These three states of atherosclerotic plaque lesions demonstrated unique RR molecular fingerprints from key molecules, rendering their spectra unique with respect to one another. The vibrational modes of lipids, cholesterol, carotenoids, tryptophan and heme proteins, the amide I, II, III bands, and methyl/methylene groups from the intrinsic atherosclerotic VPs in tissues were studied. The salient outcome of the investigation was demonstrating the correlation between RR measurements of VPs and the thickness measurements of fibrous caps on VPs using standard histopathology methods, an important metric in evaluating the stability of a VP. The RR results show that VPs undergo a structural change when their caps thin to 66 ?? ? m , very close to the 65 - ? m empirical medical definition of a thin cap fibroatheroma plaque, the most unstable type of VP.

Zirconia phase transformation, metal transfer, and surface roughness in retrieved ceramic composite femoral heads in total hip arthroplasty.

Ceramic femoral heads have had promising results as a bearing surface in total hip arthroplasty. Our objective was to evaluate a series of retrieved alumina-zirconia composite ceramic femoral heads for evidence of the tetragonal to monoclinic zirconia phase transformation, metal transfer and articular surface roughness. Raman spectra showed evidence of the zirconia phase transformation in all retrieved specimens, with distinct monoclinic peaks at 183, 335, 383, and 479 cm(-1). All components displayed metal transfer. An increase in the zirconia phase transformation was seen with increasing time in vivo. No correlation between extent of zirconia phase transformation and the surface roughness was found. These short-term results suggest that the use of an alumina-zirconia composite ceramic is a viable option for femoral heads in THA.

The prion dilemma confounding science educators.

In this paper, the issue of the prion hypothesis, a simmering controversy within the scientific community, is addressed. We inquire into the appropriateness of the use of certain augmentations and rhetoric approaches used during scientific debates, as well as the aptness of unequivocal statements in textbooks that indicate "abnormal prions" as a primary cause of Transmissible Spongiform Encephalopathies.

Human brain cancer studied by resonance Raman spectroscopy.

The resonance Raman (RR) spectra of six types of human brain tissues are examined using a confocal micro-Raman system with 532-nm excitation in vitro. Forty-three RR spectra from seven subjects are investigated. The spectral peaks from malignant meningioma, stage III (cancer), benign meningioma (benign), normal meningeal tissues (normal), glioblastoma multiforme grade IV (cancer), acoustic neuroma (benign), and pituitary adenoma (benign) are analyzed. Using a 532-nm excitation, the resonance-enhanced peak at 1548 cm-1 (amide II) is observed in all of the tissue specimens, but is not observed in the spectra collected using the nonresonance Raman system. An increase in the intensity ratio of 1587 to 1605 cm-1 is observed in the RR spectra collected from meningeal cancer tissue as compared with the spectra collected from the benign and normal meningeal tissue. The peak around 1732 cm-1 attributed to fatty acids (lipids) are diminished in the spectra collected from the meningeal cancer tumors as compared with the spectra from normal and benign tissues. The characteristic band of spectral peaks observed between 2800 and 3100 cm-1 are attributed to the vibrations of methyl (─CH3) and methylene (─CH2─) groups. The ratio of the intensities of the spectral peaks of 2935 to 2880 cm-1 from the meningeal cancer tissues is found to be lower in comparison with that of the spectral peaks from normal, and benign tissues, which may be used as a distinct marker for distinguishing cancerous tissues from normal meningeal tissues. The statistical methods of principal component analysis and the support vector machine are used to analyze the RR spectral data collected from meningeal tissues, yielding a diagnostic sensitivity of 90.9% and specificity of 100% when two principal components are used.

Depression in chronic pain patients: prevalence and measurement.

This study aimed to: (1) determine prevalence of depression in patients referred to specialist pain services using the Structured Clinical Interview (SCID) diagnostic interview, (2) compare results on the Beck Depression Inventory II (BDI-II) with the SCID to determine the utility of the BDI-II as a screening tool in this population. Thirty-six participants were recruited, mainly women, with a mean age = 47.83 years (standard deviation = 12.85 years), who were heterogeneous with regard to their pain. All completed the BDI-II and SCID. The SCID diagnosed 26 (72%) cases of depression. BDI-II scores showed 31 (86%) that reported at least mild depression. Agreement between BDI-II scores over threshold for mild depression and SCID diagnosis were assessed by Cohen's kappa (= 0.6). ROC analysis for BDI-II scores against SCID diagnosis gave a large area under the curve (0.97, 95% confidence interval 0.93 to 1.02), suggesting BDI-II is an excellent screen for this population, although the curve was unusual in that sensitivity was high even when the false positive rate was zero. ROC analysis suggested 22 or above as an optimum cut-off score for depression on the BDI-II-higher than for a general population sample. It has been suggested that the BDI overestimates incidence of depression in pain patients, but this study confirmed through diagnostic interview the very high incidence of depression in this population. It is therefore questionable whether there is value in screening referrals for depression. When using BDI-II for screening, audit or evaluation purposes with a pain clinic population, we suggest a cut-off of 22 or above.

Cell-cycle-dependent variations in FTIR micro-spectra of single proliferating HeLa cells: principal component and artificial neural network analysis.

We have previously reported spectral differences for cells at different stages of the eukaryotic cell division cycle. These differences are due to the drastic biochemical and morphological changes that occur as a consequence of cell proliferation. We correlate these changes in FTIR absorption and Raman spectra of individual cells with their biochemical age (or phase in the cell cycle), determined by immunohistochemical staining to detect the appearance (and subsequent disappearance) of cell-cycle-specific cyclins, and/or the occurrence of DNA synthesis. Once spectra were correlated with their cells' staining patterns, we used methods of multivariate statistics to analyze the changes in cellular spectra as a function of cell cycle phase.

Raman and infrared microspectral imaging of mitotic cells.

We report the first ever Raman and infrared microspectroscopic images of human cells at different stages of mitosis. These spectroscopic methods monitor the distribution of condensed nuclear chromatin, and other biochemical components, utilizing inherent protein and DNA spectral markers, and, therefore, do not require the use of any stains. In conjunction with previously reported data from the G1, S, and G2 phases of the cell cycle, the complete cell division cycle has now been mapped by spectroscopic methods. Although the results reported here do not offer new insights into the distribution of biochemical components during mitosis, the recognition of cell division without the use of stains, and the possibility of doing so on living cells, may be useful for an automatic, spectroscopic determination of the proliferation rates of cells and tissues. Spectral images were constructed by plotting spectral intensities of DNA or protein versus the coordinates from which spectra were recorded. We found that both Raman and infrared intensities depend on the overall chromatin density variation among the individual subphases of mitosis.