In our study, we applied 0.1% tacrolimus and corticosteroid eye drops in tapering doses to patients with high-risk keratoplasty and concluded that they are effective in reducing immune rejection and prolonging graft survival. Mix tacrolimus oral granules with water right before you take them. The volume and structure uniformity of the formulation drops are also important properties to ensure accurate drug dosage and avoid treatment variability. The use of 40% (w/v) HPCD allowed to prepare eye drop solutions with a 0.02% (w/v) tacrolimus concentration that could be in the therapeutic range for uveitis treatment. Hyaluronic acid-coated niosomes facilitate tacrolimus ocular delivery: Mucoadhesion, precorneal retention, aqueous humor pharmacokinetics, and transcorneal permeability. Campos M.S.T., Fialho S.L., Pereira B.G., Yoshida M.I., De Oliveira M.A. [(accessed on 21 January 2021)]; Anguiano-Igea S., Otero-Espinar F., Vila-Jato J., Blanco-Mndez J. Interaction of clofibrate with cyclodextrin in solution; Phase solubility, 1H NMR and molecular modelling studies. tacrolimus oral - Uses, Side Effects, and More Three batches of each formulation were prepared and subjected to a double filtration with 0.22-m PES (polyethersulfone) filters. Scheme of the corneal mucoadhesion method. Why do some eye drops need to be refrigerated? | Eye Care Corneal opacity changes were measured by two different techniques, these being photometry and UVVis spectrophotometry. Three STD spectra were obtained by STDon saturation of the tacrolimus signals at 6.30, 6.12 and 2.12 ppm, respectively. The time needed to prepare the aforementioned tacrolimus topical ophthalmic formulations will be a key preparation parameter in HPDs. ; Yu, J.M. WebTopical 0.03% tacrolimus eye drops successfully improved tear stability and ocular surface status in patients with dry eyes. Topical corticosteroids constitute the first therapeutic line to treat the disease, but remarkable adverse effects can appear due to continuous treatment with these drugs. ; Hoshino-Ruiz, D.R. Do not save this mixture for later use. Besides, high doses may cause the patient to suffer from side effects, while underdosing may cause damage or prolonged drug therapy. Different formulations are proposed in the present work as new pharmacological alternatives, specifically intended for topical ophthalmic administration for uveitis treatment. ; Luin, T.T. ; Silva, F.Q. Therefore, the same type of packaging for testing was used. Ezquer-Garin, C.; Ferriols-Lisart, R.; Als-Almiana, M. Stability of Tacrolimus Ophthalmic Solution. Siegl C., Knig-Schuster M., Nakowitsch S., Koller C., Graf P., Unger-Manhart N., Schindlegger Y., Kirchoff N., Knecht C., Prieschl-Grassauer E., et al. A thermostatic bath with a controlled temperature (37 2 C) and under stirring (100 rpm) during the whole assay was used to incubate all Franz diffusion cells. Photometry was assessed using a luxmeter (Gossen Mavolux 5032C USB; Nrnberg, Germany), where corneas were placed between two cylindrical supporting black holders (fabricated with polylactic acid filaments using a 3D printer, Witbox BQ, Madrid, Spain) and illuminated with a pipe light (Olympus Highlight 200, Tokyo, Japan) with fixed brightness values [55]. Therefore, this hydrophilic cyclodextrin derivative can form highly water-soluble complexes with lipophilic drugs, as it happens with tacrolimus. A phase solubility diagram was used to estimate the stability constant (K) of the tacrolimus/HPCD inclusion complex. Each sample was assayed in triplicate. Hemorrhage, lysis and coagulation of the CAM were measured; these reactions can be quantified through an irritation score (IS) following the Kalweit et al. Successful treatment of surgically induced necrotizing scleritis with tacrolimus. The development of new ophthalmic topical vehicles for increasing drugs permanence on the ocular surface is important to improve drug bioavailability in the eye as well as the treatment adherence by patients [81]. [42]. Comparison of the Efficacy of 0.03% Tacrolimus Eye Drops Diluted in Olive Oil and Linseed Oil for the Treatment of Keratoconjunctivitis Sicca in Dogs. As presented in Figure 7, 20% (w/v) HPCD formulations containing tacrolimus reached 100% solubilization in a 90-h period, while 40% (w/v) HPCD formulations containing tacrolimus showed different solubilization time, being quicker for the TLI 40 (72-h period, against the 90-h period for TBS 40). The authors would like to thank Lauralee Wnuk, Marie Mula and Franoise Picq for their help in performing the sterility assays, and Valentine Vannaire for her help during the simulated use study. Tacrolimus 0.03% drops refrigerating question My friends pug uses tacrolimus in each eye daily. The tacrolimus concentration was corrected in each measure according to the volume that was left (0.5 mL less in each sample). Refrigerated and accelerated samples were kept at room temperature for 20 minutes before quantification. Garg V., Jain G.K., Nirmal J., Kohli K. Topical tacrolimus nanoemulsion, a promising therapeutic approach for uveitis. Guide for the Care and Use of Laboratory Animals. Furthermore, microbiological control growth is a test to take into account the quality control of the prepared formulations since it ensures the sterility of the preparations and, therefore, the conditions of asepsis in the production process. Stability studies proved these formulations to be stable for at least 3 months in refrigeration. studied tacrolimus degradation in aqueous HPCD solutions [27]. Use sunscreen and wear clothing and eyewear that protects you from the Licensee MDPI, Basel, Switzerland. Using Instruments to Quantify Colour. Tam P.M.K., Young A.L., Cheng L.L., Lam P.T.H. Clinical treatment of dry eye using 0.03% tacrolimus A two-way ANOVA was further carried out to study differences in tacrolimus solubilization time among the formulations. Very friendly customer service and fast delivery. Macy R. Surface tension by the ring method. Tacrolimus Tacrolimus (Topical Route) Proper Use - Mayo Clinic Log in to browse, order and prescribe from our compounded drugs formulary. The cationic liposomes notably prolonged the ocular retention time of eye drops, leading to an increased tacrolimus concentration in the ocular surface. Stability of tacrolimus ophthalmic solution - PubMed This fact becomes important when transferring research to the clinic. Tukeys multiple comparison test was also performed, and no statistically significant differences were found between the TLI 20 and TLI 40 formulations, but significant differences were observed between the rest of the formulations ( < 0.05). The column used was a Poroshell 120, EC-C18 (4.6 100 mm, 4 m) and at a temperature of 60 C. Kheirkhah, A.; Zavareh, M.K. Image analysis was performed using the Amides Medical Image Data Analysis Tool [64]. Clinical treatment of dry eye using 0.03% tacrolimus eye ; Blender, N.; Tran, T.; Vantipalli, S. Ocular Benzalkonium Chloride Exposure: Problems and Solutions. Tacrolimus powder was acquired from Guinama S.L.U. The .gov means its official. ; Ho, A.M.; Raghavan, A.; Kim, J.; Jain, J.; Park, J.; Sharma, S.; Rao, A.; Hogan, P.G. ; Boulanger, B.; Chapuzet, E.; Cohen, N.; Compagnon, P.-A. Here, 63% light transmission corresponds to the total light transmitted through bovine corneas incubated in PBS. The efficacy of these in vitro and ex vivo procedures has been well studied by pharmaceutical industries and some national regulatory agencies [76]. This allows programming the preparation of the eye drops every In this study, the PET/CT imaging technique was used to determine the residence times of the proposed tacrolimus topical ophthalmic formulations on the ocular surface, and they were compared with the tacrolimus eye drop (REF) elaborated by HPDs. Available online: Endocrine Disruptor List. A Lauda TD1 tensiometer (LAUDA Scientific GmbH, Lauda-Knigshofen, Germany) fitted with a platinum ring (2-cm diameter) was used to measure the surface tension of the tacrolimus formulations. The percentage of unaltered drug versus time was fitted to a first order kinetics using GraphPad Prism 8 v.8.2.1 software and the degradation constant (K), expiration time (t90) and determination coefficient (R2) were calculated. The value of K1:2 is often lower than that of K1:1. Surface tension determination constitutes a key assay for a topical ophthalmic formulation. Development and Characterization of a Tacrolimus/Hydroxypropyl--Cyclodextrin Eye Drop. Preclinical characterization and clinical evaluation of tacrolimus eye drops. The determinations were carried out in triplicate. The STDon and STDoff scans were measured in alternate scans and subtracted by the phase cycling, providing the subtracted STDoff-on spectra. No peaks were seen when silicone parts were put into contact with only water. Great pharmacy where I get my dog's eye prescription. Initial mean pH was of 5.97 2.05% and 5.56 5.03%, respectively, for the 1 mg/mL and 0.2 mg/mL tacrolimus formulations. Received 2020 Dec 20; Accepted 2021 Jan 19. This research was partially supported by the Spanish Ministry of Science, Innovation and Universities (RTI2018-099597-B-100), the ISCIII (PI17/00940, RETICS Oftared, RD16/0008/0003 and RD12/0034/0017) and by Xunta de Galicia, grant numbers GPC2013/015 and GRC2017/015. ; Wouessidjewe, D.; Choisnard, L.; Gze, A. 405 HERON DRIVE SUITE 200 SWEDESBORO, NJ 08085-1749 | 2004-2023 WEDGEWOOD PHARMACY, ALL RIGHTS RESERVED. Taormina, D.; Abdallah, H.Y. Trial registration number UMIN 000008640. tacrolimus ; Albers, M.B.V. ; Dew, W.; Feinberg, M.; Lallier, M.; et al. Peppas N.A., Mongia N.K. Stability and Sorption of FK 506 in 5% Dextrose Injection and 0.9% Sodium Chloride Injection in Glass, Polyvinyl Chloride, and Polyolefin Containers. ; Bergles, J.; Ham, Z.; Grahek, R.; Urleb, U. Available online: Mazet, R.; Yamogo, J.B.G. Characterization of a Tacrolimus/Hydroxypropyl Some states restrict the information we may provide about controlled substances. All samples stayed limpid and with a slight yellow tinge throughout the study, for both tested concentrations and conservation temperatures, and there was no appearance of any visible particulate matter, haziness or gas development. Tacrolimus IR Oral Capsules: Side Effects, Uses, and More WebSome individuals also prefer to refrigerate their drops so that they can more easily determine if they put the drop in their eye properly, or the drop may feel more soothing This additional compound presented a very similar retention time as one of the breakdown products observed at other storage temperatures and in the 0.2 mg/mL formulation. The conventional pharmacological treatments for uveitis are associated with strict patient compliance, limited efficacy due to the appearance of refractory processes and different severe side effects. You are encouraged to speak with your prescriber as to the appropriate use of any medication. ; Investigation: M.B., Y.L.B. Based on this, they can be classified as follows: 00.9, no irritation; 14.9, slight irritation; 58.9, moderate irritation; and 921, severe irritation. The spectrometer control software was TopSpin 4.0 (Billerica, MA, USA, 2020). Tacrolimus diluted to 0.3 mg/mL in eye drop solution was stable for 20 days when stored at 25 C and for at least 85 days when stored at 2-8 C or between -15 and Test parameters were set after the method optimization; the upper probe moved down at a speed of 0.5 mm/s and an assessment of the required force to spill one drop of the formulation was performed. Avoid lots of sun, sunlamps, and tanning beds. the contents by NLM or the National Institutes of Health. tacrolimus ; Martino, P.A. Can cause a lot of side-effects, such as high blood sugar, high blood pressure, and kidney damage. previously studied the surface tension of commercialized ophthalmic formulations and the results showed that these topical ophthalmic solutions had surface tensions greater than that of tears (34.370.9 mN/m), most likely increasing the tear film stability and allowing for a greater lubrication of the eye [72]. As presented in Figure 13, it can be seen that temperature was an important factor in the stability under storage of tacrolimus/HPCD ophthalmic formulations. The 1st In-ternational Electronic Conference on Pharmaceutics session Cyclodextrins in Pharmaceutics. Astellas Pharma Inc. A Randomized, Placebo-Controlled, Double-Masked Study of 0.1% Tacrolimus (FK506) Ophthalmic Suspension in Vernal Keratoconjunctivitis. Bodaghi B., Cassoux N., Wechsler B., Hannouche D., Fardeau C., Papo T., Huong D.L.T., Piette J.-C., LeHoang P. Chronic Severe Uveitis. In the initial tacrolimus solution, the impurities specified by the European Pharmacopeia were detected at 220 nm and identified. Wan, Q.; Tang, J.; Han, Y.; Wang, D.; Ye, H. Therapeutic Effect of 0.1% Tacrolimus Eye Drops in the Tarsal Form of Vernal Keratoconjunctivitis. Elevated IOP was Direct and indirect resource use, healthcare costs and work force absence in patients with non-infectious intermediate, posterior or panuveitis. All tacrolimus eyedrops were tested on the eggs CAM as well as two controls, NaCl as a negative control (C-) and NaOH as a positive control (C+). Signals of HPCD are indicated in spectrum (a). Reasonable pricing. The determination of tacrolimus was performed as previously mentioned (see Section 2.1.1. WebTacrolimus may be prescribed for: Keratoconjunctivitis Sicca; About Ophthalmic Solution: One of the dosage forms available for Tacrolimus is Ophthalmic Solution. The rigid doughnut-shaped structure makes it a natural complexing agent, being able to form inclusion complexes with several drugs, where their structure (or part of it) may fit in the cyclodextrin cavity [39]. The squeezing force test may be affected by different factors such as the formulation viscosity, surface tension or dropper tip design [74]. Scheme of the squeezing force determination. A Receptor for the Immuno-Suppressant FK506 Is a CisTrans Peptidyl-Prolyl Isomerase. Tacrolimus MCT 0.02% and 0.03% Ophthalmic Solution, 15 The reference formulation was prepared just as it is formulated in an HPD; a mixture of 0.03% (w/v) tacrolimus in Liquifilm was prepared by a Prograf (5 mg/mL) intravenous ampoule dilution as it was done in previous work [15], instead of using the tacrolimus powder. Purpose: 1,083 customers recently purchased this item. Discussion Guide for Pet Owners and Veterinarians, Medication Information for Pet and Horse Owners. The pH and osmolality measurements were performed following the same experimental procedure previously described (see Section 2.4.1. pH and osmolality determination). Eighty-three percent of eyes with extremely low initial STT (< or = 2 mm/min), increased 5 mm/min after tacrolimus. Hayes, R.; Ahmed, A.; Edge, T.; Zhang, H. CoreShell Particles: Preparation, Fundamentals and Applications in High Performance Liquid Chromatography. WebSide Effects. Overall, these NMR results strongly suggest that tacrolimus is forming a large self-aggregate in the water solution and it is partially solubilized by forming a complex with HPCD. tacrolimus Van Santvliet, L.; Ludwig, A. Determinants of Eye Drop Size. These samples were grown at 37 C for predetermined periods (48 h, 15 days and 10 days, respectively). The phase solubility diagram of tacrolimus in aqueous HPCD solutions at 25 C is shown in Figure 3. This process may cause irreversible tissue damage and visual impairment. The squeezing force test evaluates the force needed to dispense a drop from 5-mL polypropylene eyedropper bottles that are commonly used in HPDs. Balls M., Botham P., Bruner L., Spielmann H. The EC/HO international validation study on alternatives to the draize eye irritation test. ; Venkataramanan, R.; Logue, L.; Burckart, G.J. Ghiglioni, D.G. NMR experiments were conducted at two different temperature conditions, 278 and 298 K, on a Bruker NEO 17.6 T spectrometer (proton resonance 750 MHz) (Billerica, MA, USA), equipped with a 1H/13C/15N triple resonance PA-TXI probe with a deuterium lock channel and a shielded Pulse Field Gradient (PFG) z-gradient. To prevent the rats from scratching their eyes by removing the instilled formulations, an Elizabethan collar was placed between PET studies. Formulations also showed good ophthalmic properties in terms of pH, osmolality and safety. Use of them does not imply any affiliation with or endorsement by them. Submit Office Orders & Patient Prescriptions. On the orange bottle it has a brighter orange sticker that Four different ophthalmic formulations were prepared based on the tacrolimus/hydroxypropyl--cyclodextrin (HPCD) inclusion complexes formation. The pathogenesis of uveitis is often caused by an autoimmune response. Preclinical characterization and clinical evaluation Sterility is one of the most important requirements when preparing ophthalmic formulations as it reduces the risk of eye infections. Garnero C., Zoppi A., Aloisio C., Longhi M.R. ; Che, C.-Y. Conceptualization: M.B., M.W., M.J. and P.C. Tukeys multiple comparison test was also applied, and statistically significant differences were found between the TBS 20 and TLI 20 formulations and between the REF and TLI 20 and TBS 40, but no significant differences were observed between the rest of the formulations ( > 0.05). Lamprecht A., Yamamoto H., Takeuchi H., Kawashima Y. Accelerated Aging: Prediction of Chemical Stability of Pharmaceuticals. ; Lee, J.-E. Newton, D.W. Pharmacokinetics parameters (K, t1/2, AUC0, mean residence time (MRT) and % remaining formulation at 75 min) of the tacrolimus eye drops obtained by the fitting of the percentage formulation remaining on ocular surface. Likewise, the fluorescein permeability test was further applied on the corneas previously treated with the tested formulations. Arima H., Yunomae K., Miyake K., Irie T., Hirayama F., Uekama K. Comparative Studies of the Enhancing Effects of Cyclodextrins on the Solubility and Oral Bioavailability of Tacrolimus in Rats. Tukeys multiple comparisons test was subsequently performed in order to compare all formulations. US005591426A. Phase solubility diagrams, Nuclear Magnetic Resonance (NMR) and molecular modeling studies showed the formation of 1:1 and 1:2 tacrolimus/HPCD inclusion complexes, being possible to obtain a 0.02% (w/v) tacrolimus concentration by using 40% (w/v) HPCD aqueous solutions. Zanjani H., Aminifard M.N., Ghafourian A., Pourazizi M., Maleki A., Arish M., Shahrakipoor M., Rohani M.R., Abrishami M., Zare E.K., et al. The formulation signal on the eye surface is coded on a color scale: blue areas show low radioactive activity whereas red areas show high radioactive activity. Because tacrolimus is considered as a drug with a narrow therapeutic range, the choice of accepting a 90110% range of the initial concentration can be debatable. However, the United States Pharmacopoeia allows this interval for a tacrolimus compounded oral solution [, This work also used the Arrhenius equation to be able to estimate the impact of various temperatures on tacrolimus degradation. ; Verification: M.Y., Y.B. Topical tacrolimus is used to treat skin diseases that arise from an overactive immune system such as lupus, pemphigus in dogs or cats, pinnal vascular Tacrolimus is a macrolide with a high molecular weight (804.02 g/mol) isolated from Streptomyces tsukubaensis, with a great immunosuppressive activity (100 times more potent than cyclosporine A) [10,11] that inhibits T cell proliferation and suppresses the release of inflammatory cytokines; it can theoretically be used to reduce inflammatory activity in uveitis patients [3]. The initial turbidity was of 10 and 3.5 FNU for, respectively, the 1 mg/mL and 0.2 mg/mL tacrolimus concentration. Christian M.S., Diener R.M. Tacrolimus eye drop solution (0.3%) was found to be stable at 25 C for only 20 days, whereas when stored at refrigerated conditions (28 C) and frozen conditions (15 and 25 C) in polypropylene bottles, in June 2005, the company had discontinued developing tacrolimus eye drops due to the safety concerns [92]. The low values of stability constant indicate that tacrolimus and HPCD interactions were weak, especially in the 1:2 complex. The positron emission tomography (PET) and computed tomography (CT) procedures for conducting the radiolabeling of the formulations and the quantitative ocular permanence study were described in our previous works [15,61,62]. Mills R., Jones D.B., Winkler C.R., Wallace G.W., Wilhelmus K.R. Taddio A., Cimaz R., Caputo R., DeLibero C., Di Grande L., Simonini G., Mori F., Novembre E., Pucci N. Childhood chronic anterior uveitis associated with vernal keratoconjunctivitis (VKC): Successful treatment with topical tacrolimus. Tacrolimus concentration was determined for each sample using an HPLC system (Agilent 1260 series; Agilent Technologies, Santa Clara, CA, USA) equipped with a Diode Array Detector HS, a solvent delivery quaternary pump system, 400 bar maximum pressure and an autosampler. Based on these statements, it would be interesting to design new topical ophthalmic formulations with the lowest possible toxic potential and better tolerability. The improvement of aqueous tacrolimus eye drops is still a challenge because of its low chemical stability and solubility in particular [27]. Abstract Tacrolimus Capsules: Indications, Side Effects, Warnings The authors declare no conflict of interest. ; Ptachcinski, R.J.; Todo, S.; Fung, J.J.; Starzl, T.E. Hubert, P.H. Nonetheless, if these are not synthesized to be marketed, their elaboration in HPDs will be complicated. Pharmacokinetics of topically applied tacrolimus dissolved in Marinosolv, a novel aqueous eye drop formulation. 1 Subgroup 3. those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). ); se.csu.iar@zaid.airotciv (V.D.-T.); se.csu.iar@zednanref.alerav.nebur (R.V.-F.); se.csu@zednem.ocnalb.esoj (J.B.-M.), 2Molecular Imaging Group, University Clinical Hospital, Health Research Institute of Santiago de Compostela (IDIS), 15706 Santiago de Compostela, Spain, 3Clinical Pharmacology Group, University Clinical Hospital, Health Research Institute of Santiago de Compostela (IDIS), 15706 Santiago de Compostela, Spain; se.sagres@aicrab.zelaznog.leugim (M.G.-B. BSS is an isotonic salt solution for use in irrigating eye tissues, with pH 7.5 and a 300 mOsm/kg osmolality [46]. Opaque bottles offer protection from light - no paper bags, no bottle transfer! For the 0.2 mg/mL concentration, turbidity did not vary by more than 0.7 FNU, 1.4 FNU and 0.4 FNU for, respectively, the 5 C 25 C and 35 C storage conditions. Cox C.H. The selective saturation was applied during 2 s at a specific frequency of the 1H spectrum, covering a region of the spectrum of 125 Hz around the chosen frequency (i.e., 0.17 ppm in a 750 spectrometer). Zeng W., Li Q., Wan T., Liu C., Pan W., Wu Z., Zhang G., Pan J., Qin M., Lin Y., et al. tacrolimus eye drops Available online: French Society of Clinical Pharmacy (SFPC) and Evaluation and Research Group on Protection in Controlled Atmospher (GERPAC). It was observed that during the separation stage of the cornea from the formulation, a formulation film remained adhered to the cornea when the load cell was lifted. National Center for Biotechnology Information PubChem Compound Summary for CID 445643, Tacrolimus. Multiple requests from the same IP address are counted as one view. Long-Term Results of Topical 0.02% Tacrolimus Ointment for Refractory Ocular Surface Inflammation in Pediatric Patients. For both concentrations, the results showed that the tacrolimus formulation remained stable throughout the study when stored at 5 C, but tacrolimus degradation occurred when the formulations were stored at 25 C and 35 C. This compound can be seen in the absence of tacrolimus, thus confirming that the leachable compound was not linked in any way to tacrolimus. Three STDon-off spectra were measured at 278 and 298 K under otherwise identical conditions. Prajapati M., Eiriksson F.F., Loftsson T. Stability characterization, kinetics and mechanism of tacrolimus degradation in cyclodextrin solutions. Throughout the study, turbidity did not vary by more than 0.4 FNU when stored at 5 C and 1 FNU for the 25 C and 35 C storage temperature conditions for the 1 mg/mL concentration. STD spectra were measured with auto-subtraction of alternate scans acquired with off- and on-irradiation providing the so-called STDon-off spectra [45]. Tacrolimus oral and injection Uses, Side Effects & Warnings The physiological pH of tears is around 7.5 [, For both tested concentrations, all parameters were in favour of a physicochemical stability of nine months when stored at 5 C. Briefly, PET and CT images were acquired using the Albira PET/CT Preclinical Imaging System (Bruker Biospin; Woodbridge, Connecticut, USA). ); se.sagres@aicrag.olednom.anitsirc (C.M.-G.), 4Clinical Neurosciences Group, University Clinical Hospital, Health Research Institute of Santiago de Compostela (IDIS), 15706 Santiago de Compostela, Spain, 5Nuclear Magnetic Resonance Unit, Research Infrastructures Area, University of Santiago de Compostela (USC), 15782 Santiago de Compostela, Spain; se.csu@nitram.leunam, 6Paraquasil Group, University Clinical Hospital, Health Research Institute of Santiago de Compostela (IDIS), 15706 Santiago de Compostela, Spain, 7Physiology DepartmentCIMUS, University of Santiago de Compostela (USC), 15782 Santiago de Compostela, Spain; se.cdu@zedumreb.zeravla.airam, 8Ophthalmology Department, Clinical University Hospital Santiago de Compostela (SERGAS), 15706 Santiago de Compostela, Spain; se.csu@zelaznog.ocsicnarf, 9Department of Surgery and Medical-Surgical Specialties and CIMUS, University of Santiago de Compostela (USC), 15782 Santiago de Compostela, Spain.
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