In-Situ Molecular Vapor Composition Measurements During Lyophilization

Purpose

Monitoring process conditions during lyophilization is essential to ensuring product quality for lyophilized pharmaceutical products. Residual gas analysis has been applied previously in lyophilization applications for leak detection, determination of endpoint in primary and secondary drying, monitoring sterilization processes, and measuring complex solvents. The purpose of this study is to investigate the temporal evolution of the process gas for various formulations during lyophilization to better understand the relative extraction rates of various molecular compounds over the course of primary drying.

Methods

In this study, residual gas analysis is used to monitor molecular composition of gases in the product chamber during lyophilization of aqueous formulations typical for pharmaceuticals. Residual gas analysis is also used in the determination of the primary drying endpoint and compared to the results obtained using the comparative pressure measurement technique.

Results

The dynamics of solvent vapors, those species dissolved therein, and the ballast gas (the gas supplied to maintain a set-point pressure in the product chamber) are observed throughout the course of lyophilization. In addition to water vapor and nitrogen, the two most abundant gases for all considered aqueous formulations are oxygen and carbon dioxide. In particular, it is observed that the relative concentrations of carbon dioxide and oxygen vary depending on the formulation, an observation which stems from the varying solubility of these species. This result has implications on product shelf life and stability during the lyophilization process.

Conclusions

Chamber process gas composition during lyophilization is quantified for several representative formulations using residual gas analysis. The advantages of the technique lie in its ability to measure the relative concentration of various species during the lyophilization process. This feature gives residual gas analysis utility in a host of applications from endpoint determination to quality assurance. In contrast to other methods, residual gas analysis is able to determine oxygen and water vapor content in the process gas. These compounds have been shown to directly influence product shelf life. With these results, residual gas analysis technique presents a potential new method for real-time lyophilization process control and improved understanding of formulation and processing effects for lyophilized pharmaceutical products.

     

Spondylodiscitis by drug-multiresistant bacteria: a single-center experience of 25 cases

Background contextAlthough the incidence of pyogenic spinal infections is increasing, the ideal treatment of spondylodiscitis is still a controversially discussed issue. Furthermore, the proportion of multiresistant bacteria in spondylodiscitis is increasing, and treatment recommendations or reported results are missing for this especially difficult subset of patients.PurposeThe aim of this study is to evaluate the surgical outcome and the postoperative antibacterial treatment regime.Study designRetrospective case series.Patient samplePatients treated for a spondylodiscitis from multiresistant bacteria at our department between 2006 and 2011.MethodsData were gathered through review of patients' case notes, relevant imaging, and electronic records. Magnetic resonance imaging of the whole spine including gadolinium (Gd)-enhanced T1 sequences and computed tomography scans of the affected regions were obtained in all cases.Outcome measuresC-reactive protein (CRP) and complete blood cell count were analyzed in all cases using routine laboratory techniques. Neurologic deficits were classified according to the American Spinal Injury Association (ASIA) impairment scale.ResultsTwenty-five patients were identified (15 gram-positive and 10 gram-negative drug-multiresistant bacteria). The mean age at presentation was 66 years, and 14 patients were male (56%). All patients presented with pain, and a neurologic deficit was present in 11 (44%) cases. An epidural abscess was found in 11 (44%) cases. At admission, CRP was elevated in all cases with a mean of 13±9.2 mg/dL. The main source of infection was previous spine surgery (36%). All patients in this series underwent surgical debridement of the infection and instrumentation of the spine. Postoperative intravenous antibiotics were administered for 19±8.6 days followed by 3±0.3 months of oral antibiotic therapy. Eradication of the infection was achieved ultimately in all surviving patients. Out of 11 patients with neurologic deficits, 4 had a full recovery, 4 improved incompletely, and 3 remained unchanged after surgery.ConclusionsStaged surgical immobilization and instrumentation and optimal debridement at the interdiscal space and spinal canal is a reliable approach to achieve complete healing of spinal infection with multiresistant bacteria. A period of intravenous antibiotic therapy of 2 to 3 weeks followed by a 3-month oral antibiotic therapy seems appropriate for most cases.     

Impact of Chemoradiotherapy on CSF Leak Repair after Skull Base Surgery

Background Transnasal endoscopic resection (TER) has become the treatment of choice for many skull base tumors. A major limitation of TER is the management of large dural defects and the need for repair of cerebrospinal fluid (CSF) leaks, particularly among patients who are treated with chemotherapy (CTX) or radiotherapy (RT). The objective of this study is to determine the impact of CTX and RT on the success of CSF leak repair after TER. Methods We performed a retrospective chart review of a single-institution experience of TER from 1992 to 2011. Results We identified 28 patients who had endoscopic CSF leak repair after resection of malignant skull base tumors. Preoperative RT was utilized in 18 patients, and 9 had undergone CTX. All patients required CSF leak repair with rotational flaps after cribriform and/or dural resection. CSF leak repair failed in three patients (11%). A history of RT or CTX was not associated with failed CSF leak repair. Conclusion Adjuvant or neoadjuvant CTX or RT is not associated with failed CSF leak repair. Successful CSF leak repair can be performed in patients with malignant skull base tumors with an acceptable risk profile.     

A retrospective study of 113 consecutive cases of surgically treated spondylodiscitis patients. A single-center experience

Background

Recommendations for the operative treatment of spondylodiscitis are still a controversial issue.

Methods

A retrospective review identified 113 consecutive patients who underwent surgical debridement and instrumentation for spondylodiscitis between 2006 and 2010 at our department.

Results

The mean age at presentation was 65 years; 78 patients were male (69 %). Distribution of the inflammation was lumbar in 68 (60 %), thoracic in 19 (17 %) and cervical in 20 (18 %) cases. Six patients (5 %) had two concomitant non-contiguous spondylodiscitis foci in different segments of the spine. Epidural abscess was found in 33 patients (29 %). One hundred four patients (92 %) had pain. Neurological deficit was found in 40 patients (35 %). In the thoracic and lumbar cases, dorsal instrumentation alone was considered sufficient in 26 cases; additional interbody fusion from the posterior was performed in 44 cases. A 360° instrumentation was performed in 22 cases. In the cervical cases, only ventral spondylodesis and plating were performed in eight cases, only dorsal instrumentation in five and 360° instrumentation in seven. Postoperative intravenous antibiotics were administered for 14.4?±?9.3 (mean ± SD) days followed by 3.2?±?0.8 (mean ± SD) months of oral antibiosis. Complete healing of the inflammation was achieved in 111 (98 %) cases. Two patients died because of septic shock, both with fulminant endocarditis. Pain resolved in all cases. Neurological deficits were completely resolved in 20 patients, and 14 patients had a partial recovery.

Conclusion

The results of our retrospective study show that surgical treatment of spondylodiscitis with a staged surgical approach (if needed) and a short 1-2-week period of intravenous antibiotics followed by 3 months of oral antibiotics is appropriate for most patients in whom conservative treatment has failed or is not advisable. Furthermore, surgical treatment of newly diagnosed spondylodiscitis might be recommended as an initial treatment option in many cases. Thereby the choice of fusion material (autologous bone, titanium, PEEK) seems less important.     

Evaluation of fluoride release from experimental TiF4 and NaF varnishes in vitro

Fluoride varnishes play an important role in the prevention of dental caries, promoting the inhibition of demineralization and the increase of remineralization.

Objective

This study aimed to analyze the amount of fluoride released into water and artificial saliva from experimental TiF₄ and NaF varnishes, with different concentrations, for 12 h.

Material and Methods

Fluoride varnishes were applied on acrylic blocks and then immersed in 10 ml of deionized water and artificial saliva in polystyrene bottles. The acrylic blocks were divided in seven groups (n=10): 1.55% TiF₄ varnish (0.95% F, pH 1.0); 3.10% TiF₄ varnish (1.90% F, pH 1.0); 3.10% and 4% TiF₄ varnish (2.45% F, pH 1.0); 2.10% NaF varnish (0.95% F, pH 5.0); 4.20% NaF varnish (1.90% F, pH 5.0); 5.42% NaF varnish (2.45% F, pH 5.0) and control (no treatment, n=5). The fluoride release was analyzed after 1/2, 1, 3, 6, 9 and 12 h of exposure. The analysis was performed using an ion-specific electrode coupled to a potentiometer. Two-way ANOVA and Bonferroni''s test were applied for the statistical analysis (p<0.05).

Results

TiF₄ varnishes released larger amounts of fluoride than NaF varnishes during the first 1/2 h, regardless of their concentration; 4% TiF₄ varnish released more fluoride than NaF varnishes for the first 6 h. The peak of fluoride release occurred at 3 h. There was a better dose-response relationship among the varnishes exposed to water than to artificial saliva.

Conclusions

The 3.10% and 4% TiF₄ -based varnishes have greater ability to release fluoride into water and artificial saliva compared to NaF varnish; however, more studies must be conducted to elucidate the mechanism of action of TiF₄ varnish on tooth surface.     

Influence of bismuth oxide concentration on the pH level and biocompatibility of white Portland cement

Objectives

To investigate if there is a relation between the increase of bismuth oxide and the decrease of pH levels and an intensification of toxicity in the Portland cement.

Material and Methods

White Portland cement (WPC) was mixed with 0, 15, 20, 30 and 50% bismuth oxide, in weight. For the pH level test, polyethylene tubes were filled with the cements and immersed in Milli-Q water for 15, 30 and 60 days. After each period, the increase of the pH level was assessed. For the biocompatibility, two polyethylene tubes filled with the cements were implanted in ninety albino rats (n=6). The analysis of the intensity of the inflammatory infiltrate was performed after 15, 30 and 60 days. The statistical analysis was performed using the Kruskal-Wallis, Dunn and Friedman tests for the pH level and the Kruskal-Wallis and Dunn tests for the biological analysis (p<0.05).

Results

The results showed an increase of the pH level after 15 days, followed by a slight increase after 30 days and a decrease after 60 days. There were no significant statistical differences among the groups (p>0.05). For the inflammatory infiltrates, no significant statistical differences were found among the groups in each period (p>0.05). The 15% WPC showed a significant decrease of the inflammatory infiltrate from 15 to 30 and 60 days (p<0.05).

Conclusions

The addition of bismuth oxide into Portland cement did not affect the pH level and the biological response. The concentration of 15% of bismuth oxide resulted in significant reduction in inflammatory response in comparison with the other concentrations evaluated.     

Erosive cola-based drinks affect the bonding to enamel surface: an in vitro study

Objective

This study aimed to assess the impact of in vitro erosion provoked by different cola-based drinks (Coke types), associated or not with toothbrushing, to bonding to enamel.

Material and Methods

Fifty-six bovine enamel specimens were prepared and randomly assigned into seven groups (N=8): C- Control (neither eroded nor abraded), ERO-RC: 3x/1-minute immersion in Regular Coke (RC), ERO-LC: 3x/1-minute immersion in Light Coke (LC), ERO-ZC: 3x/1-minute immersion in Zero Coke (ZC) and three other eroded groups, subsequently abraded for 1-minute toothbrushing (EROAB-RC, EROAB-LC and EROAB-ZC, respectively). After challenges, they were stored overnight in artificial saliva for a total of 24 hours and restored with Adper Single Bond 2/Filtek Z350. Buildup coronal surfaces were cut in 1 mm² -specimens and subjected to a microtensile test. Data were statistically analyzed by two-way ANOVA/Bonferroni tests (α=0.05). Failure modes were assessed by optical microscopy (X40). The interface of the restorations were observed using Confocal Laser Scanning Microscopy (CLSM).

Results

All tested cola-based drinks significantly reduced the bond strength, which was also observed in the analyses of interfaces. Toothbrushing did not have any impact on the bond strength. CLSM showed that except for Zero Coke, all eroded specimens resulted in irregular hybrid layer formation.

Conclusions

All cola-based drinks reduced the bond strength. Different patterns of hybrid layers were obtained revealing their impact, except for ZC.     

Revision knee arthroplasty using a distal femoral replacement prosthesis for periprosthetic fractures in elderly patients

Purpose

Distal femoral periprosthetic fractures above a total knee replacement in elderly patients are technically challenging to treat. Bone quality is often poor, the fractures comminuted, and post-operative mobilisation is difficult. This study assesses the clinical, radiological and functional outcome of revision knee distal femoral replacement (DFR) in these fractures.

Methods

We identified 14 patients over 70 years of age (70–94) who underwent DFR for periprosthetic fractures above a knee replacement. All the 14 fractures were classified as Su type III. Clinical and radiological records were retrospectively reviewed. The mean of clinical follow-up was 27 months (8–46). Functional outcome was assessed using Oxford Knee Score and EQ-5D (UK English Version) score at a mean time of 35 months (20–65). The Knee Society patient category score was also evaluated.

Results

The median post-operative knee flexion was 100° (range 90°–135°). Nine patients (64%) returned to their pre-fracture level of mobility or better. The median post-operative Oxford Knee Score was 27 (range 4–40). The median EQ-5D was 11 (range 6–12). Cognitive impairment negatively impacted the functional outcome in four patients. One patient died early post-operatively, and two patients had complications.

Conclusions

DFR led to satisfactory outcome in our patients with a relatively low complication rate. In our experience, revision knee distal femoral replacement is an appropriate method to treat elderly patients who sustained periprosthetic Su et al. type III distal femoral fractures in association with poor bone stock, caused by osteoporosis and/or comminution.

     

Association between CD226 polymorphism and soluble levels in rheumatoid arthritis: Relationship with clinical activity

Objective: To study the relation between CD226 rs763361 gene polymorphism and CD226 serum level and to evaluate their role in susceptibility and disease activity of RA in a cohort of Egyptian individuals.

Methods: The serum level of CD226 was measured using a suitable ELISA kit and the CD226 rs763361 gene polymorphism was typed by PCR-RFLP for 112 RA patients and 100 healthy controls.

Results: Significant association with RA was found with CD226 T allele (OR (95%CI) = 1.6 (1.04–2.4), P = 0.032), and higher CD226 serum level (P = 0.001). Higher CD226 levels were associated with higher ESR values (P = 0.035), positive CRP (0.048), increased number of tender joints (P = 0.045), and higher DAS score (P = 0.035). Serum CD226 is an independent risk factor for the prediction of RA (P = 0.001). No correlations were found between the serum level of CD226 and different CD226 genotypes and also between them and RA activity grades.

Conclusion: The CD226 T allele may be susceptibility risk factors for the development of RA and the higher serum level of CD226 may be involved in the pathogenesis of RA in Egyptian patients. The serum level of CD226 and not CD226 genotypes could be considered as an independent risk factor for the prediction of RA within healthy individuals and also for RA disease activity.