Biowaiver monographs for immediate release solid oral dosage forms: prednisolone.

Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release (IR) solid oral dosage forms containing prednisolone are reviewed. Data on its solubility, oral absorption, and permeability are not totally conclusive, but strongly suggest a BCS Class 1 classification. Prednisolone's therapeutic indications and therapeutic index, pharmacokinetics, and the possibility of excipient interactions were also taken into consideration. Available evidence indicates that a biowaiver for IR solid oral dosage forms formulated with the excipients tabulated in this article would be unlikely to expose patients to undue risks

Biowaiver monographs for immediate release solid oral dosage forms: acetaminophen (paracetamol).

Literature data are reviewed on the properties of acetaminophen (paracetamol) related to the biopharmaceutics classification system (BCS). According to the current BCS criteria, acetaminophen is BCS Class III compound. Differences in composition seldom, if ever, have an effect on the extent of absorption. However, some studies show differences in rate of absorption between brands and formulations. In particular, sodium bicarbonate, present in some drug products, was reported to give an increase in the rate of absorption, probably caused by an effect on gastric emptying. In view of Marketing Authorizations (MAs) given in a number of countries to acetaminophen drug products with rapid onset of action, it is concluded that differences in rate of absorption were considered therapeutically not relevant by the Health Authorities. Moreover, in view of its therapeutic use, its wide therapeutic index and its uncomplicated pharmacokinetic properties, in vitro dissolution data collected according to the relevant Guidances can be safely used for declaring bioequivalence (BE) of two acetaminophen formulations. Therefore, accepting a biowaiver for immediate release (IR) acetaminophen solid oral drug products is considered scientifically justified, if the test product contains only those excipients reported in this paper in their usual amounts and the test product is rapidly dissolving, as well as the test product fulfils the criterion of similarity of dissolution profiles to the reference product

Biowaiver monographs for immediate release solid oral dosage forms: Doxycycline hyclate

Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release (IR) solid oral dosage forms containing doxycycline hyclate are reviewed. According to the Biopharmaceutics Classification System (BCS), doxycycline hyclate can be assigned to BCS Class I. No problems with BE of IR doxycycline formulations containing different excipients and produced by different manufacturing methods have been reported and hence the risk of bio in equivalence caused by these factors appears to be low. Doxycycline has a wide therapeutic index. Further, BCS-based dissolution methods have been shown to be capable of identifying formulations which may dissolve too slowly to generate therapeutic levels. It is concluded that a biowaiver is appropriate for IR solid oral dosage forms containing doxycycline hyclate as the single Active Pharmaceutical Ingredient (API) provided that (a) the test product contains only excipients present in doxycycline hyclate IR solid oral drug products approved in the International Conference on Harmonization (ICH) or associated countries; and (b) the comparator and the test products comply with the BCS criteria for “very rapidly dissolving” or, alternatively, when similarity of the dissolution profiles can be demonstrated and the two products are “rapidly dissolving.”. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99: 1639–1653, 2010Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/64911/1/21954_ftp.pd

Biowaiver monographs for immediate release solid oral dosage forms: Aciclovir

Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing (biowaiver) for the approval of immediate release (IR) solid oral dosage forms containing aciclovir are reviewed. Aciclovir therapeutic use and therapeutic index, pharmacokinetic properties, data related to the possibility of excipient interactions and reported BE/bioavailability (BA) studies were also taken into consideration in order to ascertain whether a biowaiver can be recommended. According to the Biopharmaceutics Classification System (BCS) and considering tablet strengths up to 400 mg, aciclovir would be BCS Class III. However, in some countries also 800 mg tablets are available which fall just within BCS Class IV. Aciclovir seems not to be critical with respect to a risk for bio in equivalence, as no examples of bio in equivalence have been identified. It has a wide therapeutic index and is not used for critical indications. Hence, if: (a) the test product contains only excipients present in aciclovir solid oral IR drug products approved in ICH or associated countries, for instance as presented in this article; and (b) the comparator and the test product both are very rapidly dissolving , a biowaiver for IR aciclovir solid oral drug products is considered justified for all tablet strengths. © 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 97:5061–5073, 2008Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/61316/1/21392_ftp.pd

Statement from the American Linear Collider Committee to the P5 subpanel

This statement from the American Linear Collider Committee to the P5 subpanel has three purposes. It presents a brief summary of the case for an $e^+e^-$ Higgs factory that has emerged from Snowmass 2021. It highlights the special virtues of the ILC that are shared with other linear colliders but not with circular colliders. Finally, it calls attention to the resources available in the ILC White Paper for Snowmass (arXiv:2203.07622). The ALCC urges P5 to move the Higgs factory forward as a global project by assigning the idea of an $e^+e^-$ Higgs factory high priority, initiating a global discussion of the technology choice and cost sharing, and offering the option of siting the Higgs factory in the U.S.Comment: 6 page

Depth-resolved measurement of the Meissner screening profile in a niobium thin film from spin-lattice relaxation of the implanted β\beta-emitter 8^{8}Li

We report measurements of the Meissner screening profile in a Nb(300 nm)/Al$_{2}$O$_{3}$ thin film using $^{8}$Li $\beta$-detected nuclear magnetic resonance ($\beta$-NMR). The NMR probe $^{8}$Li was ion-implanted into the Nb film at energies $\leq$ 20 keV, corresponding to mean stopping depths comparable to Nb's magnetic penetration depth $\lambda$. $^{8}$Li's strong dipole-dipole coupling with the host $^{93}$Nb nuclei provided a "cross-relaxation" channel that dominated in low magnetic fields, which conferred indirect sensitivity to the local magnetic field via the spin-lattice relaxation (SLR) rate $1/T_{1}$. From a fit of the $1/T_{1}$ data to a model accounting for its dependence on temperature, magnetic field, and $^{8}$Li$^{+}$ implantation energy, we obtained a magnetic penetration depth $\lambda_{0}$ = 51.5(22) nm, consistent with a relatively short carrier mean-free-path $\ell$ = 18.7(29) nm typical of similarly prepared Nb films. The results presented here constitute an important step towards using $^{8}$Li $\beta$-NMR to characterize bulk Nb samples with engineered surfaces, which are often used in the fabrication of particle accelerators.Comment: 16 pages, 4 figure

Expression of chemokine receptor CXCR4 in esophageal squamous cell and adenocarcinoma

BACKGROUND: Prognosis of esophageal cancer is poor despite curative surgery. The chemokine receptor CXCR4 has been proposed to distinctly contribute to tumor growth, dissemination and local immune escape in a limited number of malignancies. The aim of our study was to evaluate the role of CXCR4 in tumor spread of esophageal cancer with a differentiated view of the two predominant histologic types – squamous cell and adenocarcinoma. METHODS: Esophageal cancer tissue samples were obtained from 102 consecutive patients undergoing esophageal resection for cancer with curative intent. The LSAB+ System was used to detect the protein CXCR4. Tumor samples were classified into two groups based on the homogeneous staining intensity. A cut-off between CXCR4w (= weak expression) and CXCR4s (= strong expression) was set at 1.5 (grouped 0 – 1.5 versus 2.0 – 3). Long-term survival rates were calculated using life tables and the Kaplan-Meier method. Using the Cox's proportional hazards analysis, a model of survival prediction was established. RESULTS: The overall expression rate for CXCR4 in esophageal squamous cell carcinoma was 94.1%. Subdividing these samples, CXCR4w was found in 54.9% and CXCR4s in 45.1%. In adenocarcinoma, an overall expression rate of 89.1% was detected with a weak intensitiy in 71.7% compared to strong staining in 29.3% (p = 0.066 squamous cell versus adenocarcinoma). The Cox's proportional hazards analysis identified the pM-category with a hazard ratio (HR) of 1.860 (95% CI: 1.014–3.414) (p = 0.045), the histologic tumor type (HR: 0.334; 95% CI: 0.180–0.618) (p = 0.0001) and the operative approach (transthoracic > transhiatal esophageal resection) (HR: 0.546; 95% CI: 0.324–0.920) (p = 0.023) as independent factors with a possible influence on the long-term prognosis in patients with esophageal carcinoma, whereas CXCR4 expression was statistically not significant (>0.05). CONCLUSION: Expression of the chemokine receptor CXCR4 in esophageal cancer is of major relevance in both histologic entities – squamous cell and adenocarcinoma. Though with lack of statistical significance, strong CXCR4 expression revealed a poorer long-term prognosis following curative esophagectomy in both histologic subtypes. Thus, the exact biological functions of CXCR4 in terms of tumor dissemination of esophageal cancer is yet undetermined. Inhibition of esophageal cancer progression by CXCR4 antagonists might be a promising therapeutic option in the future

Developments in esophageal surgery for adenocarcinoma: a comparison of two decades

<p>Abstract</p> <p>Background</p> <p>The objective of this study was to examine outcomes in patients undergoing esophageal resection for adenocarcinoma at our institution during a 20-year period and, in particular, to address temporal trends in long-term survival.</p> <p>Methods</p> <p>Out of 470 patients who underwent esophagectomy for malignancy between September 1985 and September 2005, a total number of 175 patients presented with esophageal adenocarcinoma. Patients enrolled in this study included AEG (adenocarcinoma of the esophagogastric junction) type I tumors only. Time trends were studied comparing two decades, 9/1985 to 9/1995 (DI) and 10/1995 to 9/2005 (DII).</p> <p>Results</p> <p>The overall survival was significantly more favourable in patients undergoing esophageal resection for adenocarcinoma in the recent time period (DII, 10/1995 to 9/2005) as compared to the early time period (DI, 9/1985 to 9/1995) (log rank test: p = 0.0329). Significant differences in the recent decade were seen based on lower ASA-classifications, earlier tumor stages, and the operative procedure with a higher frequency of transhiatal resections (p < 0.05). 30-day mortality improved from 8.3% to 3.1% during the 20-year time-interval, thus without statistical significance.</p> <p>Conclusion</p> <p>Based on our experience, overall survival is improving over time for adenocarcinoma of the esophagus. Factors that may play an important role in this trend include early diagnosis and improved patient selection through better preoperative staging, improved surgical technique with a tailored approach carefully evaluated by physiologic patient status, comorbidity and tumor extent.</p