A retrospective regulatory analysis of FDA recalls carried out by pharmaceutical companies from 2012 to 2023.

To introduce products in the US market, pharmaceutical companies must first obtain FDA clearance. Manufacturers might recall a product if it poses a risk of damage or violates FDA regulations. This study investigates the types, causes and consequences of recalls, as well as FDA participation and suitable recall strategies. We relied on the FDA website to gather recall data sets from 2012 to 2023, collecting information on the date of issuance, company and type of violation. The most frequent causes for recalls were sterility issues and inadequate compliance with current good manufacturing practices (cGMP). An examination of sterility recalls revealed two primary causes: a lack of assurance in sterility (accounting for 48% of recalls) and instances of non-sterility (making up 45% of recalls). A thorough examination of cGMP recalls revealed five primary types of violations: process control issues, inadequate storage practices, manufacturing problems, the presence of nitroso-amine impurities and concerns regarding stability. The findings demonstrate that sterility and cGMP compliance are FDA priorities. Pharmaceutical companies must, therefore, enhance quality compliance and create effective quality management systems that oversee the manufacturing process, quality control, personnel training and documentation to avoid these recalls. Companies should establish an internal compliance checklist and be prepared for the rectification process.

Clozapine-laden carbon dots delivered to the brain via an intranasal pathway: Synthesis, characterization, ex vivo, and in vivo studies.

Clozapine, which is widely used to treat schizophrenia, shows low bioavailability due to poor solubility and high first-pass metabolism. The study aimed to design clozapine-loaded carbon dots (CDs) to enhance availability of the clozapine to the brain via intranasal pathway. The CDs were synthesized by pyrolysis of citric acid and urea at 200 °C by hydrothermal technique and characterized by photoluminescence, transmission electron microscopy (TEM), X-ray Photoelectron Spectrometer (XPS), and Fourier transform infrared spectrum (FTIR). The optimized clozapine-loaded CDs (CLZ-CDs-1:3-200) showed a quasi-spherical shape (9-12 nm) with stable blue fluorescence. The CDs showed high drug solubilization capacity (1.5 mg drug in 1 mg/ml CDs) with strong electrostatic interaction with clozapine (drug loading efficiency = 94.74%). The ex vivo release study performed using nasal goat mucosa showed sustained release of clozapine (43.89%) from CLZ-CDs-1:3-200 for 30 h. The ciliotoxicity study (histopathology) confirmed no toxicity to the nasal mucosal tissues using CDs. In the rat model (in vivo pharmacokinetic study), when CDs were administrated by the intranasal route, a significantly higher concentration of clozapine in the brain tissue (Cmax = 58.07 ± 5.36 µg/g and AUCt (µg/h*g) = 105.76 ± 12.31) was noted within a short time (tmax = 1 h) compared to clozapine suspension administered by intravenous route (Cmax = 20.99 ± 3.91 µg/g, AUC t (µg/h*g) = 56.89 ± 12.31, and tmax = 4 h). The high value of drug targeting efficiency (DTE, 486%) index and direct transport percentage (DTP, 58%) indicates the direct entry of clozapine-CDs in the brain via the olfactory route. In conclusion, designed CDs demonstrated a promising dosage form for targeted nose-to-brain delivery of clozapine for the effective treatment of schizophrenia.

Precise Fabrication of Ocular Inserts Using an Innovative Laser-Driven CaliCut Technology: In Vitro and in Vivo Evaluation.

Ocular inserts offer distinct advantages, including a preservative-free drug delivery system, the ability to provide tailored drug release, and ease of administration. The present research paper delves into the development of an innovative ocular insert using CaliCut technology. Complementing the hot melt extrusion (HME) process, CaliCut, an advanced technology in ocular insert development, employs precision laser gauging to achieve impeccable cutting of inserts with desired dimensions. Its intelligent control over the stretching process through auto feedback-based belt speed adjustment ensures unparalleled accuracy and consistency in dosage form manufacturing. Dry eye disease (DED) poses a significant challenge to ocular health, necessitating innovative approaches to alleviate its symptoms. In this pursuit, castor oil has emerged as a promising therapeutic agent, offering beneficial effects by increasing the thickness of the lipid layer in the tear film, thus improving tear film stability, and reducing tear evaporation. To harness these advantages, this study focuses on the development and comprehensive characterization of castor oil-based ocular inserts. Additionally, in-vivo irritancy evaluation in rabbits has been undertaken to assess the inserts' safety and biocompatibility. By harnessing the HME and CaliCut techniques in the formulation process, the study demonstrates their instrumental role in facilitating the successful development of ocular inserts.

Recent Advances in Teriparatide Delivery by-virtue-of Novel Drug Delivery Approaches for the Management of Osteoporosis.

Osteoporosis is a bone incapacitating malady which globally accounts for over hundred million fractures annually. Therapeutic interventions for management of osteoporosis are divided as antiresorptive agents and osteoanabolic agents. Teriparatide is the only osteoana-bolic peptide which is available world-wide for the treatment of osteoporosis. It is administered as a daily subcutaneous injection for the treatment of osteoporosis which results in both poor patient compliance and increase in the cost of the therapy. Even after 20 years of clinical use of teriparatide, no formulation of teriparatide has yet been translated from lab to clinic which can be delivered by non-invasive route The present review critically discusses attempts made by the researchers for efficient delivery of teriparatide through various non-invasive routes such as oral, nasal, pulmonary, and transdermal route. It also discusses long-acting injectable formulations of teriparatide to improve patient compliance. Understanding on the pharmacology of teriparatide highlights the enhanced effectiveness of intermittent/pulsatile mode of teriparatide delivery which has also been elaborated. In addition, targeted delivery of teriparatide using different bone specific targeting moieties has been also discussed.

Peptide Engraftment on PEGylated Nanoliposomes for Bone Specific Delivery of PTH (1-34) in Osteoporosis.

Bone-specific functionalization strategies on liposomes are promising approaches to delivering the drug in osteoporotic conditions. This approach delivers the drug to the bone surface specifically, reduces the dose and off-target effects of the drug, and thereby reduces the toxicity of the drug. The purpose of the current research work was to fabricate the bone-specific peptide conjugated pegylated nanoliposomes to deliver anabolic drug and its physicochemical evaluations. For this, a bone-specific peptide (SDSSD) was synthesized, and the synthesized peptide was conjugated with a linker (DSPE-PEG2000-COOH) to obtain a bone-specific conjugate (SDSSD-DSPE). Purified SDSSD-DSPE was characterized by HPLC, Maldi-TOF, NMR, and Scanning Electron Microscope/Energy Dispersive Spectroscopy (SEM/EDS). Further, peptide-conjugated and anabolic drug-encapsulated liposomes (SDSSD-LPs) were developed using the ethanol injection method and optimized by Central Composite Design (CCD) using a statistical approach. Optimized SDSSD-LPs were evaluated for their physicochemical properties, including surface morphology, particle size, zeta potential, in vitro drug release, and bone mineral binding potential. The obtained results from these studies demonstrated that SDSSD-DSPE conjugate and SDSSD-LPs were optimized successfully. The particle size, % EE, and zeta potential of SDSSD-LPs were observed to be 183.07 ± 0.85 nm, 66.72 ± 4.22%, and -25.03 ± 0.21 mV, respectively. SDSSD-LPs demonstrated a sustained drug release profile. Further, the in vitro bone mineral binding assay demonstrated that SDSSD-LPs deliver the drug to the bone surface specifically. These results suggested that SDSSD-LPs could be a potential targeting approach to deliver the anabolic drug in osteoporotic conditions.

Effect of pharmacogenomic testing on pediatric mental health outcome: a 6-month follow-up.

Aim: This retrospective, case-control study evaluated the effect of pharmacogenomic testing (PGT) on the management of pediatrics with anxiety, major depressive disorder (MDD) and attention-deficit/hyperactivity disorder (ADHD). Methods: The authors examined psychiatric diagnoses, medication histories, CYP450 profiles, SLC6A4, HTR2A, COMT and MTHFR. Results: The authors found no difference in clinical improvement between the two groups. However, the number of medication changes was significantly larger after PGT. The treatment response in MDD and anxiety was not different between the groups, while ADHD treatment response was substantially improved in PGT and correlated with COMT status. Conclusion: PGT had some value with ADHD with doubtful benefit for MDD or anxiety disorders. Accordingly, pediatric indications must be weighed against cost, utility and clinician experience. Limitations included sample size and selection bias.

A comprehensive review of SARS-CoV-2 vaccines: Pfizer, Moderna & Johnson & Johnson.

The novel coronavirus outbreak was declared a pandemic in March 2020. We are reviewing the COVID-19 vaccines authorized for use in the United States by discussing the mechanisms of action, administration, side effects, and efficacy of vaccines developed by Pfizer, Moderna, and Johnson & Johnson. Pfizer and Moderna developed mRNA vaccines, encoding the spike protein of SARS-CoV-2, whereas Johnson & Johnson developed an adenovirus vector-based vaccine. Safety has been shown in a large cohort of participants in clinical trials as well as the general population since emergency approval of vaccine administration in the US. Clinical trial results showed the Pfizer and Moderna vaccines to be 95.0%, and the Johnson & Johnson vaccine to be 66.0% effective in protecting against moderate and symptomatic SARS-CoV-2 infection. It is important to keep medical literature updated with the ongoing trials of these vaccinations, especially as they are tested among different age groups and upon the emergence of novel variants of the SARS-CoV-2 coronavirus.

Micromotion and Migration of Cementless Tibial Trays Under Functional Loading Conditions.

BACKGROUND: The outcome of cementless total knee arthroplasty (TKA) relies on successful bony ingrowth into the implant surfaces. Failures due to aseptic loosening are still reported, especially in younger and more active patients. The objective of this study is to quantify the micromotion of a commercially available design of cementless tibial tray under loading conditions simulating walking and stair descent. METHOD: A commercially available design of cementless total knee arthroplasty was implanted in 7 cadaveric knees which were preconditioned with 500 cycles of 0°-100° flexion under a vertical load of 1050 N in a custom-built, multiaxial functional activity simulator. This was followed by application of the peak forces and moments occurring during walking and stair descent. During each loading procedure, 3-dimensional motion at the bone-prosthesis interface was measured using digital image correlation. RESULTS: The tray migrated 101 ± 25 µm on average during preconditioning, which was dominated by rotation in the sagittal plane (92% of total migration), combined with posterior translation (28%) and minimal rotation in the transverse plane (14%). The migration varied 2.7-fold (61-167 µm) between the 6 measurement zones. Stair descent produced significantly higher total micromotion than walking in zone #5 (62 ± 9 vs 51 ± 10 µm, P < .05) and zone #6 (68 ± 17 vs 37 ± 10 µm, P < .05). In addition, during stair descent, the tray exhibited significantly more tilting (anterior zones: 31 ± 17 vs -16 ± 20 µm, P < .05; posterior zones: -60 ± 8 vs -40 ± 7 µm, P < .05) and more anteroposterior displacement in the anterior zones (-25 ± 3 vs -13 ± 2 µm, P < .05) when compared to walking. CONCLUSION: The relative motion at the bone-prosthesis interface varied substantially around the periphery of the cementless tray. Under the loading conditions evaluated, the tray primarily underwent a rocking motion in the sagittal plane. Compared with walking, stair descent produced significantly more micromotion, especially in the posterior zones.

Growth curves: The experiences of Canadian paediatricians in their first 5 years of independent practice.

OBJECTIVES: Completing training is a rite of passage common to all physicians, yet our knowledge of the components in postgraduate paediatric education that equip learners for successful transition to practice is limited. In order to optimally design training programs, it is critical to develop a better sense of what early career paediatricians (ECPs) experience as they navigate this time of transition. METHODS: We created and distributed a 23-question survey via e-mail to 481 Canadian ECPs in September 2017, specifically to those who received Royal College certification in 2011 or later. Survey responses were obtained confidentially through an online platform (Survey Monkey). Descriptive statistics and thematic analysis were used to analyze responses to closed-ended and free text questions, respectively. RESULTS: Response rate was 42% with nearly 70% of the respondents self-identifying as general paediatricians. Factors facilitating transition to practice included: dedicated mentorship; supportive new colleagues and workplace environment; and ease of finding work. Identified challenges included: billing, finances, and practice management; adjusting to a different scope of practice and learning local resources; managing comfort level; and achieving work-life balance. Nearly half of the respondents expressed interest in mentoring new ECP colleagues. CONCLUSIONS: Our findings suggest that ECPs find clear value in mentorship, but desire further support to adapt to new practice contexts and activities. As a result, we must consider strategies in both individual programs and nationally that effectively prepare learners prior to transition and align with needs in the first years of independent practice.

Effects of Diaphorina citri Population Density on Daily Timing of Vibrational Communication Calls: Potential Benefits in Finding Forage.

Adult Diaphorina citri (ACP) use visual and chemical cues to locate young citrus flush shoots on which they forage and oviposit, and they use vibrational communication duetting calls as cues to help locate mates. For individual pairs, calling and mating usually peaks between 10:00 and 15:00. To explore whether call rates (calls/h) are affected by interactions with nearby conspecifics, rates were compared in small citrus trees on which either 5 or 25 ACP female and male pairs had been released at 17:00 for later recording from sunrise (06:00) to 22:00. Final ACP locations were noted 40 h after release. Call rates were similar in both treatments during normal mating hours. However, rates were significantly higher for low- than high-density treatments between 06:00 and 10:00, which suggests calling during this period may be affected by conspecific density. Both sexes aggregated on flush at both densities. We discuss the potential that ACP producing calls near sunrise, outside of normal mating hours, might benefit from gains in reproductive fitness in low-density contexts if they call not only to locate mates but also to locate preferred flush-in which case, co-opting of vibrations to disrupt both mating and foraging may be feasible.

The continuum of hip range of motion: From soft-tissue restriction to bony impingement.

Traditional studies of hip kinematics have not identified which anatomic structures limit the range of motion (ROM) when the hip is placed in different maneuvers. In this study, we attempted to answer two questions: (a) During which maneuvers is the motion of the hip limited by bony impingement between the femur and pelvis? (b) When is hip ROM determined by the constraint of soft tissues and to what extent? ROM of eight cadaveric hips was measured in 17 maneuvers using a motion capture system. The maneuvers were recreated in silico using 3D CT models of each specimen to detect the occurrence of bony impingement. If bony impingement was not detected, the variable component of 3D hip motion was increased until a collision was detected. The difference between the virtual ROM at the point of bony impingement and the initial ROM measured experimentally was termed as the soft-tissue restriction. The results showed that bony impingement was present in normal hips during maneuvers consisting of high abduction with flexion, and high flexion combined with adduction and internal rotation. At impingement-free maneuvers, the degree of soft tissue restriction varies remarkably, ranging from 4.9° ± 3.8° (internal rotation) at 90° of flexion to 80.0° ± 12.5° (internal rotation) at maximum extension. The findings shed light on the relative contributions of osseous and soft tissues to the motion of the hip in different maneuvers and allow for a better understanding of physical exams of different purposes in diagnosing bone- or soft tissue-related diseases.

Pelvic Tilt and Range of Motion in Hips With Femoroacetabular Impingement Syndrome.

INTRODUCTION: Physiotherapy is a management option for the treatment of femoroacetabular impingement (FAI) syndrome. This study examines the influence of changes in pelvic tilt and hip adduction on the range of motion (ROM) of the hip. METHODS: Ten FAI hips were used to simulate impingement at two positions: (1) 20° internal rotation (IR) with 100° flexion and 10° adduction and (2) 40° IR with 35° flexion and 10° adduction; the amount of IR was measured at the point of bony impingement or to the defined limit. Each simulation was performed at neutral and 5° and 10° anterior and posterior pelvic tilt. Then, the hip was placed in 10° of abduction, and all simulations were repeated. RESULTS: With neutral pelvic tilt, impingement occurred at 4.3 ± 8.4° of IR at the high-flexion position. An increase in anterior pelvic tilt led to a loss of IR, that is, earlier occurrence of FAI, whereas an increase in posterior pelvic tilt led to an increase in IR, that is, later occurrence of FAI. At the high-flexion position, abduction provided more IR before impingement (neutral: 9.1 ± 5.7°, P < 0.01; 10° anterior tilt: 14.6 ± 5.2°, P < 0.01; 10° posterior tilt: 4.2 ± 3.7° IR, P = 0.01). Placing the hip in abduction and posteriorly tilting the pelvis produce a combined effect that increased IR relative to the neutrally tilted pelvis (5° posterior tilt: 11.4 ± 7.6°, P = 0.01; 10° posterior tilt: 12.8 ± 7.6°, P < 0.01). The ROM in the mid-flexion position was not affected by any combination of pelvic tilt and hip abduction or adduction (average IR: 37.4 ± 5.0°, P > 0.05). CONCLUSIONS: Abduction and posterior pelvic tilt increased the impingement-free ROM in the hips with FAI. Thus, rehabilitation aimed at altering the tilt of the pelvis may reduce the frequency of impingement and limit further joint damage.

Pathophysiology of narrow complex dilated cardiomyopathy insight derived from the velocity equation: velocity = distance/time.

The pathophysiology of narrow complex dilated cardiomyopathy is not defined, so therapeutic options are limited. By utilising the velocity equation, the pathophysiology of narrow complex cardiomyopathy allows above normal conduction propagation velocities. There are two pathophysiological theories that allow above normal conduction velocities and failure to capture the myocardium: (1)insulating fibres of the conduction system extending beyond the apex and (2) reduction of axon branching. A patient with narrow complex cardiomyopathy was subjected to graded increase in amplitude and pulse width pacing to overcome the failure of native conduction to capture the myocardium. Peak systolic strain maps demonstrated a progressive increase in apical contractility with increasing pulse width and amplitude. Ejection fraction improved from 17% to 31%. Understanding the pathophysiology of narrow complex cardiomyopathy leads to proposed therapies. One potential pacing therapy is multi-lead pacing at high amplitude and pulse width to capture myocardial cells not captured by native conduction.

Current concepts in intraosseous Platelet-Rich Plasma injections for knee osteoarthritis.

Knee osteoarthritis (OA) is a degenerative process that slowly destroys the joints producing pain and loss of function, and diminishes the quality of life. Current treatments alleviate this symptomatology but do not stop the disease, being total knee arthroplasty the only definitive solution. Among the emerging treatments, Platelet-Rich Plasma (PRP) has shown promising results in the treatment of OA. However, to improve its effectiveness, it is necessary to approach this pathology targeting the whole joint, not only the cartilage, but including other tissues such as subchondral bone. The pathological processes that occur in the subchondral bone have influence of the cartilage loss, aggravating the disease. The combination of intraarticular infiltrations with intraosseous infiltrations regulates the biological processes of the tissues, reducing the inflammatory environment and modulating the overexpression of biomolecules that generate an aberrant cellular behavior. Although the first clinical results using this technique are promising, further research and developing adequate protocols are necessary to achieve good clinical results.

MDCKpred: a web-tool to calculate MDCK permeability coefficient of small molecule using membrane-interaction chemical features.

Structure-based models to understand the transport of small molecules through biological membrane can be developed by enumerating intermolecular interactions of the small molecule with a biological membrane, usually a dimyristoylphosphatidylcholine (DMPC) monolayer. This ADME (absorption, distribution, metabolism, and excretion) property based on Madin-Darby Canine Kidney (MDCK) cell line demonstrates intestinal drug absorption of small molecules and correlated to human intestinal absorption which acts as a determining factor to forecast small-molecule prioritization in drug-discovery projects. We present here the development of MDCKpred web-tool which calculates MDCK permeability coefficient of small molecule based on the regression model, developed using membrane-interaction chemical features. The web-tool allows users to calculate the MDCK permeability coefficient (nm/s) instantly by providing simple descriptor inputs. The chemical-interaction features are derived from different parts of the DMPC molecule viz. head, middle, and tail regions and accounts overall intermolecular contacts of the small molecule when passively diffused through the phospholipid-rich biological membrane. The MDCKpred model is both internally (R2 = .76; [Formula: see text]= .68; Rtrain = .87; Rtest = .69) and externally (Rext = .55) validated. Furthermore, we used natural molecules as application examples to demonstrate its utility in lead exploration and optimization projects. The MDCKpred web-tool can be accessed freely at http://www.mdckpred.in . This web-tool is designed to offer an intuitive way of prioritizing small molecules based on calculated MDCK permeabilities.

Tibial Stems in Revision Total Knee Arthroplasty: Is There an Anatomic Conflict?

Tibial stems are frequently used in revision total knee arthroplasty (TKA). We investigated the effect of tibial stems on final component alignment and tray position. Thirty 3D reconstructed cadaveric tibial models were classified according to canal bow angle. After virtual implantation of 120 mm and 200 mm stemmed tibial components, deviation from native mechanical axis was measured. Tibial alignment valgus malposition of up to three degrees occurred and most pronounced with 120 mm stems. Canal alignment using 200 mm stems deviated tray position medially and posteriorly. Mild to moderate valgus bowing of the tibial canal is not uncommon (57% in our series) possibly leading to valgus malalignment. Anatomic conflict between the tibial mechanical axis and intramedullary canal can exist, with alignment and tray placement implications.

Pediatric faculty and residents' perspectives on In-Training Evaluation Reports (ITERs).

BACKGROUND: In-training evaluation reports (ITERs) are used by over 90% of postgraduate medical training programs in Canada for resident assessment. Our study examined the perspectives of faculty and residents in one pediatric program as a means to improve the ITER as an evaluation tool. METHOD: Two separate focus groups were conducted, one with eight pediatric residents and one with nine clinical faculty within the pediatrics program of Memorial University's Faculty of Medicine to discuss their perceptions of, and suggestions for improving, the use of ITERs. RESULTS: Residents and faculty shared many similar suggestions for improving the ITER as an evaluation tool. Both the faculty and residents emphasized the importance of written feedback, contextualizing the evaluation and timely follow-up. The biggest challenge appears to be the discrepancy in the quality of feedback sought by the residents and the faculty members' ability to do so in a time effective manner. Others concerns related to the need for better engagement in setting rotation objectives and more direct observation by the faculty member completing the ITER. CONCLUSIONS: The ITER is a useful tool in resident evaluations, but a number of issues relating to its actual use could improve the quality of feedback which residents receive.