Formulation matters! A spectroscopic and molecular dynamics investigation on the peptide CIGB552 as itself and in its therapeutical formulation.

Synthetic therapeutic peptides (STP) are intensively studied as new-generation drugs, characterized by high purity, biocompatibility, selectivity and stereochemical control. However, most of the studies are focussed on the bioactivity of STP without considering how the formulation actually used for therapy administration could alter the physico-chemical properties of the active principle. The aggregation properties of a 20-mer STP (Ac-His-Ala-Arg-Ile-Lys-D-Pro-Thr-Phe-Arg-Arg-D-Leu-Lys-Trp-Lys-Tyr-Lys-Gly-Lys-Phe-Trp-NH2 ), showing antitumor activity, were investigated by optical spectroscopy and atomic force microscopy imaging, as itself (CIGB552) and in its therapeutic formulation (CIGB552TF). It has found that the therapeutic formulation deeply affects the aggregation properties of the investigated peptide and the morphology of the aggregates formed on mica by deposition of CIGB552 and CIGB552TF millimolar solutions. Molecular dynamics simulations studied the first steps of CIGB552 aggregation under physiological ionic strength conditions (NaCl 150 mM), showing that peptide oligomers, from dimers to tetramers, are preferentially formed in this environment. Interestingly, cell viability assays performed on H-460 cell lines indicate a major antiproliferative activity of the peptide in its therapeutic formulation with respect to the peptide aqueous solution.

A first-in-class, first-in-human, phase I trial of CIGB-552, a synthetic peptide targeting COMMD1 to inhibit the oncogenic activity of NF-κB in patients with advanced solid tumors.

CIGB-552 is a synthetic peptide that interacts with COMMD1 and upregulates its protein levels. The objectives of this phase I study were safety, pharmacokinetic profile, evaluation of the lymphocytes CD4+ and CD8+ and preliminary activity in patients with advanced tumors. A 3 + 3 dose-escalation design with seven dose levels was implemented. Patients were included until a grade 3 related adverse event occurred and the maximum tolerated dose was reached. The patients received subcutaneous administration of CIGB-552 three times per week for 2 weeks. Single-dose plasma pharmacokinetics was characterized at two dose levels, and tumor responses were classified by RECIST 1.1. Twenty-four patients received CIGB-552. Dose-limiting toxicity was associated with a transient grade 3 pruritic maculopapular rash at a dose of 7.0 mg. The maximum tolerated dose was defined as 4.7 mg. Ten patients were assessable for immunological status. Seven patients had significant changes in the ratio CD4/CD8 in response to CIGB-552 treatment; three patients did not modify the immunological status. Stable disease was observed in five patients, including two metastatic soft sarcomas. We conclude that CIGB-552 at dose 4.7 mg was well tolerated with no significant adverse events and appeared to provide some clinical benefits.

An ELISA for quantification of recombinant human EGF in production process samples, serum and urine.

A sandwich enzyme-linked immunosorbent assay for quantifying a recombinant human Epidermal Growth Factor (rhEGF) protein used in a vacunal preparation is described. The protein was detected with high specificity in a short incubation time at elevated temperature, the assay showing a linear range between 0.0625 and 1 ng/mL. According to the regression analysis for the dilutional linearity data, r2 = 0.9998, slope = 1.07 and intercept = 0.05 were obtained. The intra- and inter-assay coefficient of variation, ranged from 0.79 to 2.87% and 4.87-9.69% respectively demonstrating high reproducibility and precision. The ANOVA test used in the specificity/interference study revealed parallelism among curves (p > 0.1), which indicated lack of interference in the working range. Recovery obtained in accuracy test for three concentration levels varied between 89 and 111%; evidencing a reliable analytical assay to characterize the quality of the recombinant protein in the manufacturing process at large scale, and other biological matrixes as: urine and serum.

[Simultaneous diagnosis of pseudomeningocele, tethered cord syndrome and cerebrospinal fluid fistula: Report of a case]. / Diagnóstico simultáneo de pseudomeningocele, síndrome de médula anclada y fístula de líquido cefalorraquídeo: a propósito de un caso.

The clinical case is presented on a patient with an extensive sacral dysraphism, a history of myelomeningocele surgical repair in her childhood, as well as tethered cord syndrome. The patient was also diagnosed with pseudomeningocele and a cerebrospinal fluid cutaneous fístula. A surgical approach was used, with encouraging results being obtained in the clinical outcome of the patient. A review of the literature was performed to support the surgical decision in this case.

How does growth hormone releasing hexapeptide self-assemble in nanotubes?

Growth hormone releasing peptide, GHRP-6, a hexapeptide (His-(D-Trp)-Ala-Trp-(D-Phe)-Lys-NH2, MW = 872.44 Da) that belongs to a class of synthetic growth hormone secretagogues, can stimulate growth hormone secretion from somatotrophs in several species including humans. In the present study, we demonstrate that GHRP-6 dispersed in aqueous solution, at pH 7.0, room temperature of 22 °C, is able to form long nanotubes, which is evidenced by combining small angle X-ray scattering (SAXS), transmission electron microscopy and molecular dynamics simulation results. Such nanotubes possess inner and outer cross-sections equal to 6.7(2) nm and 13.4(5) nm, respectively. The mechanism of peptide self-assembly was determined by molecular dynamics simulations revealing that the peptides self-assemble like amphiphilic molecules in aqueous solution in a partially interdigitated structure. In this case, the position of the positively charged amino terminus is located at the peptide-water interface, whereas the neutral NH2-capped carboxy terminus remains buried at the hydrophobic core. In contrast, the long side chain of Lys-6 stretches out of the hydrophobic core positioning its positive charge near the cylinder surface. The peptide configuration in the nanotube wall comes from the interplay between the hydrophobic interactions of the aromatic side chains of GHRP-6 and the electrostatic repulsion of its cationic charges. On increasing the peptide concentration, the long nanotubes self-arrange in solution displaying a bi-dimensional hexagonal-like packing in the SAXS curves, with a center-to-center distance of ∼15 nm. Further, we also show that the nanostructure formed in solution is quite stable and is preserved following transfer to a solid support.

Stabilization of a recombinant human epidermal growth factor parenteral formulation through freeze-drying.

Development studies were performed to design a pharmaceutical composition that allows the stabilization of a parenteral rhEGF formulation in a lyophilized dosage form. Unannealed and annealed drying protocols were tested for excipients screening. Freeze-dry microscopy was used as criterion for excipients and formulation selection; as well as to define freeze-drying parameters. Excipients screening were evaluated through their effect on freeze-drying recovery and dried product stability at 50 °C by using a comprehensive set of analytical techniques assessing the chemical stability, protein conformation and bioactivity. The highest stability of rhEGF during freeze-drying was achieved by the addition of sucrose or trehalose. After storing the dried product at 50 °C, the highest stability was achieved by the addition of dextran, sucrose, trehalose or raffinose. The selected formulation mixture of sucrose and dextran could prevent protein degradation during the freeze-drying and delivery processes. The degradation rate assessed by RP-HPLC could decrease 100 times at 37 °C and 70 times at 50 °C in dried with respect to aqueous formulation. These results indicate that the freeze-dried formulation represents an appropriate technical solution for stabilizing rhEGF.

Ping pong fractures: treatment using a new medical device.

PURPOSE: The aim of this study was to assess the use of a new medical device to elevate depressed skull fractures (DSFs) in newborns and minor infants. METHODS: Nine patients (ranging from 1 day to 9 months of age) with simple DSF underwent skull elevation by a new elevator medical device. This medical device comprises two elements: a pediatric resuscitator (CPR mask) connected to a 50-ml syringe. Pediatric CPR face mask is placed on the depressed region and negative pressure is generated through syringe plunger elevation until fracture reduction is observed. RESULTS: Fracture reduction was confirmed in eight of nine patients by computed tomography scan without underlying brain damage and associated complications. Skull asymmetry was eliminated recovering normal shape. Up to now, there are no neurological concerns. Another treatment was chosen to be applied for one patient who did not respond to manipulation. CONCLUSION: The new device is a safe, affordable, and effective choice in the treatment of simple depressed skull fractures in newborns and minor infants.

Bluetooth Tactical Headsets Improve The Speed of Accurate Patient Handoffs.

BACKGROUND: The Committee on En Route Combat Casualty Care recently ranked the patient handoff as their fourth research priority. Bluetooth technology has been introduced to the battlefield and has the potential to improve the tactical patient handoff. The purpose of this study is to compare the traditional methods of communication used in tactical medical evacuation by Special Operations medical personnel (radio push-to-talk [PTT] and Tactical Medic Intercom System [TM-ICS]) to Bluetooth communication. METHODS: Twenty-four simulated tactical patient handoffs were performed to compare Bluetooth and traditional methods of communication used in tactical medical evacuation. Patient scenario order and method of communication were randomized. Accuracy and time required to complete the patient handoff were determined. The study took place using a rotary-wing aircraft kept at level 2 to simulate real-world background noise. Preferred method of communication for each study participant was determined. RESULTS: There were no differences in accuracy of the received patient handoffs between groups or patient handoff transmission times at the ramp of the aircraft. However, when comparing patient handoff times to the medical team within the aircraft, Bluetooth communication was significantly faster than both TM-ICS and radio PTT, while Bluetooth PTT and radio PTT were also significantly faster than TM-ICS. Bluetooth communication was ranked as the preferred method of handoff by all study participants. CONCLUSION: The study demonstrated that utilization of Bluetooth technology for patient handover results in faster handoffs compared with traditional methods without sacrificing any accuracy in a scenario with high levels of noise.

Stability-indicative and conformation-specific enzyme linked immunosorbent assay for analysis of recombinant human gamma interferon.

Recombinant human interferon gamma (rhIFN-γ) is a promising molecule for the treatment of several diseases. A pair of conformation-specific monoclonal antibodies (mAbs) against rhIFN-γ was selected from generated hybridoma cell lines to design a sensitive, stability-indicative, sandwich-type ELISA. The main assay parameters were optimized by the checkerboard method for the highest signal-to-noise ratio: assay buffer composition, coating buffer pH and composition, coating temperature-incubation time parameters, and coating mAb concentration and conjugate dilution. Detection and quantification limits were estimated between 0.019 and 0.078 ng/mL, respectively, and recovery values were from 92.03% to 98.40%. The coefficient of variation of intra-assay precision parameters ranged from 2.32% to 9.21% while the inter-analyst variation was between 4.70% and 10.63%, supporting the method's repeatability. The ELISA was specific for correctly folded and non-aggregated molecular species, as compared to intrinsic Trp fluorescence (chemical denaturation) and optical density at 340 nm (thermal aggregation), respectively. However, the method was not sensitive to the small C-terminal degradation of full-length rhIFN-γ1-144 (losses of 6-12 amino acid residues) as compared to results with mass spectrometry and gel electrophoresis. ELISA showed good correlation with rhIFN-γ antiviral biological activity. This method was applied to the stability evaluation of rhIFN-γ in physiological buffer at low concentrations using polypropylene and glass vials also in the presence of adsorption protectant excipients. Furthermore, ELISA could be adapted to other applications such as quantification of IFN-γ in serum samples, Mycobacterium tuberculosis diagnosis, etc.

Combined nuclear magnetic resonance spectroscopy and molecular dynamics study of growth hormone releasing hexapeptide GHRP-6 and a cyclic analogue.

The Growth Hormone Releasing Hexapeptide, GHRP-6 was the first of a family of synthetic peptides that enhance the release of the Growth Hormone by the pituitary gland in a dose-dependent manner. Since its discovery, it has been used as a benchmark and starting point in numerous researches aiming to obtain new drugs. Complete resonance assignment of GHRP-6 NMR spectra in both open and cyclic forms are reported, showing some differences to random coil chemical shifts. Connectivities observed in the ROESY spectra indicate spatial proximity between the aromatic residues side-chains in both molecules, as well as between residues DPhe5 and Lys6 sidechains. An ensemble of 10 structures was generated for each one of the molecules, showing RMSD values indicative of nonrandom structures. Molecular Dynamics simulations, both with and without explicit solvent, were carried out for GHRP-6 and its cyclic analogue. Conformational analysis performed on the trajectories showed a nonrandom structure with a well preserved backbone. The presence of geometrical patterns resembling those typical of π-π interactions in both peptides, suggest that this kind of interactions may be relevant for the biological activity of GHRP-6. Same conclusion can be drawn from the spatial proximity of residues DPhe5 and Lys6 sidechains.

[Mexican National Consensus on Assisted Reproduction Treatment]. / Consenso Nacional Mexicano de Reproducción Asistida.

BACKGROUND: It is estimated that 15% of couples living in industrialized countries are infertile, ie have failed to conceive, reproductive age, after 12 months ormore of regular intercourse without contraception. During the past decade has increased the demand for fertility treatments because they believe are moreeffective now. OBJECTIVE: To unify the therapeutic approach and service to patients and set a precedent for a Mexican Official Standard respect and support for the legislation of these procedures. METHOD: Consensus by technical experts group panel with the participation of 34 national centers accredited for use in assisted reproduction. He organized seven workshops with the following themes: 1) selection of patients for assisted reproduction treatment, 2) schemes controlled ovarian stimulation for assisted reproduction techniques of high complexity, 3) preparation and egg retrieval technique, 4) transferembryo; 5) luteal phase supplementation; 6) indications and techniques of cryopreservation and 7) informed consent. Each table had a coordinator who wrote and presented the findings to the full, it made a number of observations until they reached unanimity of criteria, which are reflected in this document. RESULTS: Patient selection for assisted reproduction techniques is the first step of the process. Proper selection lead to success, in the same way that a bad pick up for failure. In the case of egg donation the most important recommendation is that only one to two embryos transferred in order to reduce multiple pregnancy rates and maintaining high pregnancy rates.

DELOS Nanovesicles-Based Hydrogels: An Advanced Formulation for Topical Use.

Topical delivery has received great attention due to its localized drug delivery, its patient compliance, and its low risk for side effects. Recent developments have focused on studying new drug delivery systems as a strategy for addressing the challenges of current topical treatments. Here we describe the advances on an innovative drug delivery platform called DELOS nanovesicles for topical drug delivery. Previously, the production of DELOS nanovesicles demonstrated potentiality for the topical treatment of complex wounds, achieving well-tolerated liquid dispersions by this route. Here, research efforts have been focused on designing these nanocarriers with the best skin tolerability to be applied even to damaged skin, and on exploring the feasibility of adapting the colloidal dispersions to a more suitable dosage form for topical application. Accordingly, these drug delivery systems have been efficiently evolved to a hydrogel using MethocelTM K4M, presenting proper stability and rheological properties. Further, the integrity of these nanocarriers when being gellified has been confirmed by cryo-transmission electron microscopy and by Förster resonance energy transfer analysis with fluorescent-labeled DELOS nanovesicles, which is a crucial characterization not widely reported in the literature. Additionally, in vitro experiments have shown that recombinant human Epidermal Growth Factor (rhEGF) protein integrated into gellified DELOS nanovesicles exhibits an enhanced bioactivity compared to the liquid form. Therefore, these studies suggest that such a drug delivery system is maintained unaltered when hydrogellified, becoming the DELOS nanovesicles-based hydrogels, an advanced formulation for topical use.

Mass spectrometric and kinetics characterization of modified species of Growth Hormone Releasing Hexapeptide generated under thermal stress in different pH and buffers.

Growth Hormone Releasing Peptide-6 (GHRP-6) is a promising molecule (H-His1-d-Trp- Ala-Trp-d-Phe-Lys6-NH2) for the treatment of several diseases. Studies on the degradation pathways of this molecule under stressed conditions are needed to develop appropriate formulations. Degradation products (DPs) of GHRP-6, generated by heating in the dark at 60 °C with pH ranging from 3.0 to 8.0 and in presence of common buffers, were isolated by RP-HPLC and characterized by ESI-MS/MS. C-terminal deamidation of GHRP-6 was generated preferentially at pH 3.0 and 8.0. Hydrolysis and head-to-tail cyclization were favored at pH ranging from 6.0 to 7.0 in phosphate containing buffers. A DP with +12 Da molecular mass was presumably originated by the reaction with formaldehyde derived from some of the additives and/or elastomeric closures. Certain DPs derived from the acylation reaction of the tri- and di-carboxylic buffering species were favored at pH 3.0-6.0 and indicate that buffer components, including those "Generally Recognized as Safe", may potentially introduce chemical modifications and product heterogeneity. Nano LC-MS/MS analysis revealed GHRP-6 was also detected as a low-abundance species with Trp oxidized to 5-hydroxy, kynurenine, and N-formylkynurenine. The kinetics for the formation of the major degradation products was also studied by RP-HPLC.

A study of the septa in the maxillary sinuses and the subantral alveolar processes in 30 patients.

The objective of this paper is to study the incidence of septa in the maxillary sinus and measure the height of the underlying alveolar process using panoramic radiography and computerized tomography (CT scans). Thirty patients who were going to be treated with dental implants were submitted to panoramic radiographs and CT scans. Sixty maxillary sinuses were analysed and divided into 2 groups: group 1 (totally edentulous) and group 2 (partially edentulous). The sinuses were divided into 3 regions (anterior, middle, and posterior), the septa were analysed, and the heights of the alveolar processes were calculated in these 3 areas. Of the 30 patients, 36.5% had maxillary sinuses, and 25% of these sinuses had septa, and 11.8% of the panoramic radiographs were false-negatives. In the panoramic radiographs of 10 patients, 3 had bilateral septa, 5 had a septum in only one sinus, and 2 patients had 2 unilateral septa. In the CT scans of 11 patients, 4 patients had a bilateral septa, 5 had a septum in only 1 sinus, and 2 patients had 2 unilateral septa. Therefore, 2 more septa were observed in the CT scans. In the study of the height of the subantral alveolar process, the least amount of difference between both techniques occurred in the middle region of the sinus. The CT scan is more reliable than the panoramic radiograph in diagnosing maxillary septa because of its greater accuracy. In the panoramic radiograph, the middle portion of the alveolar process in the posterior subantral segment was the least distorted of the three portions measured.

The first report of cases of pet dogs with naturally occurring cancer treated with the antitumor peptide CIGB-552.

The absence of an effective therapy against human solid tumors has fostered the development of promising antineoplastic therapeutic candidates, as the CIGB-552 peptide. This synthetic peptide has shown to be effective in reducing tumor size and increasing the lifespan in tumor-bearing mice. Therefore, this work was aimed to explore the safety profile and preliminary assessment of antitumor activity of the CIGB-552 peptide therapeutic candidate in a small population of dogs (n=9) having malignant spontaneously-arising solid tumors. The peptide was administered by subcutaneous (s.c.) route, at three dosage levels (0.075, 0.15 and 0.3mg/kg). The results showed no dose-limiting toxicities in any dogs. The antitumor activity observed in dogs receiving CIGB-552 was associated with the reduction in the tumor volume. Given the antitumor effects of CIGB-552 as mediated by COMMD1 protein, which function is highly conserved among eukaryotic organisms, and the similarities of canine and human types of cancer with respect to tumor biology, it is likely that CIGB-552 could demonstrate comparable anti-cancer activity in human patients. Synthetic peptide, COMMD1, Tumor, Dog, CIGB-552.

Pain and inflammation in 41 patients following the placement of 131 dental implants.

AIMS: To study pain and swelling in the first week after dental implant placement. MATERIAL AND METHODS: A total of 131 implants were placed in 41 patients (17 males and 24 females) under local anesthesia. Pain was scored by means of a verbal and visual analog scale (VAS), while swelling was evaluated by a verbal scale. RESULTS: Most patients who experienced pain reported the latter to be slight, with a peak intensity 6 hours after the operation in 41.5% of cases. A significant relation was observed between pain and the number of implants placed. Swelling was moderate in most patients who reported pain -- peak intensity of inflammation being recorded after 48 hours in 48.8% of cases. A significant association was observed between swelling and older patients, the placement of more than four dental implants, and operations in which sinus lift or bone regeneration procedures were carried out. Swelling was greater in patients with implants positioned in the posterior sector versus those placed in the anterior zone, and in those located at free extreme or totally edentulous patients, versus those placed in interdental spaces. CONCLUSIONS: Following implant placement, pain tends to be mild, with moderate inflammation. The latter is seen to be greater in older patients, in subjects receiving a larger number of implants, and in interventions involving regenerative techniques.

Stability Studies of a Freeze-Dried Recombinant Human Epidermal Growth Factor Formulation for Wound Healing.

UNLABELLED: We report on the stability assessment of a recombinant human epidermal growth factor (rhEGF) freeze-dried formulation for wound healing by intra-lesional injections. The suitability of packaging material for the light protection of finished dried powder was evaluated after stressed exposure conditions. Degradation kinetics of powder for injection was investigated at concentrations of 25-250 µg/vial and temperatures of 45, 60, and 70 °C. The long-term stability was evaluated after storage at 25 ± 2 °C/60 ± 5% relative humidity (6 months) and 2-8 °C (24 months) in the dark and analyzed at several time points. The stability after reconstitution with various diluents was also assessed after 24 h storage at 2-8 °C. The rhEGF samples were analyzed for structural integrity by reversed-phase high-performance liquid chromatography (RP-HPLC), size-exclusion HPLC, and sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE). Biological activity was investigated by measuring the cell proliferation in a murine fibroblast cell line. Results show that freeze-dried rhEGF in primary packaging only was photosensitive, as degradation by RP-HPLC that was completely suppressed by the secondary carton package was revealed. An increase in freeze-dried rhEGF stability was observed with the increase in protein concentration from 25 to 250 µg/vial. The long-term stability study showed no significant rhEGF degradation or physical change within the freeze-dried formulations containing 25 or 250 µg/vial of rhEGF. No physical, chemical or biological changes were observed for rhEGF after reconstitution in water for injection or 0.9% sodium chloride during the storage conditions studied. LAY ABSTRACT: The stability of a recombinant human epidermal growth factor (rhEGF) freeze-dried formulation for wound healing by intra-lesional injections was assessed. The suitability of packaging material for the light protection of finished dried powder was evaluated after stressed exposure conditions. Degradation kinetics of powder for injection was investigated at concentrations of 25-250 µg/vial and temperatures of 45, 60, and 70 °C. The accelerated, long-term, and reconstitution stabilities were examined according to ICH guidelines for their utility time. The stability of rhEGF samples was analyzed by different chemical, physical, and biological activity assays. Results show that freeze-dried rhEGF in primary packaging only was photosensitive, as degradation by reversed-phase high performance liquid chromatography that was completely suppressed by the secondary carton package was revealed. An increase in freeze-dried rhEGF stability was observed with the increase in protein concentration. No significant rhEGF degradation or physical changes were observed within the freeze-dried formulations after 6 months storage at 25 ± 2 °C/60 ± 5% relative humidity or 24 months storage at 2-8 °C. No physical, chemical, or biological changes were observed for rhEGF after reconstitution in water for injection or 0.9% sodium chloride after 24 h storage at 2-8 °C.

Multimodal management of craniopharyngiomas: neuroendoscopy, microsurgery, and radiosurgery.

OBJECT: The goal of this study was to examine the role of gamma knife radiosurgery (GKS) and adjuvant neuroendoscopic procedures by assessing the outcome in 10 patients with craniopharyngiomas who were treated between 1998 and 2001. METHODS: In 10 consecutive patients (six males and four females, mean age 12 years [range 7-32 years]), there were nine mixed and one solid craniopharyngioma. In the last three cases, neuroendoscopic procedures were conducted. Two cases required insertion of an Ommaya reservoir. In another case partial removal of the cyst wall was performed using an endoscope to create a communication with the cerebrospinal pathways and thereby preclude the need for shunt insertion. CONCLUSIONS: Multimodal management of craniopharyngiomas seems to provide a better rate of survival and greater long-term disease control. It is suggested that GKS combined with adjuvant neuroendoscopy should be used as an alternative in treating recurrent or residual craniopharyngiomas if additional microsurgical removal cannot guarantee a cure.

Screening for stability and compatibility conditions of recombinant human epidermal growth factor for parenteral formulation: effect of pH, buffers, and excipients.

A successful parenteral formulation can be developed by studying stability and compatibility of biopharmaceuticals as a function of solution composition. Here, we evaluate the influence of pH, buffers, ionic strength, protein concentration and presence of excipients on recombinant human epidermal growth factor (rhEGF) stability. The stability was accessed by reversed-phase high performance liquid chromatography (RP-HPLC), size exclusion chromatography (SEC-HPLC), enzyme-linked immunosorbent assay (ELISA), Far-UV circular dichroism (CD) and light scattering. The overall maximal stability was obtained in pH near to 7.0 in phosphate, Tris and histidine buffers as the results of the different methods revealed. The CD results revealed that this protein is stable in an extensive pH range. Aggregation of rhEGF was minimized at pH values ranged from 6.0 to 8.0 as indicated the SEC-HPLC and light scattering results. Nor the ionic strength neither the rhEGF concentration had significant effect on the reaction rate constants. Most rhEGF-excipient instability occurs among this protein and reducing sugars. Polymers like poly(ethylene glycol) (PEG) and polysorbates increased methionine oxidation. The rhEGF oxidation and deamidation were the most common degradation pathways. This research identified critical solution factors to be considered for the development of a successful rhEGF parenteral formulation.

[Intracranial tumor behavior of plasma cell neoplasms. Report of 2 cases and literature review]. / Comportamiento tumoral de neoplasias intracraneales de células plasmáticas. Reporte de 2 casos y revisión de la bibliografía.

BACKGROUND: Multiple myeloma is a plasmatic cell neoplasm that is characterized by skeletal destruction, renal failure, anemia and hypercalcemia. The skull plasmacytomas represent less than 1% of the head and neck tumors, they can be the primary lesion or occur as a secondary manifestation of multiple myeloma in 20-30% of the patients, or they can even manifest several years later after the diagnosis of plasmacytoma. Although some of the lesions may be surgically accessible, the aggressive natural behavior will complicate the evolution of the patients. We present two cases of Mexican women with intracranial plasmacytomas, one of them associated with multiple myeloma. CLINICAL CASES: The first case was a 24 year-old woman diagnosed with a multiple myeloma with plasmacytic-plasmablastic bone infiltration that was removed in 90%. She presented a local recurrence that required a second intervention for removal. The second case was a 62 year-old female with a malignant intracranial tumor of plasma cells that was totally resected. Both patients received adjuvant treatment based on chemotherapy and radiation therapy with favorable results. The patients died at 5 and 1.5 years respectively due to renal failure secondary to systemic disease. CONCLUSIONS: We propose chemotherapy and radiation therapy as an essential part of treatment for this condition, as the aggressive behavior of the neoplasms can complicate the evolution, despite being surgically accessible.

Antecedentes: el mieloma múltiple es una neoplasia de células plasmáticas caracterizada por destrucción ósea, insuficiencia renal, anemia e hipercalcemia. Los plasmacitomas de los huesos del cráneo representan menos de 1% de los tumores de cabeza y cuello. Se manifiestan como lesión primaria o secundaria a mieloma múltiple en 20-30%, incluso pueden aparecer varios años después del diagnóstico. Los autores comunicamos dos casos de pacientes mexicanas con lesiones plasmocíticas intracraneales, asociadas con mieloma múltiple.Casos clínicos: el primer caso es el de una paciente de 24 años de edad, con diagnóstico de mieloma múltiple e infiltración ósea que fue extirpado en 90%. Experimentó una recidiva local que requirió otra intervención para su remoción. El segundo caso es el de una mujer de 62 años de edad con un tumor intracraneal de células plasmáticas que se resecó en su totalidad. Ambas recibieron terapia adyuvante con quimio y radioterapia con resultados favorables. Las pacientes fallecieron a los 5 y 1.5 años, respectivamente, por insuficiencia renal como consecuencia de la enfermedad sistémica. Conclusiones: se propone a la quimioterapia y radioterapia como parte esencial del tratamiento de este tumor porque su comportamiento natural agresivo puede complicar la evolución, a pesar de ser accesibles quirúrgicamente.