Lumbar Pedicle Morphology and Vertebral Dimensions in Isthmic and Degenerative Spondylolisthesis-A Comparative Study.

BACKGROUND: The pedicle screw is the most common device used to achieve fixation in fusion of spondylolistheses. Safe and accurate placement with this technique relies on a thorough understanding of the bony anatomy. There is a paucity of literature comparing the surgically relevant osseous anatomy in patients with a degenerative spondylolisthesis (DS) and an isthmic spondylolisthesis (IS). The goal of this study was to determine the differences in the osseous anatomy in patients with a DS and those with an IS. METHODS: A retrospective comparative cohort study was conducted on patients with a single-level, symptomatic L4-L5 DS or a single-level, symptomatic L5-S1 IS. Magnetic resonance imaging for these patients was reviewed. Morphometries of the pedicle and vertebral body were analyzed by 2 independent observers for the levels from L3 to S1, and radiographic parameters were compared between groups. RESULTS: A total of 572 levels in 143 patients were studied, including 103 patients with a DS and 40 with an IS. After accounting for confounders, IS and DS had an independent effect on transverse vertebral body width, pedicle height and width, and sagittal pedicle angle. Patients with an IS had a smaller pedicle height (P < .001) and pedicle width (P = .001) than patients with DS. In addition, the angulation of the pedicles varied on the basis of the diagnosis. CONCLUSIONS: The osseous anatomy is significantly different in patients with a DS than with an IS. Patients with an IS have smaller pedicles in the lumbar spine. Also, the L4 and L5 pedicles are more caudally angulated and the S1 pedicle is less medialized. LEVEL OF EVIDENCE: 3. CLINICAL RELEVANCE: Understanding the differences in pedicle anatomy is important for the safe placement of pedicle screws.

Platelet-Rich Plasma Injection With Percutaneous Needling for Recalcitrant Lateral Epicondylitis: Comparison of Tenotomy and Fenestration Techniques.

BACKGROUND: Recalcitrant lateral epicondylitis (LE) is a common debilitating condition, with numerous treatment options of varying success. An injection of platelet-rich plasma (PRP) has been shown to improve LE, although it is unclear whether the method of needling used in conjunction with a PRP injection is of clinical importance. PURPOSE: To determine whether percutaneous needle tenotomy is superior to percutaneous needle fenestration when each is combined with a PRP injection for the treatment of recalcitrant LE. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: A total of 93 patients with recalcitrant LE were treated with a PRP injection and percutaneous needle fenestration (n = 45) or percutaneous needle tenotomy (n = 48) over a 5-year study interval. Preoperative patient data, including visual analog scale for pain (VAS-P), Quick Disabilities of the Arm, Shoulder and Hand (QuickDASH), and Patient-Rated Tennis Elbow Evaluation (PRTEE) scores and grip strength, were obtained from a chart review and compared with postoperative values obtained prospectively. Secondary outcomes included the incidence of complications, need for additional interventions, return to work, and patient satisfaction. RESULTS: At a mean follow-up of 40 months, significant improvements in VAS-P (mean, -6.1; 95% CI, -6.8 to -5.5; P < .0001), QuickDASH (mean, -46; 95% CI, -52 to -40; P < .0001), and PRTEE (mean, -57; 95% CI, -64 to -50; P < .0001) scores and grip strength (mean, +6.1 kg; 95% CI, 4.9 to 7.3; P < .0001) were observed across the entire study cohort, with no significant differences noted between the fenestration and tenotomy groups. Nine of 45 patients (22%) underwent additional procedures to treat recurrent symptoms in the fenestration group compared with 5 of 48 patients (10%) in the tenotomy group (P = .05). No complications occurred in any patients, and no patients expressed dissatisfaction with their treatment course. CONCLUSION: A PRP injection with concomitant percutaneous needling is an effective treatment for recalcitrant LE, with sustained improvements in pain, strength, and function demonstrated at a mean follow-up of longer than 3 years. Although the method of concomitant needling does not appear to have a significant effect on treatment outcomes, more aggressive needle tenotomy is less likely to require conversion to open tenotomy than needle fenestration in the short term to midterm.

Identification of critical process parameters and its interplay with nanosuspension formulation prepared by top down media milling technology--a QbD perspective.

The purpose of this study was to optimize the process parameters of a poorly soluble drug by top down media milling process using different polymer systems. Process parameters including agitation rate (RPM), size of grinding media and drug content were studied through a Quality by Design (QbD) approach, using three different polymeric stabilizers (HPMC 3 cps, PVP K-30 and HPC-EXF) with the addition of Vitamin E TPGS as a surface active agent. From the statistical analysis, the RPM of the media milling was determined to be the most significant process parameter with respect to influence on particle size. The effects of varying the size of grinding media or drug content were not found to be as significant as the effects of RPM. Finally, the polymeric stabilizer played an important role in the production of nanoparticles. Among the different polymers, HPMC stabilized systems demonstrated superior results with regards to the consistency in producing successful nanoparticles and inhibition of crystal growth during storage. This study established the interplay among the formulation parameters in order to select the design space, which helped us in the identification and rank ordering of critical and noncritical variables related to the quality attributes of nanosuspension formulation during the early phase of product development.

Identification of a drug degradation product found in a stressed dosage form using LC/MSn, LC/TOF MS and on-line H/D exchange MS.

An unknown degradation product was found when a dosage form was stressed under base and heat. Comprehensive LC-MS studies have been conducted to identify this degradation product. The approach included the use of an ion-trap MS for MS(n) ion fragmentation patterns, a time-of-flight (TOF) MS to measure the accurate mass for its potential chemical formula, and on-line hydrogen/deuterium (H/D) exchange LC-MS to determine the number of exchangeable hydrogen atoms in the gradation product. Based upon the above LC-MS results, the unknown was identified to result from the conversion of a trifluoromethyl moiety in the drug substance to a carboxylic acid under the combination of thermal and base stress. Different ion fragmentation pathways between the drug substance and its degradation product were discussed. The reaction mechanism was proposed to be nucleophilic substitution through S(N)2 mechanism.

Evaluation of hydroxypropyl methylcellulose matrix systems as swellable gastro-retentive drug delivery systems (GRDDS).

Utilizing gastro-retentive drug delivery systems (GRDDS) to increase absorption of weakly basic drugs by extending their transit time is a promising approach. Swellable systems were evaluated for this purpose. Such systems demonstrate dual mechanism of release-diffusion and erosion. GRDDS requires maintaining its dimensions, which demands diffusion as a predominant mechanism of release (Fickian). In this work, dypyridamole, a weakly basic drug, together with various grades of hydroxypropyl methylcellulose and different excipients were evaluated for release and swelling properties. Dissolution data were analyzed by curve fitting to various models to estimate predominant release mechanism. It was found that matrices containing a swellable diluent like microcrystalline cellulose demonstrated predominantly Fickian mechanism of release, whereas soluble diluents (lactose and mannitol) contributed to a mixed mechanism of release. Addition of copovidone increased the swelling and survivability, whereas sodium chloride altered the erosion behavior. A correlation between matrix weight loss and drug release was obtained, which further consolidated the analysis. Correlation for the soluble excipients was linear, whereas that for the swellable excipient was nonlinear, implying predominance of Fickian release mechanism for the latter. Hence, the selection of excipients can influence matrix survivability and release kinetics, which can be used for developing GRDDS.

Identification of pharmaceutical impurities in formulated dosage forms.

Structure elucidation of pharmaceutical impurities is an important part of the drug product development process. Impurities can have unwanted pharmacological or toxicological effects that seriously impact product quality and patient safety. This review focuses on current analytical strategies for chemical and structural identification of pharmaceutical impurities. Potential sources and mechanisms of impurity formation are discussed for both drug substance and drug product applications. The utility of liquid chromatography-mass spectrometry (LC/MS) for providing structure-rich information is highlighted throughout this review. Other hyphenated analytical techniques including LC/nuclear magnetic resonance, gas chromatography/MS, and size-exclusion chromatography/chemiluminescent nitrogen detectors are also discussed, as LC/MS alone sometimes cannot reveal or confirm the final structures as required during dosage form development.

Combined application of high resolution and tandem mass spectrometers to characterize methionine oxidation in a parathyroid hormone formulation.

Identification and monitoring of degradation products is a critical aspect of drug product stability programs. This process can present unique challenges when working with complex biopharmaceutical formulations that do not readily lend themselves to straightforward HPLC analysis. The therapeutic 34 amino acid parathyroid hormone fragment (PTH1-34) contains methionine (Met) residues at positions 8 and 18. Oxidation of these Met residues results in reduced biological activity and thus efficacy of the potential drug product. Here, we present an effective approach for the identification of PTH1-34 oxidation products in a drug product formulation in which the stability indicating method used non-MS compatible HPLC conditions to separate excipients, drug substance and degradation products. High resolution and tandem mass spectrometers were used in conjunction with cyanogen bromide (CNBr) mediated digestion to accurately identify the oxidation products observed in an alternative MS compatible HPLC method used for drug substance analysis. All anticipated CNBr digested peptide fragments, including both oxidized and nonoxidized peptide fragments, were positively identified using TOF MS without the need for additional enzymatic digestion. Once identified, the oxidation products generated were injected onto the original non-MS compatible HPLC drug product stability indicating method and the respective retention times were confirmed. This allowed the oxidative stability of different formulations to be effectively monitored during the solid state stability program and during variant selection.

Application of surface area measurement for identifying the source of batch-to-batch variation in processability.

The primary goal of this study was to evaluate the use of specific surface area as a measurable physical property of materials for understanding the batch-to-batch variation in the flow behavior. The specific surface area measurements provide information about the nature of the surface making up the solid, which may include defects or void space on the surface. These void spaces are often present in the crystalline material due to varying degrees of disorderness and can be considered as amorphous regions. In the present work, the specific surface area for 10 batches of the same active pharmaceutical ingredient (compound 1) with varying quantity of amorphous content was investigated. Some of these batches showed different flow behavior when processed using roller compaction. The surface area value was found to increase in the presence of low amorphous content, and decrease with high amorphous content as compared to crystalline material. To complement the information obtained from the above study, physical blends of another crystalline active pharmaceutical ingredient (compound 2) and its amorphous form were prepared in known proportions. Similar trend in specific surface area value was found. Tablets prepared from known formulation with varying amorphous content of the active ingredient (compound 3) also exhibited the same trend. A hypothesis to explain the correlation between the amorphous content and specific surface area has been proposed. The results strongly support the use of specific surface area as a measurable tool for investigation of source of batch to batch variation in processability.